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  • 1.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nilsson, Lars-Göran
    Aging Research Center, Karolinska Institutet.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Free Recall Episodic Memory Performance Predicts Dementia 10 Years Prior to Clinical Diagnosis: Findings from the Betula Longitudinal Study2015In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 5, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

  • 2. Cammaerts, Sophia
    et al.
    Strazisar, Mojca
    Smets, Bart
    Weckhuysen, Sarah
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Jonghe, Peter
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Rijk, Peter
    Del Favero, Jurgen
    Schizophrenia-Associated MIR204 Regulates Noncoding RNAs and Affects Neurotransmitter and Ion Channel Gene Sets2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0144428Article in journal (Refereed)
    Abstract [en]

    As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.

  • 3. Ceulemans, Shana
    et al.
    De Zutter, Sonia
    Heyrman, Lien
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Goran
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Claes, Stephan
    Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population2011In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 13, no 7-8, p. 614-623Article in journal (Refereed)
    Abstract [en]

    Objectives: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.

    Methods: Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population.

    Results: Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3 > untranslated region (UTR) of NR3C1.

    Conclusions: This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.

  • 4. Crowley, James
    et al.
    Mudgal, Poorva
    Nordin Adolfsson, Annelie
    Umeå University.
    Åberg, Karolina
    Alaerts, Maaike
    Genovese, Giulio
    McCarroll, Steven
    Del-Favero, Jurgen
    Adolfsson, Rolf
    Umeå University.
    Sullivan, Patrick
    The genomics of bipolar and schizophrenic disorders in a large pedigree from a northern Swedish isolate2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S902-S903Article in journal (Other academic)
  • 5. de Jong, Simone
    et al.
    Abdalla Diniz, Mateus Jose
    Saloma, Andiara
    Gadelha, Ary
    Santoro, Marcos L.
    Ota, Vanessa K.
    Noto, Cristiano
    Curtis, Charlesg
    Newhouse, Stephen J.
    Patel, Hamel
    Hall, Lynsey S.
    O'Reilly, Paul F.
    Belangero, Sintia, I
    Bressan, Rodrigo A.
    Breen, Gerome
    Wray, Naomi R.
    Ripke, Stephan
    Mattheisen, Manuel
    Trzaskowski, Maciej
    Byrne, Enda M.
    Abdellaoui, Abdel
    Adams, Mark J.
    Agerbo, Esben
    Air, Tracy M.
    Andlauer, Till F. M.
    Bacanu, Silviu-Alin
    Baekvad-Hansen, Marie
    Beekman, Aartjan T. F.
    Bigdeli, Tim B.
    Binder, Elisabeth B.
    Blackwood, Douglas H. R.
    Bryois, Julien
    Buttenschon, Henriette N.
    Bybjerg-Grauholm, Jonas
    Cai, Na
    Castelao, Enrique
    Christensen, Jane Hvarregaard
    Clarke, Toni-Kim
    Coleman, Jonathan R., I
    Colodro-Conde, Lucia
    Couvy-Duchesne, Baptiste
    Craddock, Nick
    Crawford, Gregory E.
    Davies, Gail
    Deary, Ian J.
    Degenhardt, Franziska
    Derks, Eske M.
    Direk, Nese
    Dolan, Conor, V
    Dunn, Erin C.
    Eley, Thalia C.
    Escott-Price, Valentina
    Kiadeh, Farnush Farhadi Hassan
    Finucane, Hilary K.
    Forstner, Andreas J.
    Frank, Josef
    Gaspar, Helena A.
    Gill, Michael
    Goes, Fernando S.
    Gordon, Scott D.
    Grove, Jakob
    Hansen, Christine Soholm
    Hansen, Thomas F.
    Herms, Stefan
    Hickie, Ian B.
    Hoffmann, Per
    Homuth, Georg
    Horn, Carsten
    Hottenga, Jouke-Jan
    Hougaard, David M.
    Ising, Marcus
    Jansen, Rick
    Jones, Ian
    Jones, Lisa A.
    Jorgenson, Eric
    Knowles, James A.
    Kohane, Isaac S.
    Kraft, Julia
    Kretzschmar, Warren W.
    Krogh, Jesper
    Kutalik, Zoltan
    Li, Yihan
    Lind, Penelope A.
    MacIntyre, Donald J.
    MacKinnon, Dean F.
    Maier, Robert M.
    Maier, Wolfgang
    Marchini, Jonathan
    Mbarek, Hamdi
    Mcgrath, Patrick
    Mcguffin, Peter
    Medland, Sarah E.
    Mehta, Divya
    Middeldorp, Christel M.
    Mihailov, Evelin
    Milaneschi, Yuri
    Milani, Lili
    Mondimore, Francis M.
    Montgomery, Grant W.
    Mostafavi, Sara
    Mullins, Niamh
    Nauck, Matthias
    Ng, Bernard
    Nivard, Michel G.
    Nyholt, Dale R.
    Oskarsson, Hogni
    Owen, Michael J.
    Painter, Jodie N.
    Pedersen, Carsten Bocker
    Pedersen, Marianne Giortz
    Peterson, Roseann E.
    Pettersson, Erik
    Peyrot, Wouter J.
    Pistis, Giorgio
    Posthuma, Danielle
    Quiroz, Jorge A.
    Qvist, Per
    Rice, John P.
    Riley, Brien P.
    Rivera, Margarita
    Mirza, Saira Saeed
    Schoevers, Robert
    Schulte, Eva C.
    Shen, Ling
    Shyn, Stanley, I
    Sigurdsson, Engilbert
    Sinnamon, Grant C. B.
    Smit, Johannes H.
    Smith, Daniel J.
    Stefansson, Hreinn
    Steinberg, Stacy
    Streit, Fabian
    Strohmaier, Jana
    Tansey, Katherine E.
    Teismann, Henning
    Teumer, Alexander
    Thompson, Wesley
    Thomson, Pippa A.
    Thorgeirsson, Thorgeir E.
    Traylor, Matthew
    Treutlein, Jens
    Trubetskoy, Vassily
    Uitterlinden, Andre G.
    Umbricht, Daniel
    Van der Auwera, Sandra
    van Hemert, Albert M.
    Viktorin, Alexander
    Visscher, Peter M.
    Wang, Yunpeng
    Webb, Bradley T.
    Weinsheimer, Shantel Marie
    Wellmann, Juergen
    Willemsen, Gonneke
    Witt, Stephanie H.
    Wu, Yang
    Xi, Hualin S.
    Yang, Jian
    Zhang, Futao
    Arolt, Volker
    Baune, Bernhard T.
    Berger, Klaus
    Boomsma, Dorret, I
    Cichon, Sven
    Dannlowski, Udo
    de Geus, E. J. C.
    DePaulo, J. Raymond
    Domenici, Enrico
    Domschke, Katharina
    Esko, Tonu
    Grabe, Hans J.
    Hamilton, Steven P.
    Hayward, Caroline
    Heath, Andrew C.
    Kendler, Kenneth S.
    Kloiber, Stefan
    Lewis, Glyn
    Li, Qingqin S.
    Lucae, Susanne
    Madden, Pamela A. F.
    Magnusson, Patrik K.
    Martin, Nicholas G.
    McIntosh, Andrew M.
    Metspalu, Andres
    Mors, Ole
    Mortensen, Preben Bo
    Mueller-Myhsok, Bertram
    Nordentoft, Merete
    Noethen, Markus M.
    O'Donovan, Michael C.
    Paciga, Sara A.
    Pedersen, Nancy L.
    Penninx, Brenda W. J. H.
    Perlis, Roy H.
    Porteous, David J.
    Potash, James B.
    Preisig, Martin
    Rietschel, Marcella
    Schaefer, Catherine
    Schulze, Thomas G.
    Smoller, Jordan W.
    Stefansson, Kari
    Tiemeier, Henning
    Uher, Rudolf
    Voelzke, Henry
    Weissman, Myrna M.
    Werge, Thomas
    Lewis, Cathryn M.
    Levinson, Douglas F.
    Borglum, Anders D.
    Sullivan, Patrick F.
    Meier, Sandra
    Strauss, John
    Xu, Wei
    Vincent, John B.
    Matthews, Keith
    Ferreira, Manuel
    O'Dushlaine, Colm
    Purcell, Shaun
    Raychaudhuri, Soumya
    Ruderfer, Douglas M.
    Sklar, Pamela
    Scott, Laura J.
    Flickinger, Matthew
    Burmeister, Margit
    Li, Jun
    Guan, Weihua
    Absher, Devin
    Thompson, Robert C.
    Meng, Fan Guo
    Schatzberg, Alan F.
    Bunney, William E.
    Barchas, Jack D.
    Watson, Stanley J.
    Myers, Richard M.
    Akil, Huda
    Boehnke, Michael
    Chambert, Kimberly
    Moran, Jennifer
    Scolnick, Edward
    Djurovic, Srdjan
    Melle, Ingrid
    Morken, Gunnar
    Corvin, Aiden
    Anjorin, Adebayo
    Kandaswamy, Radhika
    Lawrence, Jacob
    McLean, Alan W.
    Pickard, Benjamin S.
    Bergen, Sarah E.
    Nimgaonkar, Vishwajit
    Landen, Mikael
    Schalling, Martin
    Osby, Urban
    Backlund, Lena
    Frisen, Louise
    Langstrom, Niklas
    Stahl, Eli
    Dobbyn, Amanda
    Jamain, Stephane
    Etain, Bruno
    Bellivier, Frank
    Leber, Markus
    Maaser, Anna
    Fischer, Sascha B.
    Reinbold, Celine S.
    Kittel-Schneider, Sarah
    Fullerton, Janice M.
    Oruc, Lilijana
    Para, Jose G.
    Mayoral, Fermin
    Rivas, Fabio
    Czerski, Piotr M.
    Kammerer-Ciernioch, Jutta
    Vedder, Helmut
    Borrmann-Hassenbach, Margitta
    Pfennig, Andrea
    Brennan, Paul
    McKay, James D.
    Kogevinas, Manolis
    Schwarz, Markus
    Schofield, Peter R.
    Muehleisen, Thomas W.
    Schumacher, Johannes
    Bauer, Michael
    Wright, Adam
    Mitchell, Philip B.
    Hautzinger, Martin
    Kelsoe, John R.
    Greenwood, Tiffany A.
    Nievergelt, Caroline M.
    Shilling, Paul D.
    Smith, Erin N.
    Bloss, Cinnamon S.
    Edenberg, Howard J.
    Koller, Daniel L.
    Gershon, Elliot S.
    Liu, Chunyu
    Badner, Judith A.
    Scheftner, William A.
    Lawson, William B.
    Nwulia, Evaristus A.
    Hipolito, Maria
    Coryell, William
    Rice, John
    Byerley, William
    McMahon, Francis J.
    Lohoff, Falk W.
    Zandi, Peter P.
    Mahon, Pamela B.
    McInnis, Melvin G.
    Zollner, Sebastian
    Zhang, Peng
    Szelinger, Szabolcs
    St Clair, David
    Caesar, Sian
    Gordon-Smith, Katherine
    Fraser, Christine
    Green, Elaine K.
    Grozeva, Detelina
    Hamshere, Marian L.
    Kirov, George
    Nikolov, Ivan
    Collier, David A.
    Elkin, Amanda
    Williamson, Richard
    Young, Allan H.
    Ferrier, I. Nicol
    Milanova, Vihra
    Alda, Martin
    Cervantes, Pablo
    Cruceanu, Cristiana
    Rouleau, Guy A.
    Turecki, Gustavo
    Paciga, Sara
    Winslow, Ashley R.
    Grigoroiu-Serbanescu, Maria
    Ophoff, Roel
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Pato, Carlos
    Biernacka, Joanna M.
    Frye, Mark A.
    Morris, Derek
    Schork, Nicholas J.
    Reif, Andreas
    Lissowska, Jolanta
    Hauser, Joanna
    Szeszenia-Dabrowska, Neonila
    McGhee, Kevin
    Quinn, Emma
    Moskvina, Valentina
    Holmans, Peter A.
    Farmer, Anne
    Kennedy, James L.
    Andreassen, Ole A.
    Mattingsdal, Morten
    Bass, Nicholas J.
    Gurling, Hugh
    McQuillin, Andrew
    Breuer, Rene
    Hultman, Christina
    Lichtenstein, Paul
    Huckins, Laura M.
    Leboyer, Marion
    Lathrop, Mark
    Nurnberger, John
    Steffens, Michael
    Foroud, Tatiana M.
    Berrettini, Wade H.
    Craig, David W.
    Shi, Jianxin
    Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder2018In: Communications Biology, ISSN 2399-3642, Vol. 1, article id 163Article in journal (Refereed)
    Abstract [en]

    Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

  • 6.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Wennstedt, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Maintained memory in aging is associated with young epigenetic age2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, p. 167-171Article in journal (Refereed)
    Abstract [en]

    Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.

  • 7. Dries, Daniel R.
    et al.
    Zhu, Yi
    Brooks, Mieu M.
    Forero, Diego A.
    Adachi, Megumi
    Cenik, Basar
    West, James M.
    Han, Yu-Hong
    Yu, Cong
    Arbella, Jennifer
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Lu, Q. Richard
    Callaerts, Patrick
    Birnbaum, Shari G.
    Yu, Gang
    Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 22, p. 11647-11656Article in journal (Refereed)
    Abstract [en]

    The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of gamma-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate gamma-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

  • 8. Ekström, Ingrid
    et al.
    Sjölund, Sara
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Larsson, Maria
    Olofsson, Jonas K.
    Smell Loss Predicts Mortality Risk Regardless of Dementia Conversion2017In: Journal of The American Geriatrics Society, ISSN 0002-8614, E-ISSN 1532-5415, Vol. 65, no 6, p. 1238-1243Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine whether dementia could explain the association between poor olfactory performance and mortality risk within a decade-long follow-up period. Design: Prospective cohort study. SettingBetula Study, Umea, Sweden. ParticipantsA population-based sample of adult participants without dementia at baseline aged 40 to 90 (N = 1,774). Measurements: Olfactory performance using the Scandinavian Odor-Identification Test (SOIT) and self-reported olfactory function; several social, cognitive, and medical risk factors at baseline; and incident dementia during the following decade. Results: Within the 10-year follow-up, 411 of 1,774 (23.2%) participants had died. In a Cox model, the association between higher SOIT score and lower mortality was significant (hazard ratio (HR) = 0.74 per point interval, 95% confidence interval (CI) = 0.71-0.77, P < .001). The effect was attenuated, but remained significant, after controlling for age, sex, education, and health-related and cognitive variables (HR = 0.92, 95% CI = 0.87-0.97, P = .001). The association between SOIT score and mortality was retained after controlling for dementia conversion before death (HR = 0.92, 95% CI = 0.87-0.97, P = .001). Similar results were obtained for self-reported olfactory dysfunction. Conclusion: Poor odor identification and poor self-reported olfactory function are associated with greater likelihood of future mortality. Dementia does not attenuate the association between olfactory loss and mortality, suggesting that olfactory loss might mark deteriorating health, irrespective of dementia.

  • 9.
    Figueira, Joao
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Serum Metabolite Markers of Dementia Through Quantitative NMR Analysis: The Importance of Threonine-Linked Metabolic Pathways2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 69, no 3, p. 763-774Article in journal (Refereed)
    Abstract [en]

    There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage.

  • 10.
    Figueira, Joao
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls2016In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 8, p. 2562-2571Article in journal (Refereed)
    Abstract [en]

    Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.

  • 11. Hagg, S.
    et al.
    Zhan, Y.
    Karlsson, R.
    Gerritsen, L.
    Ploner, A.
    van der Lee, S. J.
    Broer, L.
    Deelen, J.
    Marioni, R. E.
    Wong, A.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Zhu, G.
    Hansell, N. K.
    Sillanpaa, E.
    Fedko, I. O.
    Amin, N. A.
    Beekman, M.
    de Craen, A. J. M.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harris, S. E.
    Kan, K-J
    Martin-Ruiz, C. M.
    Montgomery, G. W.
    Adolfsson, Annelie N.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Reynolds, C. A.
    Samani, N. J.
    Suchiman, H. E. D.
    Viljanen, A.
    von Zglinicki, T.
    Wright, M. J.
    Hottenga, J-J
    Boomsma, D. I.
    Rantanen, T.
    Kaprio, J. A.
    Nyholt, D. R.
    Martin, N. G.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Kuh, D.
    Starr, J. M.
    Deary, I. J.
    Slagboom, P. E.
    van Duijn, C. M.
    Codd, V.
    Pedersen, N. L.
    Short telomere length is associated with impaired cognitive performance in European ancestry cohorts2017In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, article id e1100Article in journal (Refereed)
    Abstract [en]

