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  • 1. Athanasiu, Lavinia
    et al.
    Giddaluru, Sudheer
    Fernandes, Carla
    Christoforou, Andrea
    Reinvang, Ivar
    Lundervold, Astri J.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Kauppi, Karolina
    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.
    Eriksson, Elias
    Sundet, Kjetil
    Djurovic, Srdjan
    Espeseth, Thomas
    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.
    Steen, Vidar M.
    Andreassen, Ole A.
    Le Hellard, Stephanie
    A genetic association study of CSMD1 and CSMD2 with cognitive function2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 209-216Article in journal (Refereed)
    Abstract [en]

    The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.

  • 2. Chen, Chi-Hua
    et al.
    Wang, Yunpeng
    Lo, Min-Tzu
    Schork, Andrew
    Fan, Chun-Chieh
    Holland, Dominic
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, La Jolla, California, USA.
    Smeland, Olav B.
    Djurovic, Srdjan
    Sanyal, Nilotpal
    Hibar, Derrek P.
    Thompson, Paul M.
    Thompson, Wesley K.
    Andreassen, Ole A.
    Dale, Anders M.
    Leveraging genome characteristics to improve gene discovery for putamen subcortical brain structure2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15736Article in journal (Refereed)
    Abstract [en]

    Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5′UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum-specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 × 10−8). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen.

  • 3.
    Fernandes, Carla Patricia Duarte
    et al.
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Westlye, Lars Tjelta
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Giddaluru, Sudheer
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Christoforou, Andrea
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University and Stockholm Brain Institute, Uppsala, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundervold, Astri Johansen
    Department of Biological and Medical Psychology, K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital.
    Reinvang, Ivar
    Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Steen, Vidar Martin
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Le Hellard, Stéphanie
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Espeseth, Thomas
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Lack of association of the rs1344706 ZNF804A variant with cognitive functions and DTI indices of white matter microstructure in two independent healthy populations2014In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 222, no 1-2, p. 60-66Article in journal (Refereed)
    Abstract [en]

    The rs1344706 single nucleotide polymorphism within intron 2 of the ZNF804A gene is strongly associated with schizophrenia and bipolar disorder. This variant has also been associated in some studies with a range of cognitive and neuroimaging phenotypes, but several studies have reported no effect on the same phenotypes in other samples. Here, we genotyped 670 healthy adult Norwegian subjects and 1753 healthy adult Swedish subjects for rs1344706, and tested for associations with cognitive phenotypes including general intellectual abilities, memory functions and cognitive inhibition. We also tested whether rs1344706 is associated with white matter microstructural properties using diffusion tensor imaging (DTI) data from 250 to 340 of the Norwegian and Swedish subjects, respectively. Whole-brain voxel-wise statistical modeling of the effect of the ZNF804A variant on two DTI indices, fractional anisotropy (FA) and radial diffusivity (RD), was performed using tract-based spatial statistics (TBSS), and commonly reported effect sizes were calculated within several large-scale white matter pathways based on neuroanatomical atlases. No significant associations were found between rs1344706 and the cognitive traits or white matter microstructure. We conclude that the rs1344706 SNP has no significant effect on these phenotypes in our two reasonably powered samples.

  • 4.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Genes to remember: imaging genetics of hippocampus-based memory functions2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the field of imaging genetics, brain function and structure are used as intermediate phenotypes between genes and cognition/diseases to validate and extend findings from behavioral genetics. In this thesis, three of the strongest candidate genes for episodic memory, KIBRA, BDNF, and APOE, were examined in relation to memory performance and hippocampal/parahippocampal fMRI blood-oxygen level-dependent (BOLD) signal. A common T allele in the KIBRA gene was previously associated with superior memory, and increased hippocampal activation was observed in noncarriers of the T allele which was interpreted as reflecting compensatory recruitment. The results from the first study revealed that both memory performance and hippocampal activation at retrieval was higher in T allele carriers (study I). The BDNF 66Met and APOE ε4 alleles have previously been associated with poorer memory performance, but their relation to brain activation has been inconsistent with reports of both increased and decreased regional brain activation relative to noncarriers. Here, decreased hippocampal/parahippocampal activation was observed in carriers of BDNF 66Met (study II) as well as APOE ε4 (study III) during memory encoding. In addition, there was an additive gene-gene effect of APOE and BDNF on hippocampal and parahippocampal activation (study III). Collectively, the results from these studies on KIBRA, BDNF, and APOE converge on higher medial temporal lobe activation for carriers of a high-memory associated allele, relative to carriers of a low-memory associated allele. In addition, the observed additive effect of APOE and BDNF demonstrate that a larger amount of variance in BOLD signal change can be explained by considering the combined effect of more than one genetic polymorphism. These imaging genetics findings support and extend previous knowledge from behavioral genetics on the role of these memory-related genes.

