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  • 1. Auer-Grumbach, Michaela
    et al.
    Toegel, Stefan
    Schabhuettl, Maria
    Weinmann, Daniela
    Chiari, Catharina
    Bennett, David L. H.
    Beetz, Christian
    Klein, Dennis
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Boehme, Ilka
    Fink-Puches, Regina
    Gonzalez, Michael
    Harms, Matthew B.
    Motley, William
    Reilly, Mary M.
    Renner, Wilfried
    Rudnik-Schoeneborn, Sabine
    Schlotter-Weigel, Beate
    Themistocleous, Andreas C.
    Weishaupt, Jochen H.
    Ludolph, Albert C.
    Wieland, Thomas
    Tao, Feifei
    Abreu, Lisa
    Windhager, Reinhard
    Zitzelsberger, Manuela
    Strom, Tim M.
    Walther, Thomas
    Scherer, Steven S.
    Zuchner, Stephan
    Martini, Rudolf
    Senderek, Jan
    Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies2016Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, nr 3, s. 607-623Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.

  • 2.
    Bhattacharjee, Samsiddhi
    et al.
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Rajaraman, Preetha
    Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Jacobs, Kevin B
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Wheeler, William A
    Information Management Services, Rockville, MD 20852, USA.
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hartge, Patricia
    Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    GliomaScan Consortium,
    GliomaScan Consortium investigators and affiliations are available in the Supplemental Data.
    Yeager, Meredith
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Chung, Charles C
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chanock, Stephen J
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chatterjee, Nilanjan
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits2012Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, nr 5, s. 821-835Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies.

  • 3. Blaydon, Diana C
    et al.
    Lind, Lisbet K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Plagnol, Vincent
    Linton, Kenneth J
    Smith, Francis JD
    Wilson, Neil J
    McLean, WH Irwin
    Munro, Colin S
    South, Andrew P
    Leigh, Irene M
    O'Toole, Edel A
    Lundström, Anita
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Kelsell, David P
    Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma2013Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, nr 2, s. 330-335Artikel i tidskrift (Refereegranskat)
  • 4. Han, Buhm
    et al.
    Diogo, Dorothee
    Eyre, Steve
    Kallberg, Henrik
    Zhernakova, Alexandra
    Bowes, John
    Padyukov, Leonid
    Okada, Yukinori
    Gonzalez-Gay, Miguel A.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Martin, Javier
    Huizinga, Tom W. J.
    Plenge, Robert M.
    Worthington, Jane
    Gregersen, Peter K.
    Klareskog, Lars
    de Bakker, Paul I. W.
    Raychaudhuri, Soumya
    Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity2014Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 94, nr 4, s. 522-532Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.

  • 5. Kapferer-Seebacher, Ines
    et al.
    Pepin, Melanie
    Werner, Roland
    Aitman, Timothy J
    Nordgren, Ann
    Stoiber, Heribert
    Thielens, Nicole
    Gaboriaud, Christine
    Amberger, Albert
    Schossig, Anna
    Gruber, Robert
    Giunta, Cecilia
    Bamshad, Michael
    Björck, Erik
    Chen, Christina
    Chitayat, David
    Dorschner, Michael
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Hale, Christopher J
    Hanna, David
    Hennies, Hans Christian
    Heiss-Kisielewsky, Irene
    Lindstrand, Anna
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Mitchell, Anna L
    Nickerson, Deborah A
    Reinstein, Eyal
    Rohrbach, Marianne
    Romani, Nikolaus
    Schmuth, Matthias
    Silver, Rachel
    Taylan, Fulya
    Vandersteen, Anthony
    Vandrovcova, Jana
    Weerakkody, Ruwan
    Yang, Margaret
    Pope, F Michael
    Byers, Peter H
    Zschocke, Johannes
    Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement2016Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, nr 5, s. 1005-1014Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

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  • 6. Lee, YA
    et al.
    Rüschendorf, F
    Windemuth, C
    Schmitt-Egenolf, Marcus
    Department of Dermatology, Norwegian University of Science and Technology, Trondheim, Norway.
    Stadelmann, A
    Nürnberg, G
    Ständer, M
    Wienker, TF
    Reis, A
    Traupe, H
    Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p132000Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 67, nr 4, s. 1020-1024Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.