    The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

  • 12. Huckins, Laura M.
    et al.
    Dobbyn, Amanda
    Ruderfer, Douglas M.
    Hoffman, Gabriel
    Wang, Weiqing
    Pardinas, Antonio F.
    Rajagopal, Veera M.
    Als, Thomas D.
    Nguyen, Hoang T.
    Girdhar, Kiran
    Boocock, James
    Roussos, Panos
    Fromer, Menachem
    Kramer, Robin
    Domenici, Enrico
    Gamazon, Eric R.
    Purcell, Shaun
    Demontis, Ditte
    Borglum, Anders D.
    Walters, James T. R.
    O'Donovan, Michael C.
    Sullivan, Patrick
    Owen, Michael J.
    Devlin, Bernie
    Sieberts, Solveig K.
    Cox, Nancy J.
    Im, Hae Kyung
    Sklar, Pamela
    Stahl, Eli A.
    Johnson, Jessica S.
    Shah, Hardik R.
    Klein, Lambertus L.
    Dang, Kristen K.
    Logsdon, Benjamin A.
    Mahajan, Milind C.
    Mangravite, Lara M.
    Toyoshiba, Hiroyoshi
    Gur, Raquel E.
    Hahn, Chang-Gyu
    Schadt, Eric
    Lewis, David A.
    Haroutunian, Vahram
    Peters, Mette A.
    Lipska, Barbara K.
    Buxbaum, Joseph D.
    Hirai, Keisuke
    Perumal, Thanneer M.
    Essioux, Laurent
    Rajagopal, Veera Manikandan
    Mattheisen, Manuel
    Grove, Jakob
    Werge, Thomas
    Mortensen, Preben Bo
    Pedersen, Carsten Bocker
    Agerbo, Esben
    Pedersen, Marianne Giortz
    Mors, Ole
    Nordentoft, Merete
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Baekvad-Hansen, Marie
    Hansen, Christine Soholm
    Ripke, Stephan
    Neale, Benjamin M.
    Corvin, Aiden
    Farh, Kai-How
    Holmans, Peter A.
    Lee, Phil
    Bulik-Sullivan, Brendan
    Collier, David A.
    Huang, Hailiang
    Pers, Tune H.
    Agartz, Ingrid
    Albus, Margot
    Alexander, Madeline
    Amin, Farooq
    Bacanu, Silviu A.
    Begemann, Martin
    Belliveau, Richard A., Jr.
    Bene, Judit
    Bergen, Sarah E.
    Bevilacqua, Elizabeth
    Bigdeli, Tim B.
    Black, Donald W.
    Bruggeman, Richard
    Buccola, Nancy G.
    Buckner, Randy L.
    Byerley, William
    Cahn, Wiepke
    Cai, Guiqing
    Campion, Dominique
    Cantor, Rita M.
    Carr, Vaughan J.
    Carrera, Noa
    Catts, Stanley, V
    Chambert, Kimberly D.
    Chan, Raymond C. K.
    Chen, Ronald Y. L.
    Chen, Eric Y. H.
    Cheng, Wei
    Cheung, Eric F. C.
    Chong, Siow Ann
    Cloninger, C. Robert
    Cohen, David
    Cohen, Nadine
    Cormican, Paul
    Craddock, Nick
    Crowley, James J.
    Curtis, David
    Davidson, Michael
    Davis, Kenneth L.
    Degenhardt, Franziska
    Del Favero, Jurgen
    Dikeos, Dimitris
    Dinan, Timothy
    Djurovic, Srdjan
    Donohoe, Gary
    Drapeau, Elodie
    Duan, Jubao
    Dudbridge, Frank
    Durmishi, Naser
    Eichhammer, Peter
    Eriksson, Johan
    Escott-Price, Valentina
    Fanous, Ayman H.
    Farrell, Martilias S.
    Frank, Josef
    Franke, Lude
    Freedman, Robert
    Freimer, Nelson B.
    Friedl, Marion
    Friedman, Joseph, I
    Genovese, Giulio
    Georgieva, Lyudmila
    Giegling, Ina
    Giusti-Rodriguez, Paola
    Godard, Stephanie
    Goldstein, Jacqueline, I
    Golimbet, Vera
    Gopal, Srihari
    Gratten, Jacob
    de Haan, Lieuwe
    Hammer, Christian
    Hamshere, Marian L.
    Hansen, Mark
    Hansen, Thomas
    Hartmann, Annette M.
    Henskens, Frans A.
    Herms, Stefan
    Hirschhorn, Joel N.
    Hoffmann, Per
    Hofman, Andrea
    Hollegaard, Mads, V
    Ikeda, Masashi
    Joa, Inge
    Julia, Antonio
    Kahn, Rene S.
    Kalaydjieva, Luba
    Karachanak-Yankova, Sena
    Karjalainen, Juha
    Kavanagh, David
    Keller, Matthew C.
    Kennedy, James L.
    Khrunin, Andrey
    Kim, Yunjung
    Klovins, Janis
    Knowles, James A.
    Konte, Bettina
    Kucinskas, Vaidutis
    Kucinskiene, Zita Ausrele
    Kuzelova-Ptackova, Hana
    Kahler, Anna K.
    Laurent, Claudine
    Keong, Jimmy Lee Chee
    Lee, S. Hong
    Legge, Sophie E.
    Lerer, Bernard
    Li, Miaoxin
    Li, Tao
    Liang, Kung-Yee
    Lieberman, Jeffrey
    Limborska, Svetlana
    Loughland, Carmel M.
    Lubinski, Jan
    Lonnqvist, Jouko
    Macek, Milan, Jr.
    Magnusson, Patrik K. E.
    Maher, Brion S.
    Maier, Wolfgang
    Mallet, Jacques
    Marsal, Sara
    Mattingsdal, Morten
    McCarley, Robert W.
    McDonald, Colm
    McIntosh, Andrew M.
    Meier, Sandra
    Meijer, Carin J.
    Melegh, Bela
    Melle, Ingrid
    Mesholam-Gately, Raquelle, I
    Metspalu, Andres
    Michie, Patricia T.
    Milani, Lili
    Milanova, Vihra
    Mokrab, Younes
    Morris, Derek W.
    Murphy, Kieran C.
    Murray, Robin M.
    Myin-Germeys, Inez
    Muller-Myhsok, Bertram
    Nelis, Mari
    Nenadic, Igor
    Nertney, Deborah A.
    Nestadt, Gerald
    Nicodemus, Kristin K.
    Nikitina-Zake, Liene
    Nisenbaum, Laura
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    O'Callaghan, Eadbhard
    O'Dushlaine, Colm
    O'Neill, F. Anthony
    Oh, Sang-Yun
    Olincy, Ann
    Olsen, Line
    Van Os, Jim
    Pantelis, Christos
    Papadimitriou, George N.
    Papiol, Sergi
    Parkhomenko, Elena
    Pato, Michele T.
    Paunio, Tiina
    Pejovic-Milovancevic, Milica
    Perkins, Diana O.
    Pietilainen, Olli
    Pimm, Jonathan
    Pocklington, Andrew J.
    Powell, John
    Price, Alkes
    Pulver, Ann E.
    Purcell, Shaun M.
    Quested, Digby
    Rasmussen, Henrik B.
    Reichenberg, Abraham
    Reimers, Mark A.
    Richards, Alexander L.
    Roffman, Joshua L.
    Salomaa, Veikko
    Sanders, Alan R.
    Schall, Ulrich
    Schubert, Christian R.
    Schulze, Thomas G.
    Schwab, Sibylle G.
    Scolnick, Edward M.
    Scott, Rodney J.
    Seidman, Larry J.
    Shi, Jianxin
    Sigurdsson, Engilbert
    Silagadze, Teimuraz
    Silverman, Jeremy M.
    Sim, Kang
    Slominsky, Petr
    Smoller, Jordan W.
    So, Hon-Cheong
    Spencer, Chris C. A.
    Stefansson, Hreinn
    Steinberg, Stacy
    Stogmann, Elisabeth
    Straub, Richard E.
    Strengman, Eric
    Strohmaier, Jana
    Stroup, T. Scott
    Subramaniam, Mythily
    Suvisaari, Jaana
    Svrakic, Dragan M.
    Szatkiewicz, Jin P.
    Soderman, Erik
    Thirumalai, Srinivas
    Toncheva, Draga
    Tosato, Sarah
    Veijola, Juha
    Waddington, John
    Walsh, Dermot
    Wang, Dai
    Wang, Qiang
    Webb, Bradley T.
    Weiser, Mark
    Wildenauer, Dieter B.
    Williams, Nigel M.
    Williams, Stephanie
    Witt, Stephanie H.
    Wolen, Aaron R.
    Wong, Emily H. M.
    Wormley, Brandon K.
    Xi, Hualin Simon
    Zai, Clement C.
    Zheng, Xuebin
    Zimprich, Fritz
    Wray, Naomi R.
    Stefansson, Kari
    Visscher, Peter M.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Andreassen, Ole A.
    Blackwood, Douglas H. R.
    Bramon, Elvira
    Cichon, Sven
    Darvasi, Ariel
    Ehrenreich, Hannelore
    Esko, Tonu
    Gejman, Pablo, V
    Gill, Michael
    Gurling, Hugh
    Hultman, Christina M.
    Iwata, Nakao
    Jablensky, Assen, V
    Jonsson, Erik G.
    Kendler, Kenneth S.
    Kirov, George
    Knight, Jo
    Lencz, Todd
    Levinson, Douglas F.
    Li, Qingqin S.
    Liu, Jianjun
    Malhotra, Anil K.
    McCarroll, Steven A.
    McQuillin, Andrew
    Moran, Jennifer L.
    Mortensen, Preben B.
    Mowry, Bryan J.
    Nothen, Markus M.
    Ophoff, Roel A.
    Palotie, Aarno
    Pato, Carlos N.
    Petryshen, Tracey L.
    Posthuma, Danielle
    Rietschel, Marcella
    Riley, Brien P.
    Rujescu, Dan
    Sham, Pak C.
    St Clair, David
    Weinberger, Daniel R.
    Wendland, Jens R.
    Daly, Mark J.
    Sullivan, Patrick F.
    Gene expression imputation across multiple brain regions provides insights into schizophrenia risk2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 4, p. 659-+Article in journal (Refereed)
    Abstract [en]

    Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

  • 13. Johnstone, Mandy
    et al.
    Maclean, Alan
    Heyrman, Lien
    Lenaerts, An-Sofie
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    De Rijk, Peter
    Goossens, Dirk
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    St Clair, David M
    Hall, Jeremy
    Lawrie, Stephen M
    McIntosh, Andrew M
    Del-Favero, Jurgen
    Blackwood, Douglas H R
    Pickard, Benjamin S
    Copy number variations in DISC1 and DISC1-interacting partners in major mental illness2015In: Molecular neuropsychiatry, ISSN 2296-9209, Vol. 1, no 3, p. 175-190Article in journal (Refereed)
    Abstract [en]

    Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.

  • 14.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Demographic Data Base.
    Sundström, Anna
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Pudas, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Memory profiles predict dementia over 23–28 years in normal but not successful aging2019In: International psychogeriatrics, ISSN 1041-6102, E-ISSN 1741-203XArticle in journal (Refereed)
    Abstract [en]

    Objectives: Prospective studies suggest that memory deficits are detectable decades before clinical symptoms of dementia emerge. However, individual differences in long-term memory trajectories prior to diagnosis need to be further elucidated. The aim of the current study was to investigate long-term dementia and mortality risk for individuals with different memory trajectory profiles in a well-characterized population-based sample.

    Methods: 1062 adults (aged 45–80 years) who were non-demented at baseline were followed over 23–28 years. Dementia and mortality risk were studied for three previously classified episodic memory trajectory groups: maintained high performance (Maintainers; 26%), average decline (Averages; 64%), and accelerated decline (Decliners; 12%), using multistate modeling to characterize individuals’ transitions from an initial non-demented state, possibly to a state of dementia and/or death.

    Results: The memory groups showed considerable intergroup variability in memory profiles, starting 10–15 years prior to dementia diagnosis, and prior to death. A strong relationship between memory trajectory group and dementia risk was found. Specifically, Decliners had more than a fourfold risk of developing dementia compared to Averages. In contrast, Maintainers had a 2.6 times decreased dementia risk compared to Averages, and in addition showed no detectable memory decline prior to dementia diagnosis. A similar pattern of association was found for the memory groups and mortality risk, although only among non-demented.

    Conclusion: There was a strong relationship between accelerated memory decline and dementia, further supporting the prognostic value of memory decline. The intergroup differences, however, suggest that mechanisms involved in successful memory aging may delay symptom onset.

  • 15. Marshall, Christian R.
    et al.
    Howrigan, Daniel P.
    Merico, Daniele
    Thiruvahindrapuram, Bhooma
    Wu, Wenting
    Greer, Douglas S.
    Antaki, Danny
    Shetty, Aniket
    Holmans, Peter A.
    Pinto, Dalila
    Gujral, Madhusudan
    Brandler, William M.
    Malhotra, Dheeraj
    Wang, Zhouzhi
    Fajarado, Karin V. Fuentes
    Maile, Michelle S.
    Ripke, Stephan
    Agartz, Ingrid
    Albus, Margot
    Alexander, Madeline
    Amin, Farooq
    Atkins, Joshua
    Bacanu, Silviu A.
    Belliveau, Richard A., Jr.
    Bergen, Sarah E.
    Ertalan, Marcelo
    Bevilacqua, Elizabeth
    Bigdeli, Tim B.
    Black, Donald W.
    Bruggeman, Richard
    Buccola, Nancy G.
    Buckner, Randy L.
    Bulik-Sullivan, Brendan
    Byerley, William
    Cahn, Wiepke
    Cai, Guiqing
    Cairns, Murray J.
    Campion, Dominique
    Cantor, Rita M.
    Carr, Vaughan J.
    Carrera, Noa
    Catts, Stanley V.
    Chambert, Kimberley D.
    Cheng, Wei
    Cloninger, C. Robert
    Cohen, David
    Cormican, Paul
    Craddock, Nick
    Crespo-Facorro, Benedicto
    Crowley, James J.
    Curtis, David
    Davidson, Michael
    Davis, Kenneth L.
    Degenhardt, Franziska
    Del Favero, Jurgen
    DeLisi, Lynn E.
    Dikeos, Dimitris
    Dinan, Timothy
    Djurovic, Srdjan
    Donohoe, Gary
    Drapeau, Elodie
    Duan, Jubao
    Dudbridge, Frank
    Eichhammer, Peter
    Eriksson, Johan
    Escott-Price, Valentina
    Essioux, Laurent
    Fanous, Ayman H.
    Farh, Kai-How
    Farrell, Martilias S.
    Frank, Josef
    Franke, Lude
    Freedman, Robert
    Freimer, Nelson B.
    Friedman, Joseph I.
    Forstner, Andreas J.
    Fromer, Menachem
    Genovese, Giulio
    Georgieva, Lyudmila
    Gershon, Elliot S.
    Giegling, Ina
    Giusti-Rodriguez, Paola
    Godard, Stephanie
    Goldstein, Jacqueline I.
    Gratten, Jacob
    de Haan, Lieuwe
    Hamshere, Marian L.
    Hansen, Mark
    Hansen, Thomas
    Haroutunian, Vahram
    Hartmann, Annette M.
    Henskens, Frans A.
    Herms, Stefan
    Hirschhorn, Joel N.
    Hoffinann, Per
    Hofman, Andrea
    Huang, Hailiang
    Ikeda, Masashi
    Joa, Inge
    Kahler, Anna K.
    Kahn, Rene S.
    Kalaydjieva, Luba
    Karjalainen, Juha
    Kavanagh, David
    Keller, Matthew C.
    Kelly, Brian J.
    Kennedy, James L.
    Kim, Yunjung
    Knowles, James A.
    Konte, Bettina
    Laurent, Claudine
    Lee, Phil
    Lee, S. Hong
    Legge, Sophie E.
    Lerer, Bernard
    Levy, Deborah L.
    Liang, Kung-Yee
    Lieberman, Jeffrey
    Lonnqvist, Jouko
    Loughland, Carmel M.
    Magnusson, Patrik K. E.
    Maher, Brion S.
    Maier, Wolfgang
    Mallet, Jacques
    Mattheisen, Manuel
    Mattingsdal, Morten
    McCarley, Robert W.
    McDonald, Colm
    McIntosh, Andrew M.
    Meier, Sandra
    Meijer, Carin J.
    Melle, Ingrid
    Mesholam-Gately, Raquelle I.
    Metspalu, Andres
    Michie, Patricia T.
    Milani, Lili
    Milanova, Vihra
    Mokrab, Younes
    Morris, Derek W.
    Muller-Myhsok, Bertram
    Murphy, Kieran C.
    Murray, Robin M.
    Myin-Germeys, Inez
    Nenadic, Igor
    Nertney, Deborah A.
    Nestadt, Gerald
    Nicodemus, Kristin K.
    Nisenbaum, Laura
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    O'Callaghan, Eadbhard
    O'Dushlaine, Colm
    Oh, Sang-Yun
    Olincy, Ann
    Olsen, Line
    O'Neill, F. Anthony
    Van Os, Jim
    Pantelis, Christos
    Papadimitriou, George N.
    Parkhomenko, Elena
    Pato, Michele T.
    Paunio, Tiina
    Perkins, Diana O.
    Pers, Tune H.
    Pietilainen, Olli
    Pimm, Jonathan
    Pocklington, Andrew J.
    Powell, John
    Price, Alkes
    Pulver, Ann E.
    Purcell, Shaun M.
    Quested, Digby
    Rasmussen, Henrik B.
    Reichenberg, Abraham
    Reimers, Mark A.
    Richards, Alexander L.
    Roffman, Joshua L.
    Roussos, Panos
    Ruderfer, Douglas M.
    Salomaa, Veikko
    Sanders, Alan R.
    Savitz, Adam
    Schall, Ulrich
    Schulze, Thomas G.
    Schwab, Sibylle G.
    Scolnick, Edward M.
    Scott, Rodney J.
    Seidman, Larry J.
    Shi, Jianxin
    Silverman, Jeremy M.
    Smoller, Jordan W.
    Soderman, Erik
    Spencer, Chris C. A.
    Stahl, Eli A.
    Strengman, Eric
    Strohmaier, Jana
    Stroup, T. Scott
    Suvisaari, Jaana
    Svrakic, Dragan M.
    Szatkiewicz, Jin P.
    Thirumalai, Srinivas
    Tooney, Paul A.
    Veijola, Juha
    Visscher, Peter M.
    Waddington, John
    Walsh, Dermot
    Webb, Bradley T.
    Weiser, Mark
    Wildenauer, Dieter B.
    Williams, Nigel M.
    Williams, Stephanie
    Witt, Stephanie H.
    Wolen, Aaron R.
    Wormley, Brandon K.
    Wray, Naomi R.
    Wu, Jing Qin
    Zai, Clement C.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Andreassen, Ole A.
    Blackwood, Douglas H. R.
    Bramon, Elvira
    Buxbaum, Joseph D.
    Cichon, Sven
    Collier, David A.
    Corvin, Aiden
    Daly, Mark J.
    Darvasi, Ariel
    Domenici, Enrico
    Esko, Tonu
    Gejman, Pablo V.
    Gill, Michael
    Gurling, Hugh
    Hultman, Christina M.
    Iwata, Nakao
    Jablensky, Assen V.
    Jonsson, Erik G.
    Kendler, Kenneth S.
    Kirov, George
    Knight, Jo
    Levinson, Douglas F.
    Li, Qingqin S.
    McCarroll, Steven A.
    McQuillin, Andrew
    Moran, Jennifer L.
    Mowry, Bryan J.
    Nothen, Markus M.
    Ophoff, Roel A.
    Owen, Michael J.
    Palotie, Aarno
    Pato, Carlos N.
    Petryshen, Tracey L.
    Posthuma, Danielle
    Rietschel, Marcella
    Riley, Brien P.
    Rujescu, Dan
    Sklar, Pamela
    St Clair, David
    Walters, James T. R.
    Werge, Thomas
    Siillivan, Patrick F.
    O'Donovan, Michael C.
    Scherer, Stephen W.
    Neale, Benjamin M.
    Sebat, Jonathan
    Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 1, p. 27-35Article in journal (Refereed)
    Abstract [en]

    Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

  • 16.
    Moens, Lotte N.
    et al.
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    De Rijk, Peter
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Reumers, Joke
    SWITCH Laboratory, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; Vrije Universiteit Brussel (VUB), Brussels, Belgium.
    Van den Bossche, Maarten J. A.
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Glassee, Wim
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    De Zutter, Sonia
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Lenaerts, An-Sofie
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Castello, Ignacio Medina
    Functional Genomics Unit, Bioinformatics and Genomics Department, Prince Felipe Research Centre (CIPF), Valencia, Spain.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Goossens, Dirk
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Van Steen, Kristel
    Systems and Modeling Unit, Montefiore Institute/GIGA, University of Liège, Liège, Belgium.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), Flanders, Belgium; University of Antwerp (UA), Antwerp, Belgium.
    Sequencing of DISC1 Pathway Genes Reveals Increased Burden of Rare Missense Variants in Schizophrenia Patients from a Northern Swedish Population2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, article id e23450Article in journal (Refereed)
    Abstract [en]

    In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence - both genetic and functional - indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that similar to 90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

  • 17.
    Mousavi, Malahat
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bergdahl, Jan
    Umeå University, Faculty of Social Sciences, Department of Psychology. Institute of Clinical Dentistry, University of Tromsø, Tromsø, Norway.
    Eriksson, Kåre
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Moritz, Thomas
    Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Nilsson, Lars-Göran
    Umeå Center for Functional Brain Imaging, Umeå; Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå Center for Functional Brain Imaging, Umeå.
    Serum metabolomic biomarkers of dementia2014In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 4, no 2, p. 252-62Article in journal (Refereed)
    Abstract [en]

    Aims: This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis. Methods: Cognitively healthy participants were followed up for 5-20 years. Cognitive assessment, serum sampling, and diagnosis were completed every 5 years. Multivariate analyses were conducted on the metabolite profiles generated by gas chromatography/time-of-flight mass spectrometry. Results: A significant group separation was found between demented patients and controls, and between incident cases and controls. Metabolites that contributed in both analyses were 3,4-dihydroxybutanoic acid, docosapentaenoic acid, and uric acid. Conclusions: Serum metabolite profiles are altered in demented patients, and detectable up to 5 years preceding the diagnosis. Blood sampling can make an important contribution to the early prediction of conversion to dementia.

  • 18. Musliner, Katherine L.
    et al.
    Mortensen, Preben B.
    McGrath, John J.
    Suppli, Nis P.
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Bækvad-Hansen, Marie
    Andreassen, Ole
    Pedersen, Carsten B.
    Pedersen, Marianne G.
    Mors, Ole
    Nordentoft, Merete
    Børglum, Anders D.
    Werge, Thomas
    Agerbo, Esben
    Nordin Adolfsson, Annelie (Contributor)
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 5, p. 516-525Article in journal (Refereed)
    Abstract [en]

    Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.

    Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.

    Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.

    Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.

    Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).

    Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002).

    Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

  • 19. Olofsson, Jonas K
    et al.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Ekström, Ingrid
    Wilson, Donald
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Larsson, Maria
    Long-term episodic memory decline is associated with olfactory deficits only in carriers of ApoE-є42016In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 85, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The ɛ4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of ɛ4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were ɛ4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by > 1SD). Our main result is that only in ɛ4-carriers was episodic memory decline associated with odor identification impairment. In individuals without ɛ4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by ɛ4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the ɛ4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that ɛ4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the ɛ4 should be considered when using olfactory assessment as an early-stage indicator.

  • 20.
    Oudin, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Andersson, John
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Sundström, Anna
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Oudin Åström, Daniel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Nordin, Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Traffic-Related Air Pollution as a Risk Factor for Dementia: No Clear Modifying Effects of APOEɛ4 in the Betula Cohort2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 71, no 3, p. 733-740Article in journal (Refereed)
    Abstract [en]

    It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer’s disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ɛ4 carriers than in non-carriers. Air pollution and interaction with APOE ɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ɛ4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ɛ4 carriers than in the total population.

  • 21.
    Oudin, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lind, Nina
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordin, Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging research centre, Karolinska Institutet.
    Traffic-Related Air Pollution and Dementia Incidence in Northern Sweden: A Longitudinal Study2016In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 3, p. 306-312Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Exposure to ambient air pollution is suspected to cause cognitive effects, but a prospective cohort is needed to study exposure to air pollution at the home address and the incidence of dementia.

    OBJECTIVES: We aimed to assess the association between long-term exposure to traffic-related air pollution and dementia incidence in a major city in northern Sweden.

    METHODS: Data on dementia incidence over a 15-year period were obtained from the longitudinal Betula study. Traffic air pollution exposure was assessed with a Land Use Regression Model with a spatial resolution of 50 m x 50 m. Annual mean nitrogen oxide levels at the residential address of the participants at baseline (the start of follow-up) was used as a marker for long-term exposure to air pollution.