  • 5.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Brin Rosenthal, Sara
    Lo, Min-Tzu
    Sanyal, Nilotpal
    Jiang, Mian
    Abagyan, Ruben
    McEvoy, Linda K.
    Andreassen, Ole A.
    Chen, Chi-Hua
    Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia2018In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 175, no 7, p. 674-682Article in journal (Refereed)
    Abstract [en]

    Objective: Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product.

    Method: The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328).

    Results: Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms.

    Conclusions: The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.

  • 6.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California, San Diego, La Jolla, CA, United States.
    Fan, Chun Chieh
    McEvoy, Linda K.
    Holland, Dominic
    Tan, Chin Hong
    Chen, Chi-Hua
    Andreassen, Ole A.
    Desikan, Rahul S.
    Dale, Anders M.
    Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease2018In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 12, article id 260Article in journal (Refereed)
    Abstract [en]

    Improved prediction of progression to Alzheimer's Disease (AD) among older individuals with mild cognitive impairment (MCI) is of high clinical and societal importance. We recently developed a polygenic hazard score (PHS) that predicted age of AD onset above and beyond APOE. Here, we used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to further explore the potential clinical utility of PHS for predicting AD development in older adults with MCI. We examined the predictive value of PHS alone and in combination with baseline structural magnetic resonance imaging (MRI) data on performance on the Mini-Mental State Exam (MMSE). In survival analyses, PHS significantly predicted time to progression from MCI to AD over 120 months (p = 1.07e-5), and PHS was significantly more predictive than APOE alone (p = 0.015). Combining PHS with baseline brain atrophy score and/or MMSE score significantly improved prediction compared to models without PHS (three-factor model p = 4.28e-17). Prediction model accuracies, sensitivities and area under the curve were also improved by including PHS in the model, compared to only using atrophy score and MMSE. Further, using linear mixed-effect modeling, PHS improved the prediction of change in the Clinical Dementia Rating—Sum of Boxes (CDR-SB) score and MMSE over 36 months in patients with MCI at baseline, beyond both APOE and baseline levels of brain atrophy. These results illustrate the potential clinical utility of PHS for assessment of risk for AD progression among individuals with MCI both alone, or in conjunction with clinical measures of prodromal disease including measures of cognitive function and regional brain atrophy.

  • 7.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nilsson, Lars-Göran
    Stockholm University.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Eriksson, Elias
    Gothenburg University.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    KIBRA polymorphism is related to enhanced memory and elevated hippocampal processing2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 40, p. 14218-14222Article in journal (Refereed)
    Abstract [en]

    Several studies have linked the KIBRA rs17070145 T polymorphism to superior episodic memory in healthy humans. One study investigated the effect of KIBRA on brain activation patterns (Papassotiropoulos et al., 2006) and observed increased hippocampal activation in noncarriers of the T allele during retrieval. Noncarriers were interpreted to need more hippocampal activation to reach the same performance level as T carriers. Using large behavioral (N = 2230) and fMRI (N = 83) samples, we replicated the KIBRA effect on episodic memory performance, but found increased hippocampal activation in T carriers during episodic retrieval. There was no evidence of compensatory brain activation in noncarriers within the hippocampal region. In the main fMRI sample, T carriers performed better than noncarriers during scanning but, importantly, the difference in hippocampus activation remained after post hoc matching according to performance, sex, and age (N = 64). These findings link enhanced memory performance in KIBRA T allele carriers to elevated hippocampal functioning, rather than to neural compensation in noncarriers.

  • 8.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nilsson, Lars-Göran
    Stockholm University.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Elias
    Gothenburg University.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Decreased medial temporal lobe activation in BDNF 66Met allele carriers during memory encoding2013In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 51, no 12, p. 2462-2468Article in journal (Refereed)
    Abstract [en]

    The Met allele of the Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism has been associated with impaired activity-dependent secretion of BDNF protein and decreased memory performance. Results from imaging studies relating Val(66)Met to brain activation during memory processing have been inconsistent, with reports of both increased and decreased activation in the Medial Temporal Lobe (MTL) in Met carriers relative to Val homozygotes. Here, we extensively studied BDNF Val(66)Met in relation to brain activation and white matter integrity as well as memory performance in a large imaging (n=194) and behavioral (n=2229) sample, respectively. Functional magnetic resonance imaging (fMRI) was used to investigate MTL activation in healthy participants in the age of 55-75 years during a face-name episodic encoding and retrieval task. White matter integrity was measured using diffusion tensor imaging.