  • 7. Li, Chen
    et al.
    Stoma, Svetlana
    Lotta, Luca A.
    Warner, Sophie
    Albrecht, Eva
    Allione, Alessandra
    Arp, Pascal P.
    Broer, Linda
    Buxton, Jessica L.
    Da Silva Couto Alves, Alexessander
    Deelen, Joris
    Fedko, Iryna O.
    Gordon, Scott D.
    Jiang, Tao
    Karlsson, Robert
    Kerrison, Nicola
    Loe, Taylor K.
    Mangino, Massimo
    Milaneschi, Yuri
    Miraglio, Benjamin
    Pervjakova, Natalia
    Russo, Alessia
    Surakka, Ida
    van der Spek, Ashley
    Verhoeven, Josine E.
    Amin, Najaf
    Beekman, Marian
    Blakemore, Alexandra I.
    Canzian, Federico
    Hamby, Stephen E.
    Hottenga, Jouke-Jan
    Jones, Peter D.
    Jousilahti, Pekka
    Mägi, Reedik
    Medland, Sarah E.
    Montgomery, Grant W.
    Nyholt, Dale R.
    Perola, Markus
    Pietiläinen, Kirsi H.
    Salomaa, Veikko
    Sillanpää, Elina
    Suchiman, H. Eka
    van Heemst, Diana
    Willemsen, Gonneke
    Agudo, Antonio
    Boeing, Heiner
    Boomsma, Dorret I.
    Chirlaque, Maria-Dolores
    Fagherazzi, Guy
    Ferrari, Pietro
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, 20502 Malmö Sweden.
    Gieger, Christian
    Eriksson, Johan Gunnar
    Gunter, Marc
    Hagg, Sara
    Hovatta, Iiris
    Imaz, Liher
    Kaprio, Jaakko
    Kaaks, Rudolf
    Key, Timothy
    Krogh, Vittorio
    Martin, Nicholas G.
    Melander, Olle
    Metspalu, Andres
    Moreno, Concha
    Onland-Moret, N. Charlotte
    Nilsson, Peter
    Ong, Ken K.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Pedersen, Nancy L.
    Penninx, Brenda W. J. H.
    Quirós, J. Ramón
    Riitta Jarvelin, Marjo
    Rodríguez-Barranco, Miguel
    Scott, Robert A.
    Severi, Gianluca
    Slagboom, P. Eline
    Spector, Tim D.
    Tjonneland, Anne
    Trichopoulou, Antonia
    Tumino, Rosario
    Uitterlinden, André G.
    van der Schouw, Yvonne T.
    van Duijn, Cornelia M.
    Weiderpass, Elisabete
    Denchi, Eros Lazzerini
    Matullo, Giuseppe
    Butterworth, Adam S.
    Danesh, John
    Samani, Nilesh J.
    Wareham, Nicholas J.
    Nelson, Christopher P.
    Langenberg, Claudia
    Codd, Veryan
    Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length2020Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 106, nr 3, s. 389-404Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

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  • 8. Lindholm, E
    et al.
    Ekholm, B
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Shaw, S
    Jalonen, P
    Johansson, G
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Pettersson, U
    Sherrington, R
    Adolfsson, R
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Jazin, E
    A schizophrenia-susceptibility locus at 6q25, in one of the world´s largest reported pedigree2001Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, nr 1, s. 96-105Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.