    RESULTS: Out of 1806 participants at baseline, 191 were diagnosed with Alzheimer's disease during follow-up, and 111 were diagnosed with vascular dementia. Participants in the highest exposure group were more likely to be diagnosed with dementia (Alzheimer's disease or vascular dementia), with a Hazard Ratio (HR) of 1.43 (95% Confidence Interval (CI): 0.998, 2.05 for the highest versus lowest quartile). The estimates were similar for Alzheimer's disease (HR 1.38) and vascular dementia (HR 1.47). The HR for dementia associated for the third quartile versus the lowest quartile was 1.48 (95% CI: 1.03, 2.11). A sub-analysis that excluded a younger sample that had been re-tested after only 5 years of follow-up suggested stronger associations with exposure than in the full cohort (HR = 1.71; 95% CI: 1.08, 2.73 for the highest versus lowest quartile).

    CONCLUSIONS: If the associations we observed are causal, then air pollution from traffic might be an important risk factor for vascular dementia and Alzheimer's disease.

  • 22. Pickard, Benjamin Simon
    et al.
    Van Den Bossche, Maarten J. A.
    Malloy, Mary P.
    Johnstone, Mandy
    Lenaerts, An-Sofie
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Goossens, Dirk
    St Clair, David
    Muir, Walter J.
    Nilsson, Lars-Goran
    Sabbe, Bernard
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Blackwood, Douglas H. R.
    Del-Favero, Jurgen
    Multiplex amplicon quantification screening the ABCA13 gene for copy number variation in schizophrenia and bipolar disorder2012In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 22, no 5, p. 269-270Article in journal (Refereed)
  • 23. Ripke, Stephan
    et al.
    Neale, Benjamin M.
    Corvin, Aiden
    Walters, James T. R.
    Farh, Kai-How
    Holmans, Peter A.
    Lee, Phil
    Bulik-Sullivan, Brendan
    Collier, David A.
    Huang, Hailiang
    Pers, Tune H.
    Agartz, Ingrid
    Agerbo, Esben
    Albus, Margot
    Alexander, Madeline
    Amin, Farooq
    Bacanu, Silviu A.
    Begemann, Martin
    Belliveau, Richard A., Jr.
    Bene, Judit
    Bergen, Sarah E.
    Bevilacqua, Elizabeth
    Bigdeli, Tim B.
    Black, Donald W.
    Bruggeman, Richard
    Buccola, Nancy G.
    Buckner, Randy L.
    Byerley, William
    Cahn, Wiepke
    Cai, Guiqing
    Campion, Dominique
    Cantor, Rita M.
    Carr, Vaughan J.
    Carrera, Noa
    Catts, Stanley V.
    Chambert, Kimberly D.
    Chan, Raymond C. K.
    Chen, Ronald Y. L.
    Chen, Eric Y. H.
    Cheng, Wei
    Cheung, Eric F. C.
    Chong, Siow Ann
    Cloninger, C. Robert
    Cohen, David
    Cohen, Nadine
    Cormican, Paul
    Craddock, Nick
    Crowley, James J.
    Curtis, David
    Davidson, Michael
    Davis, Kenneth L.
    Degenhardt, Franziska
    Del Favero, Jurgen
    Demontis, Ditte
    Dikeos, Dimitris
    Dinan, Timothy
    Djurovic, Srdjan
    Donohoe, Gary
    Drapeau, Elodie
    Duan, Jubao
    Dudbridge, Frank
    Durmishi, Naser
    Eichhammer, Peter
    Eriksson, Johan
    Escott-Price, Valentina
    Essioux, Laurent
    Fanous, Ayman H.
    Farrell, Martilias S.
    Frank, Josef
    Franke, Lude
    Freedman, Robert
    Freimer, Nelson B.
    Friedl, Marion
    Friedman, Joseph I.
    Fromer, Menachem
    Genovese, Giulio
    Georgieva, Lyudmila
    Giegling, Ina
    Giusti-Rodriguez, Paola
    Godard, Stephanie
    Goldstein, Jacqueline I.
    Golimbet, Vera
    Gopal, Srihari
    Gratten, Jacob
    de Haan, Lieuwe
    Hammer, Christian
    Hamshere, Marian L.
    Hansen, Mark
    Hansen, Thomas
    Haroutunian, Vahram
    Hartmann, Annette M.
    Henskens, Frans A.
    Herms, Stefan
    Hirschhorn, Joel N.
    Hoffmann, Per
    Hofman, Andrea
    Hollegaard, Mads V.
    Hougaard, David M.
    Ikeda, Masashi
    Joa, Inge
    Julia, Antonio
    Kahn, Rene S.
    Kalaydjieva, Luba
    Karachanak-Yankova, Sena
    Karjalainen, Juha
    Kavanagh, David
    Keller, Matthew C.
    Kennedy, James L.
    Khrunin, Andrey
    Kim, Yunjung
    Klovins, Janis
    Knowles, James A.
    Konte, Bettina
    Kucinskas, Vaidutis
    Kucinskiene, Zita Ausrele
    Kuzelova-Ptackova, Hana
    Kahler, Anna K.
    Laurent, Claudine
    Keong, Jimmy Lee Chee
    Lee, S. Hong
    Legge, Sophie E.
    Lerer, Bernard
    Li, Miaoxin
    Li, Tao
    Liang, Kung-Yee
    Lieberman, Jeffrey
    Limborska, Svetlana
    Loughland, Carmel M.
    Lubinski, Jan
    Lonnqvist, Jouko
    Macek, Milan, Jr.
    Magnusson, Patrik K. E.
    Maher, Brion S.
    Maier, Wolfgang
    Mallet, Jacques
    Marsal, Sara
    Mattheisen, Manuel
    Mattingsdal, Morten
    McCarley, Robert W.
    McDonald, Colm
    McIntosh, Andrew M.
    Meier, Sandra
    Meijer, Carin J.
    Melegh, Bela
    Melle, Ingrid
    Mesholam-Gately, Raquelle I.
    Metspalu, Andres
    Michie, Patricia T.
    Milani, Lili
    Milanova, Vihra
    Mokrab, Younes
    Morris, Derek W.
    Mors, Ole
    Murphy, Kieran C.
    Murray, Robin M.
    Myin-Germeys, Inez
    Mueller-Myhsok, Bertram
    Nelis, Mari
    Nenadic, Igor
    Nertney, Deborah A.
    Nestadt, Gerald
    Nicodemus, Kristin K.
    Nikitina-Zake, Liene
    Nisenbaum, Laura
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    O'Callaghan, Eadbhard
    O'Dushlaine, Colm
    O'Neill, F. Anthony
    Oh, Sang-Yun
    Olincy, Ann
    Olsen, Line
    Van Os, Jim
    Pantelis, Christos
    Papadimitriou, George N.
    Papiol, Sergi
    Parkhomenko, Elena
    Pato, Michele T.
    Paunio, Tiina
    Pejovic-Milovancevic, Milica
    Perkins, Diana O.
    Pietilainen, Olli
    Pimm, Jonathan
    Pocklington, Andrew J.
    Powell, John
    Price, Alkes
    Pulver, Ann E.
    Purcell, Shaun M.
    Quested, Digby
    Rasmussen, Henrik B.
    Reichenberg, Abraham
    Reimers, Mark A.
    Richards, Alexander L.
    Roffman, Joshua L.
    Roussos, Panos
    Ruderfer, Douglas M.
    Salomaa, Veikko
    Sanders, Alan R.
    Schall, Ulrich
    Schubert, Christian R.
    Schulze, Thomas G.
    Schwab, Sibylle G.
    Scolnick, Edward M.
    Scott, Rodney J.
    Seidman, Larry J.
    Shi, Jianxin
    Sigurdsson, Engilbert
    Silagadze, Teimuraz
    Silverman, Jeremy M.
    Sim, Kang
    Slominsky, Petr
    Smoller, Jordan W.
    So, Hon-Cheong
    Spencer, Chris C. A.
    Stahl, Eli A.
    Stefansson, Hreinn
    Steinberg, Stacy
    Stogmann, Elisabeth
    Straub, Richard E.
    Strengman, Eric
    Strohmaier, Jana
    Stroup, T. Scott
    Subramaniam, Mythily
    Suvisaari, Jaana
    Svrakic, Dragan M.
    Szatkiewicz, Jin P.
    Soderman, Erik
    Thirumalai, Srinivas
    Toncheva, Draga
    Tosato, Sarah
    Veijola, Juha
    Waddington, John
    Walsh, Dermot
    Wang, Dai
    Wang, Qiang
    Webb, Bradley T.
    Weiser, Mark
    Wildenauer, Dieter B.
    Williams, Nigel M.
    Williams, Stephanie
    Witt, Stephanie H.
    Wolen, Aaron R.
    Wong, Emily H. M.
    Wormley, Brandon K.
    Xi, Hualin Simon
    Zai, Clement C.
    Zheng, Xuebin
    Zimprich, Fritz
    Wray, Naomi R.
    Stefansson, Kari
    Visscher, Peter M.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Andreassen, Ole A.
    Blackwood, Douglas H. R.
    Bramon, Elvira
    Buxbaum, Joseph D.
    Borglum, Anders D.
    Cichon, Sven
    Darvasi, Ariel
    Domenici, Enrico
    Ehrenreich, Hannelore
    Esko, Tonu
    Gejman, Pablo V.
    Gill, Michael
    Gurling, Hugh
    Hultman, Christina M.
    Iwata, Nakao
    Jablensky, Assen V.
    Jonsson, Erik G.
    Kendler, Kenneth S.
    Kirov, George
    Knight, Jo
    Lencz, Todd
    Levinson, Douglas F.
    Li, Qingqin S.
    Liu, Jianjun
    Malhotra, Anil K.
    McCarroll, Steven A.
    McQuillin, Andrew
    Moran, Jennifer L.
    Mortensen, Preben B.
    Mowry, Bryan J.
    Noethen, Markus M.
    Ophoff, Roel A.
    Owen, Michael J.
    Palotie, Aarno
    Pato, Carlos N.
    Petryshen, Tracey L.
    Posthuma, Danielle
    Rietschel, Marcella
    Riley, Brien P.
    Rujescu, Dan
    Sham, Pak C.
    Sklar, Pamela
    St Clair, David
    Weinberger, Daniel R.
    Wendland, Jens R.
    Werge, Thomas
    Daly, Mark J.
    Sullivan, Patrick F.
    O'Donovan, Michael C.
    Biological insights from 108 schizophrenia-associated genetic loci2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 511, no 7510, p. 421-427Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