    BDNF Met allele carriers had significantly decreased activation in the MTL during encoding processes, but not during retrieval processes. In contrast to previous proposals, the effect was not modulated by age and the polymorphism was not related to white matter integrity. Met carriers had lower memory performance than Val homozygotes, but differences were subtle and not significant. In conclusion, the BDNF Met allele has a negative influence on MTL functioning, preferentially during encoding processes, which might translate into impaired episodic memory function.

  • 9.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nilsson, Lars-Göran
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Combined gene effects on hippocampal mnemonic processing: a large-scale imaging-genetics study of APOE, BDNF, KIBRA, and CLSTN22013In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 25, no Suppl., p. S140-S141Article in journal (Other academic)
  • 10.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University,106 91 Stockholm, Stockholm Brain Institute, Sweden.
    Persson, Jonas
    Aging Research Center (ARC), Karolinska Institutet, Gävlegatan 16, SE-11330 Stockholm, Stockholm University, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Additive genetic effect of APOE and BDNF on hippocampus activity2014In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 89, no 1, p. 306-313Article in journal (Refereed)
    Abstract [en]

    Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.

  • 11. Lo, Min-Tzu
    et al.
    Fan, Chun-Chieh
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California, San Diego, La Jolla, California, USA.
    Sanyal, Nilotpal
    Desikan, Rahul S.
    Farrer, Lindsay A.
    Haines, Jonathan L.
    Mayeux, Richard
    Pericak-Vance, Margaret
    Schellenberg, Gerard D.
    Chen, Chi-Hua
    Identification of Genetic Heterogeneity of Alzheimer's Disease Across Age2017In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 41, no 7, p. 706-707Article in journal (Other academic)
  • 12. Lo, Min-Tzu
    et al.
    Hinds, David A.
    Tung, Joyce Y.
    Franz, Carol
    Fan, Chun-Chieh
    Wang, Yunpeng
    Smeland, Olav B.
    Schork, Andrew
    Holland, Dominic
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California, San Diego, La Jolla, California, USA.
    Sanyal, Nilotpal
    Escott-Price, Valentina
    Smith, Daniel J.
    O'Donovan, Michael
    Stefansson, Hreinn
    Bjornsdottir, Gyda
    Thorgeirsson, Thorgeir E.
    Stefansson, Kari
    McEvoy, Linda K.
    Dale, Anders M.
    Andreassen, Ole A.
    Chen, Chi-Hua
    Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 1, p. 152-156Article in journal (Refereed)
    Abstract [en]

    Personality is influenced by genetic and environmental factors(1) and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci(2,3), significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit- hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).

  • 13. Lo, Min-Tzu
    et al.
    Wang, Yunpeng
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA 92037, USA.
    Sanyal, Nilotpal
    Fan, Chun-Chieh
    Smeland, Olav B.
    Schork, Andrew
    Holland, Dominic
    Hinds, David A.
    Tung, Joyce Y.
    Andreassen, Ole A.
    Dale, Anders M.
    Chen, Chi-Hua
    Modeling prior information of common genetic variants improves gene discovery for neuroticism2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 22, p. 4530-4539Article in journal (Refereed)
    Abstract [en]

    Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.

  • 14.
    Nyberg, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Persson, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Stockholm Brain Institute, Karolinska Institute, Stockholm, Sweden.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Karolinska Institute, Stockholm, Sweden.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Stockholm University, Stockholm Brain Institute.
    Age-related and genetic modulation of frontal cortex efficiency2014In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 26, no 4, p. 746-754Article in journal (Refereed)
    Abstract [en]

    The dorsolateral pFC (DLPFC) is a key region for working memory. It has been proposed that the DLPFC is dynamically recruited depending on task demands. By this view, high DLPFC recruitment for low-demanding tasks along with weak DLPFC upregulation at higher task demands reflects low efficiency. Here, the fMRI BOLD signal during working memory maintenance and manipulation was examined in relation to aging and catechol-O-methyltransferase (COMT) Val(158)Met status in a large representative sample (n = 287). The efficiency hypothesis predicts a weaker DLPFC response during manipulation, along with a stronger response during maintenance for older adults and COMT Val carriers compared with younger adults and COMT Met carriers. Consistent with the hypothesis, younger adults and met carriers showed maximal DLPFC BOLD response during manipulation, whereas older adults and val carriers displayed elevated DLPFC responses during the less demanding maintenance condition. The observed inverted relations support a link between dopamine and DLPFC efficiency.