  • 9. Machiela, Mitchell J.
    et al.
    Zhou, Weiyin
    Sampson, Joshua N.
    Dean, Michael C.
    Jacobs, Kevin B.
    Black, Amanda
    Brinton, Louise A.
    Chang, I-Shou
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Cook, Linda S.
    Bou, Marta Crous
    De Vivo, Immaculata
    Doherty, Jennifer
    Friedenreich, Christine M.
    Gaudet, Mia M.
    Haiman, Christopher A.
    Hankinson, Susan E.
    Hartge, Patricia
    Henderson, Brian E.
    Hong, Yun-Chul
    Hosgood, H. Dean, III
    Hsiung, Chao A.
    Hu, Wei
    Hunter, David J.
    Jessop, Lea
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Robert
    Kraft, Peter
    Lan, Qing
    Lin, Dongxin
    Liu, Jianjun
    Le Marchand, Loic
    Liang, Xiaolin
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M.
    Matsuo, Keitaro
    Olson, Sara H.
    Orlow, Irene
    Park, Jae Yong
    Pooler, Loreall
    Prescott, Jennifer
    Rastogi, Radhai
    Risch, Harvey A.
    Schumacher, Fredrick
    Seow, Adeline
    Setiawan, Veronica Wendy
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    VanDen Berg, David
    Wang, Jiu-Cun
    Wentzensen, Nicolas
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Yi-Long
    Xia, Lucy
    Yang, Hannah P.
    Yang, Pan-Chyr
    Zheng, Wei
    Zhou, Baosen
    Abnet, Christian C.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Amos, Christopher
    Amundadottir, Laufey T.
    Berndt, Sonja I.
    Blot, William J.
    Bock, Cathryn H.
    Bracci, Paige M.
    Burdett, Laurie
    Buring, Julie E.
    Butler, Mary A.
    Carreon, Tania
    Chatterjee, Nilanjan
    Chung, Charles C.
    Cook, Michael B.
    Cullen, Michael
    Davis, Faith G.
    Ding, Ti
    Duell, Eric J.
    Epstein, Caroline G.
    Fan, Jin-Hu
    Figueroa, Jonine D.
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Fuchs, Charles S.
    Gao, Yu-Tang
    Gapstur, Susan M.
    Patino-Garcia, Ana
    Garcia-Closas, Montserrat
    Gaziano, J. Michael
    Giles, Graham G.
    Gillanders, Elizabeth M.
    Giovannucci, Edward L.
    Goldin, Lynn
    Goldstein, Alisa M.
    Greene, Mark H.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Harris, Curtis C.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holly, Elizabeth A.
    Hoover, Robert N.
    Hu, Nan
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Koh, Woon-Puay
    Kolonel, Laurence N.
    Kooperberg, Charles
    Krogh, Vittorio
    Kurtz, Robert C.
    LaCroix, Andrea
    Landgren, Annelie
    Landi, Maria Teresa
    Li, Donghui
    Liao, Linda M.
    Malats, Nuria
    McGlynn, Katherine A.
    McNeill, Lorna H.
    McWilliams, Robert R.
    Melin, Beatrice S.
    Mirabello, Lisa
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M.
    Prokunina-Olsson, Ludmila
    Purdue, Mark
    Qiao, You-Lin
    Rabe, Kari G.
    Rajaraman, Preetha
    Real, Francisco X.
    Riboli, Elio
    Rodriguez-Santiago, Benjamin
    Rothman, Nathaniel
    Ruder, Avima M.
    Savage, Sharon A.
    Schwartz, Ann G.
    Schwartz, Kendra L.
    Sesso, Howard D.
    Severi, Gianluca
    Silverman, Debra T.
    Spitz, Margaret R.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R.
    Teras, Lauren R.
    Tobias, Geoffrey S.
    Viswanathan, Kala
    Wacholder, Sholom
    Wang, Zhaoming
    Weinstein, Stephanie J.
    Wheeler, William
    White, Emily
    Wiencke, John K.
    Wolpin, Brian M.
    Wu, Xifeng
    Wunder, Jay S.
    Yu, Kai
    Zanetti, Krista A.
    Zeleniuch-Jacquotte, Anne
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Ziegler, Regina G.
    De Andrade, Mariza
    Barnes, Kathleen C.
    Beaty, Terri H.
    Bierut, Laura J.
    Desch, Karl C.
    Doheny, Kimberly F.
    Feenstra, Bjarke
    Ginsburg, David
    Heit, John A.
    Kang, Jae H.
    Laurie, Cecilia A.
    Li, Jun Z.
    Lowe, William L.
    Marazita, Mary L.
    Melbye, Mads
    Mirel, Daniel B.
    Murray, Jeffrey C.
    Nelson, Sarah C.
    Pasquale, Louis R.
    Rice, Kenneth
    Wiggs, Janey L.
    Wise, Anastasia
    Tucker, Margaret
    Perez-Jurado, Luis A.
    Laurie, Cathy C.
    Caporaso, Neil E.
    Yeager, Meredith
    Chanock, Stephen J.
    Characterization of Large Structural Genetic Mosaicism in Human Autosomes2015Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, nr 3, s. 487-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

  • 10. Mochel, Fanny
    et al.
    Knight, Melanie A
    Tong, Wing-Hang
    Hernandez, Dena
    Ayyad, Karen
    Taivassalo, Tanja
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Singleton, Andrew
    Rouault, Tracey A
    Fischbeck, Kenneth H
    Haller, Ronald G
    Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance2008Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 82, nr 3, s. 652-660Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.

  • 11.
    Stattin, Eva-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Wiklund, Fredrik
    Lindblom, Karin
    Onnerfjord, Patrik
    Jonsson, Björn-Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tegner, Yelverton
    Sasaki, Takako
    Struglics, André
    Lohmander, Stefan
    Dahl, Niklas
    Heinegård, Dick
    Aspberg, Anders
    A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans2010Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, nr 2, s. 126-137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.