  • 24. Sköld, Mia
    et al.
    Källstrand, Johan
    Nehlstedt, Sara
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nielzén, Sören
    Holmberg, Jens
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Thalamocortical abnormalities in auditory brainstem response patterns distinguish DSM-IV bipolar disorder type I from schizophrenia2014In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 169, p. 105-11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bipolar disorder type I (BP-I) belongs to a spectrum of affective disorders that are expressed in many different ways and therefore can be difficult to distinguish from other conditions, especially unipolar depression, schizoaffective disorder, schizophrenia (SZ), but also anxiety and personality disorders. Since early diagnosis and treatment have shown to improve the long-term prognosis, complementary specific biomarkers are of great value. The auditory brainstem response (ABR) has previously been applied successfully to identify specific abnormal ABR patterns in SZ and Asperger syndrome.

    METHODS: The current study investigated the early auditory processing of complex sound stimuli e.g. forward masking, in BP-I compared to SZ patients. The ABR curves of BP-I patients (n=23) and SZ patients (n=20) were analyzed in terms of peak amplitudes and correlation with an ABR norm curve based on a non-psychiatric control group (n=20).

    RESULTS: BP-I patients had significantly higher wave III (p=0.0062) and wave VII (p=0.0472) amplitudes compared with SZ patients. Furthermore, BP-I patients, and to a lesser extent SZ patients, showed low correlation with the norm ABR curve in the part of the curve comprising waves VI-VII.

    LIMITATIONS: Sample size was relatively small and study groups were not matched for age and gender.

    CONCLUSIONS: BP-I patients showed specific aberrances, specifically in the latter part of the ABR curve, implicating abnormalities in thalamocortical circuitry. The abnormal ABR wave patterns significantly separated BP-I patients from SZ patients suggesting that ABR might serve as a biomarker for BP-I.

  • 25. Stahl, Eli A.
    et al.
    Breen, Gerome
    Forstner, Andreas J
    McQuillin, Andrew
    Ripke, Stephan
    Trubetskoy, Vassily
    Mattheisen, Manuel
    Wang, Yunpeng
    Coleman, Jonathan R I
    Gaspar, Héléna A
    de Leeuw, Christiaan A
    Steinberg, Stacy
    Pavlides, Jennifer M Whitehead
    Trzaskowski, Maciej
    Byrne, Enda M
    Pers, Tune H
    Holmans, Peter A
    Richards, Alexander L
    Abbott, Liam
    Agerbo, Esben
    Akil, Huda
    Albani, Diego
    Alliey-Rodriguez, Ney
    Als, Thomas D
    Anjorin, Adebayo
    Antilla, Verneri
    Awasthi, Swapnil
    Badner, Judith A
    Bækvad-Hansen, Marie
    Barchas, Jack D
    Bass, Nicholas
    Bauer, Michael
    Belliveau, Richard
    Bergen, Sarah E
    Pedersen, Carsten Bøcker
    Bøen, Erlend
    Boks, Marco P
    Boocock, James
    Budde, Monika
    Bunney, William
    Burmeister, Margit
    Bybjerg-Grauholm, Jonas
    Byerley, William
    Casas, Miquel
    Cerrato, Felecia
    Cervantes, Pablo
    Chambert, Kimberly
    Charney, Alexander W
    Chen, Danfeng
    Churchhouse, Claire
    Clarke, Toni-Kim
    Coryell, William
    Craig, David W
    Cruceanu, Cristiana
    Curtis, David
    Czerski, Piotr M
    Dale, Anders M
    de Jong, Simone
    Degenhardt, Franziska
    Del-Favero, Jurgen
    DePaulo, J Raymond
    Djurovic, Srdjan
    Dobbyn, Amanda L
    Dumont, Ashley
    Elvsåshagen, Torbjørn
    Escott-Price, Valentina
    Fan, Chun Chieh
    Fischer, Sascha B
    Flickinger, Matthew
    Foroud, Tatiana M
    Forty, Liz
    Frank, Josef
    Fraser, Christine
    Freimer, Nelson B
    Frisén, Louise
    Gade, Katrin
    Gage, Diane
    Garnham, Julie
    Giambartolomei, Claudia
    Pedersen, Marianne Giørtz
    Goldstein, Jaqueline
    Gordon, Scott D
    Gordon-Smith, Katherine
    Green, Elaine K
    Green, Melissa J
    Greenwood, Tiffany A
    Grove, Jakob
    Guan, Weihua
    Guzman-Parra, José
    Hamshere, Marian L
    Hautzinger, Martin
    Heilbronner, Urs
    Herms, Stefan
    Hipolito, Maria
    Hoffmann, Per
    Holland, Dominic
    Huckins, Laura
    Jamain, Stéphane
    Johnson, Jessica S
    Juréus, Anders
    Kandaswamy, Radhika
    Karlsson, Robert
    Kennedy, James L
    Kittel-Schneider, Sarah
    Knowles, James A
    Kogevinas, Manolis
    Koller, Anna C
    Kupka, Ralph
    Lavebratt, Catharina
    Lawrence, Jacob
    Lawson, William B
    Leber, Markus
    Lee, Phil H
    Levy, Shawn E
    Li, Jun Z
    Liu, Chunyu
    Lucae, Susanne
    Maaser, Anna
    MacIntyre, Donald J
    Mahon, Pamela B
    Maier, Wolfgang
    Martinsson, Lina
    McCarroll, Steve
    McGuffin, Peter
    McInnis, Melvin G
    McKay, James D
    Medeiros, Helena
    Medland, Sarah E
    Meng, Fan
    Milani, Lili
    Montgomery, Grant W
    Morris, Derek W
    Mühleisen, Thomas W
    Mullins, Niamh
    Nguyen, Hoang
    Nievergelt, Caroline M
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nwulia, Evaristus A
    O'Donovan, Claire
    Loohuis, Loes M Olde
    Ori, Anil P S
    Oruc, Lilijana
    Ösby, Urban
    Perlis, Roy H
    Perry, Amy
    Pfennig, Andrea
    Potash, James B
    Purcell, Shaun M
    Regeer, Eline J
    Reif, Andreas
    Reinbold, Céline S
    Rice, John P
    Rivas, Fabio
    Rivera, Margarita
    Roussos, Panos
    Ruderfer, Douglas M
    Ryu, Euijung
    Sánchez-Mora, Cristina
    Schatzberg, Alan F
    Scheftner, William A
    Schork, Nicholas J
    Shannon Weickert, Cynthia
    Shehktman, Tatyana
    Shilling, Paul D
    Sigurdsson, Engilbert
    Slaney, Claire
    Smeland, Olav B
    Sobell, Janet L
    Søholm Hansen, Christine
    Spijker, Anne T
    St Clair, David
    Steffens, Michael
    Strauss, John S
    Streit, Fabian
    Strohmaier, Jana
    Szelinger, Szabolcs
    Thompson, Robert C
    Thorgeirsson, Thorgeir E
    Treutlein, Jens
    Vedder, Helmut
    Wang, Weiqing
    Watson, Stanley J
    Weickert, Thomas W
    Witt, Stephanie H
    Xi, Simon
    Xu, Wei
    Young, Allan H
    Zandi, Peter
    Zhang, Peng
    Zöllner, Sebastian
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Agartz, Ingrid
    Alda, Martin
    Backlund, Lena
    Baune, Bernhard T
    Bellivier, Frank
    Berrettini, Wade H
    Biernacka, Joanna M
    Blackwood, Douglas H R
    Boehnke, Michael
    Børglum, Anders D
    Corvin, Aiden
    Craddock, Nicholas
    Daly, Mark J
    Dannlowski, Udo
    Esko, Tõnu
    Etain, Bruno
    Frye, Mark
    Fullerton, Janice M
    Gershon, Elliot S
    Gill, Michael
    Goes, Fernando
    Grigoroiu-Serbanescu, Maria
    Hauser, Joanna
    Hougaard, David M
    Hultman, Christina M
    Jones, Ian
    Jones, Lisa A
    Kahn, René S
    Kirov, George
    Landén, Mikael
    Leboyer, Marion
    Lewis, Cathryn M
    Li, Qingqin S
    Lissowska, Jolanta
    Martin, Nicholas G
    Mayoral, Fermin
    McElroy, Susan L
    McIntosh, Andrew M
    McMahon, Francis J
    Melle, Ingrid
    Metspalu, Andres
    Mitchell, Philip B
    Morken, Gunnar
    Mors, Ole
    Mortensen, Preben Bo
    Müller-Myhsok, Bertram
    Myers, Richard M
    Neale, Benjamin M
    Nimgaonkar, Vishwajit
    Nordentoft, Merete
    Nöthen, Markus M
    O'Donovan, Michael C
    Oedegaard, Ketil J
    Owen, Michael J
    Paciga, Sara A
    Pato, Carlos
    Pato, Michele T
    Posthuma, Danielle
    Ramos-Quiroga, Josep Antoni
    Ribasés, Marta
    Rietschel, Marcella
    Rouleau, Guy A
    Schalling, Martin
    Schofield, Peter R
    Schulze, Thomas G
    Serretti, Alessandro
    Smoller, Jordan W
    Stefansson, Hreinn
    Stefansson, Kari
    Stordal, Eystein
    Sullivan, Patrick F
    Turecki, Gustavo
    Vaaler, Arne E
    Vieta, Eduard
    Vincent, John B
    Werge, Thomas
    Nurnberger, John I
    Wray, Naomi R
    Di Florio, Arianna
    Edenberg, Howard J
    Cichon, Sven
    Ophoff, Roel A
    Scott, Laura J
    Andreassen, Ole A
    Kelsoe, John
    Sklar, Pamela
    Genome-wide association study identifies 30 loci associated with bipolar disorder2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 5, p. 793-803Article in journal (Refereed)
    Abstract [en]

    Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

  • 26.
    Stomby, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Region Jönköping County, Jönköping, Sweden.
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Psychology, Stockholm University, Stockholm, Sweden.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in elderly men and women2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 2, p. 117-126Article in journal (Refereed)
    Abstract [en]

    Objective: Elevated cortisol levels with aging have been associated with atrophy of the hippocampus and prefrontal cortex (PFC), as well as with impaired cognitive functions in men. However, coexisting diseases have confounded many studies examining these relationships. Studies in women are lacking. Our objective was to test whether salivary cortisol levels were related to morphology of the hippocampus and the PFC, and to cognitive performance. Design: A cross-sectional study including 200 elderly (55-80 years old) men and women. Method: We used magnetic resonance imaging, tests of episodic-, semantic-, and working memory, visuospatial ability, and cortisol levels in four saliva samples collected during 1 day. Results: Area under the curve (AUC) for cortisol levels was negatively related to cortical surface area of the left anterior cingulate gyrus (caudal P < 0.001; rostral P = 0.006), right lateral orbitofrontal cortex (P = 0.004), and right rostral middle frontal gyrus (P = 0.003). In women, there was also a negative relationship with cortical surface area in the left rostral middle frontal gyrus (P = 0.006). No relationship was found between cortisol levels and hippocampal volume. Conclusion: This study suggests that the structure of the medial PFC is related to cortisol levels in both elderly women and men.

  • 27.
    Stomby, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    Nilsson, Lars-Göran
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in women and menManuscript (preprint) (Other academic)
  • 28. Strazisar, M
    et al.
    Cammaerts, S
    van der Ven, K
    Forero, DA
    Lenaerts, A-S
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Almeida-Souza, L
    Genovese, G
    Timmerman, V
    Liekens, A
    De Rijk, P
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Callaerts, P
    Del-Favero, J
    MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets2015In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 20, no 4, p. 472-481Article in journal (Refereed)
    Abstract [en]

    Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.

  • 29. Szatkiewicz, Jin
    et al.
    Crowley, James J.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Åberg, Karolina A.
    Alaerts, Maaike
    Genovese, Giulio
    McCarroll, Steven
    Del-Favero, Jurgen
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Sullivan, Patrick F.
    The genomics of major psychiatric disorders in a large pedigree from Northern Sweden2019In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, article id 60Article in journal (Refereed)
    Abstract [en]

    We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.

  • 30. Van Den Bossche, Maarten J.
    et al.
    Johnstone, Mandy
    Strazisar, Mojca
    Pickard, Benjamin S.
    Goossens, Dirk
    Lenaerts, An-Sofie
    De Zutter, Sonia
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Mendlewicz, Julien
    Souery, Daniel
    De Rijk, Peter
    Sabbe, Bernard G.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Blackwood, Douglas
    Del-Favero, Jurgen
    Rare copy number variants in neuropsychiatric disorders: Specific phenotype or not?2012In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 159B, no 7, p. 812-822Article in journal (Refereed)
    Abstract [en]

    From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on additional genetic and environmental factors. Our results also suggest that the neurodevelopmental component is larger in the etiology of schizophrenia and intellectual disability than in mood disorders. Finally, our data suggest that deletions are in general more pathogenic than duplications. Given the high frequency of the examined CNVs (12%) in patients of different neuropsychiatric disorders, screening of large cohorts with an affordable and feasible method like the MAQ assays used in this study is likely to result in important progress in unraveling the genetic factors leading to an increased susceptibility for several psychiatric disorders.

  • 31. Van Den Bossche, Maarten J.
    et al.
    Strazisar, Mojca
    De Bruyne, Stephan
    Bervoets, Chris
    Lenaerts, An-Sofie
    De Zutter, Sonia
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Goossens, Dirk
    De Rijk, Peter
    Green, Elaine K.
    Grozeva, Detelina
    Mendlewicz, Julien
    Craddock, Nick
    Sabbe, Bernard G.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Souery, Daniel
    Del-Favero, Jurgen
    Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders2012In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 159B, no 4, p. 465-475Article in journal (Refereed)
    Abstract [en]

    The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7?kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 1726 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular.

  • 32.
    Wikgren, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Karlsson, Thomas
    Linköping University, Department of Behavioral Sciences and Learning.
    Söderlund, Hedvig
    Uppsala University, Department of Psychology.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Lars-Göran
    Stockholm University, Department of Psychology.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Shorter telomere length is linked to brain atrophy and white matter hyperintensities2014In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 43, no 2, p. 212-217Article in journal (Refereed)
    Abstract [en]

    Background: leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging. Methods: we investigated whether leukocyte TL was related to brain atrophy and WMHs in a sample of 102 non-demented individuals aged 64-75 years. Results: shorter TL was related to greater degree of subcortical atrophy (beta = -0.217, P = 0.034), but not to cortical atrophy. Furthermore, TL was 371 bp shorter (P = 0.041) in participants exhibiting subcortical WMHs, and 552 bp shorter (P = 0.009) in older participants exhibiting periventricular WMHs. Conclusion: this study provides the first evidence of leukocyte TL being associated with cerebral subcortical atrophy and WMHs, lending further support to the concept of TL as a marker of biological aging, and in particular that of the aging brain.

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