  • 15.
    Nyberg, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Kalpouzos, Grégoria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lind, Johanna
    Center for Study of Human Cognition, Department of Psychology, University of Oslo, Norway.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Persson, Jonas
    Department of Psychology and Stockholm Brain Institute, Stockholm University, 106 91 Stockholm, Sweden .
    Nilsson, Lars-Göran
    Department of Psychology and Stockholm Brain Institute, Stockholm University, 106 91 Stockholm, Sweden .
    Longitudinal evidence for diminished frontal cortex function in aging2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 52, p. 22682-22686Article in journal (Refereed)
    Abstract [en]

    Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.

  • 16.
    Persson, Jonas
    et al.
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden .
    Pudas, Sara
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden .
    Lind, Johanna
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden .
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nilsson, Lars-Göran
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden .
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Longitudinal structure-function correlates in elderly reveal MTL dysfunction with cognitive decline2012In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, no 10, p. 2297-2304Article in journal (Refereed)
    Abstract [en]

    By integrating behavioral measures and imaging data, previous investigations have explored the relationship between biological markers of aging and cognitive functions. Evidence from functional and structural neuroimaging has revealed that hippocampal volume and activation patterns in the medial temporal lobe (MTL) may predict cognitive performance in old age. Most past demonstrations of age-related differences in brain structure-function were based on cross-sectional comparisons. Here, the relationship between 6-year intraindividual change in functional magnetic resonance imaging (fMRI) signal and change in memory performance over 2 decades was examined. Correlations between intraindividual change in fMRI signal during episodic encoding and change in memory performance measured outside of scanning were used as an estimate for relating brain-behavior changes. The results revealed a positive relationship between activation change in the hippocampus (HC) and change in memory performance, reflecting reduced hippocampal activation in participants with declining performance. Using a similar analytic approach as for the functional data, we found that individuals with declining performance had reduced HC volume compared with individuals with intact performance. These observations provide a strong link between cognitive change in older adults and MTL structure and function and thus provide insights into brain correlates of individual variability in aging trajectories.

  • 17.
    Salami, Alireza
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Kompus, Kristiina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Habib, Reza
    Southern Illinois University , Carbondale.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Characterizing the neural correlates of modality-specific and modality-independent accessibility and availability signals in memory using partial-least squares2010In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 52, no 2, p. 686-698Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that information that currently cannot be retrieved but will be retrieved on a subsequent, more supported task (i.e. is available but not accessible) has a distinct neural signature compared with non-available information. For verbal paired-associates, an availability signal has been revealed in left middle temporal cortex, an area potentially involved in the storage of such information, raising the possibility that availability signals are expressed in modality-specific storage sites. In the present study subjects encoded pictures and sounds representing concrete objects. One day later, during fMRI scanning, a verbal cued-recall task was administrated followed by a post-scan recognition task. Items remembered on both tasks were classified as accessible; items not remembered on the first but on the second task were classified as available; and items not remembered on any of the tasks were classified as not available. Multivariate partial-least-squares analyses revealed a modality-independent accessibility network with dominant contributions of left inferior parietal cortex, left inferior frontal cortex, and left hippocampus. Additionally, a modality-specific availability network was identified which included increased activity in visual regions for available pictorial information and in auditory regions for available sound information. These findings show that availability in memory, at least in part, is characterized by systematic changes in brain activity in sensory regions whereas memory access reflects differential activity in a modality-independent, conceptual network, thus indicating qualitative differences between availability and accessibility in memory.

  • 18. Sanyal, Nilotpal
    et al.
    Lo, Min-Tzu
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Djurovic, Srdjan
    Andreassen, Ole A.
    Johnson, Valen E.
    Chen, Chi-Hua
    GWASinlps: non-local prior based iterative SNP selection tool for genome-wide association studies2019In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Motivation: Multiple marker analysis of the genome-wide association study (GWAS) data has gained ample attention in recent years. However, because of the ultra high-dimensionality of GWAS data, such analysis is challenging. Frequently used penalized regression methods often lead to large number of false positives, whereas Bayesian methods are computationally very expensive. Motivated to ameliorate these issues simultaneously, we consider the novel approach of using non-local priors in an iterative variable selection framework.