  • 12. Sung, Yun J.
    et al.
    Winkler, Thomas W.
    de las Fuentes, Lisa
    Bentley, Amy R.
    Brown, Michael R.
    Kraja, Aldi T.
    Schwander, Karen
    Ntalla, Ioanna
    Guo, Xiuqing
    Franceschini, Nora
    Lu, Yingchang
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Li, Changwei
    Feitosa, Mary F.
    Kilpelainen, Tuomas O.
    Richard, Melissa A.
    Noordam, Raymond
    Aslibekyan, Stella
    Aschard, Hugues
    Bartz, Traci M.
    Dorajoo, Rajkumar
    Liu, Yongmei
    Manning, Alisa K.
    Rankinen, Tuomo
    Smith, Albert Vernon
    Tajuddin, Salman M.
    Tayo, Bamidele O.
    Warren, Helen R.
    Zhao, Wei
    Zhou, Yanhua
    Matoba, Nana
    Sofer, Tamar
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gandin, Ilaria
    Gao, Chuan
    Giulianini, Franco
    Goel, Anuj
    Harris, Sarah E.
    Hartwig, Fernando Pires
    Horimoto, Andrea R. V. R.
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kahonen, Mika
    Kasturiratne, Anuradhani
    Kuhnel, Brigitte
    Leander, Karin
    Lee, Wen-Jane
    Lin, Keng-Hung
    Luan, Jian' an
    McKenzie, Colin A.
    Meian, He
    Nelson, Christopher P.
    Rauramaa, Rainer
    Schupf, Nicole
    Scott, Robert A.
    Sheu, Wayne H. H.
    Stancakova, Alena
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Wang, Heming
    Wang, Yajuan
    Ware, Erin B.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Alfred, Tamuno
    Amin, Najaf
    Arking, Dan
    Aung, Tin
    Barr, R. Graham
    Bielak, Lawrence F.
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Braund, Peter S.
    Brody, Jennifer A.
    Broeckel, Ulrich
    Cabrera, Claudia P.
    Cade, Brian
    Caizheng, Yu
    Campbell, Archie
    Canouil, Mickael
    Chakravarti, Aravinda
    Chauhan, Ganesh
    Christensen, Kaare
    Cocca, Massimiliano
    Collins, Francis S.
    Connell, John M.
    de Mutsert, Renee
    de Silva, H. Janaka
    Debette, Stephanie
    Dorr, Marcus
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Evangelou, Evangelos
    Faul, Jessica D.
    Fisher, Virginia A.
    Forouhi, Nita G.
    Franco, Oscar H.
    Friedlander, Yechiel
    Gao, He
    Gigante, Bruna
    Graff, Misa
    Gu, C. Charles
    Gu, Dongfeng
    Gupta, Preeti
    Hagenaars, Saskia P.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hirata, Makoto
    Hofman, Albert
    Howard, Barbara V.
    Hunt, Steven
    Irvin, Marguerite R.
    Jia, Yucheng
    Joehanes, Roby
    Justice, Anne E.
    Katsuya, Tomohiro
    Kaufman, Joel
    Kerrison, Nicola D.
    Khor, Chiea Chuen
    Koh, Woon-Puay
    Koistinen, Heikki A.
    Komulainen, Pirjo
    Kooperberg, Charles
    Krieger, Jose E.
    Kubo, Michiaki
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lehne, Benjamin
    Lewis, Cora E.
    Li, Yize
    Lim, Sing Hui
    Lin, Shiow
    Liu, Ching-Ti
    Liu, Jianjun
    Liu, Jingmin
    Liu, Kiang
    Liu, Yeheng
    Loh, Marie
    Lohman, Kurt K.
    Long, Jirong
    Louie, Tin
    Magi, Reedik
    Mahajan, Anubha
    Meitinger, Thomas
    Metspalu, Andres
    Milani, Lili
    Momozawa, Yukihide
    Morris, Andrew P.
    Mosley, Thomas H., Jr.
    Munson, Peter
    Murray, Alison D.
    Nalls, Mike A.
    Nasri, Ubaydah
    Norris, Jill M.
    North, Kari
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R.
    Palmer, Nicholette D.
    Pankow, James S.
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Raitakari, Olli T.
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Rice, Treva K.
    Ridker, Paul M.
    Robino, Antonietta
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Sabanayagam, Charumathi
    Salako, Babatunde L.
    Sandow, Kevin
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Scott, William R.
    Seshadri, Sudha
    Sever, Peter
    Sitlani, Colleen M.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Ultterlinden, Andre G.
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya X.
    Bin Wei, Wen
    Williams, Christine
    Wilson, Gregory
    Wojczynski, Mary K.
    Yao, Jie
    Yuan, Jian-Min
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Chen, Yii-Der Ida
    de Faire, Ulf
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Forrester, Terrence
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA, USA.
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Horta, Bernardo Lessa
    Hung, Yi-Jen
    Jonas, Jost B.
    Kato, Norihiro
    Kooner, Jaspal S.
    Laakso, Markku
    Lehtimaki, Terho
    Liang, Kae-Woei
    Magnusson, Patrik K. E.
    Newman, Anne B.
    Oldehinkel, Albertine J.
    Pereira, Alexandre C.
    Redline, Susan
    Rettig, Rainer
    Samani, Nilesh J.
    Scott, James
    Shu, Xiao-Ou
    van der Harst, Pim
    Wagenknecht, Lynne E.
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wickremasinghe, Ananda R.
    Wu, Tangchun
    Zheng, Wei
    Kamatani, Yoichiro
    Laurie, Cathy C.
    Bouchard, Claude
    Cooper, Richard S.
    Evans, Michele K.
    Gudnason, Vilmundur
    Kardia, Sharon L. R.
    Kritchevsky, Stephen B.
    Levy, Daniel
    O'Connell, Jeff R.
    Psaty, Bruce M.
    van Dam, Rob M.
    Sims, Mario
    Arnett, Donna K.
    Mook-Kanamori, Dennis O.
    Kelly, Tanika N.
    Fox, Ervin R.
    Hayward, Caroline
    Fornage, Myriam
    Rotimi, Charles N.
    Province, Michael A.
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Loos, Ruth J. F.
    Reiner, Alex P.
    Rotter, Jerome I.
    Zhu, Xiaofeng
    Bierut, Laura J.
    Gauderman, W. James
    Caulfield, Mark J.
    Elliott, Paul
    Rice, Kenneth
    Munroe, Patricia B.
    Morrison, Alanna C.
    Cupples, L. Adrienne
    Rao, Dabeeru C.
    Chasman, Daniel I.
    A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure2018Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, nr 3, s. 375-400Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).