    Results: We develop a variable selection method, named, iterative non-local prior based selection for GWAS, or GWASinlps, that combines, in an iterative variable selection framework, the computational efficiency of the screen-and-select approach based on some association learning and the parsimonious uncertainty quantification provided by the use of non-local priors. The hallmark of our method is the introduction of 'structured screen-and-select' strategy, that considers hierarchical screening, which is not only based on response-predictor associations, but also based on response-response associations and concatenates variable selection within that hierarchy. Extensive simulation studies with single nucleotide polymorphisms having realistic linkage disequilibrium structures demonstrate the advantages of our computationally efficient method compared to several frequentist and Bayesian variable selection methods, in terms of true positive rate, false discovery rate, mean squared error and effect size estimation error. Further, we provide empirical power analysis useful for study design. Finally, a real GWAS data application was considered with human height as phenotype.

  • 19. Smeland, Olav B.
    et al.
    Frei, Oleksandr
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California San Diego, La Jolla; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla.
    Hill, W. David
    Li, Wen
    Wang, Yunpeng
    Krull, Florian
    Bettella, Francesco
    Eriksen, Jon A.
    Witoelar, Aree
    Davies, Gail
    Fan, Chun C.
    Thompson, Wesley K.
    Lam, Max
    Lencz, Todd
    Chen, Chi-Hua
    Ueland, Torill
    Jönsson, Erik G.
    Djurovic, Srdjan
    Deary, Ian J.
    Dale, Anders M.
    Andreassen, Ole A.
    Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 10, p. 1065-1075Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. OBJECTIVE To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, aswell as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. DESIGN, SETTING, AND PARTICIPANTS Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [ cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). MAIN OUTCOMES AND MEASURES Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. RESULTS Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 x 10(-7)), general cognitive function (z score, - 4.43; P = 9.42 x 10(-6)), and verbal-numerical reasoning (z score, - 5.43; P = 5.64 x 10(-8)). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. CONCLUSIONS AND RELEVANCE The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

  • 20. Smeland, Olav B.
    et al.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Yunpeng
    Hill, W. David
    Davies, Gail
    Frei, Oleksandr
    Li, Wen
    Eriksen, Jon A.
    Witoelar, Aree
    Bettella, Francesco
    Fan, Chun C.
    Thompson, Wes
    Chen, Chi-Hua
    Djurovic, Srdjan
    Deary, Ian J.
    Dale, Anders M.
    Andreassen, Ole A.
    Shared genetic variants between schizophrenia and general cognitive function indicate common molecular genetic mechanisms2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S410-S410Article in journal (Other academic)
    Abstract [en]

    Background: Schizophrenia (SCZ) is a severe mental disorder characterized by widespread cognitive impairments including deficits in learning, memory, processing speed, attention and executive functioning. Although cognitive deficits are a strong predictor of functional outcome in SCZ, current treatment strategies largely fail to ameliorate these impairments. Thus, in order to develop more efficient treatment strategies in SCZ, a better understanding of the pathogenesis of these cognitive deficits is needed. Given that both SCZ and cognitive ability are substantially heritable, we here aimed to determine whether SCZ share genetic influences with general cognitive function (COG), a phenotype that captures the shared variation in performance across several cognitive domains. Methods: We analyzed GWAS results in the form of summary statistics (p-values and z-scores) from SCZ (the Psychiatric Genomics Consortium; n=82 315) and COG (CHARGE Consortium; n=53 949). We applied a conditional false discovery rate (FDR) framework. By leveraging SNP-associations in a secondary trait (SCZ or COG), the conditional FDR approach increases power to detect loci in the primary trait (COG or SCZ), regardless of the directions of allelic effects of the risk loci. We then applied the conjunction FDR to identify shared loci between the phenotypes. The conjunction FDR is defined as the maximum of the conditional FDRs for both directions, and we used an overall FDR threshold of 0.05. Results: To visualize pleiotropic enrichment, we constructed conditional Q-Q plots which indicate substantial polygenetic overlap between SCZ and COG. For progressively stringent p-value thresholds for SCZ SNPs, we found approximately 150-fold enrichment for COG. For progressively stringent p-value thresholds for COG SNPs, we found approximately 100-fold enrichment for SCZ. We then used the conjunction FDR and identified fourteen independent loci shared between SCZ and COG. The majority of the shared loci show inverse associations in SCZ and COG, in line with the observed cognitive dysfunction in SCZ. Discussion: Our preliminary findings indicate shared molecular genetic mechanisms between SCZ and COG, which may provide important new insights into the pathogenesis of cognitive dysfunction in SCZ.

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