  • 13. Terao, Chikashi
    et al.
    Brynedal, Boel
    Chen, Zuomei
    Jiang, Xia
    Westerlind, Helga
    Hansson, Monika
    Jakobsson, Per-Johan
    Lundberg, Karin
    Skriner, Karl
    Serre, Guy
    Ronnelid, Johan
    Mathsson-Alm, Linda
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Padyukov, Leonid
    Gregersen, Peter K.
    Barton, Anne
    Alfredsson, Lars
    Klareskog, Lars
    Raychaudhuri, Soumya
    Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype2019Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, nr 3, s. 616-624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(−) RA-affected case subjects separately. In CCP2(−) RA, we observed that the association between CCP2(−) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10−17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

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  • 14. Thomas, Minta
    et al.
    Sakoda, Lori C.
    Hoffmeister, Michael
    Rosenthal, Elisabeth A.
    Lee, Jeffrey K.
    van Duijnhoven, Franzel J. B.
    Platz, Elizabeth A.
    Wu, Anna H.
    Dampier, Christopher H.
    de la Chapelle, Albert
    Wolk, Alicja
    Joshi, Amit D.
    Burnett-Hartman, Andrea
    Gsur, Andrea
    Lindblom, Annika
    Castells, Antoni
    Win, Aung Ko
    Namjou, Bahram
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Tangen, Catherine M.
    He, Qianchuan
    Li, Christopher, I
    Schafmayer, Clemens
    Joshu, Corinne E.
    Ulrich, Cornelia M.
    Bishop, D. Timothy
    Buchanan, Daniel D.
    Schaid, Daniel
    Drew, David A.
    Muller, David C.
    Duggan, David
    Crosslin, David R.
    Albanes, Demetrius
    Giovannucci, Edward L.
    Larson, Eric
    Qu, Flora
    Mentch, Frank
    Giles, Graham G.
    Hakonarson, Hakon
    Hampel, Heather
    Stanaway, Ian B.
    Figueiredo, Jane C.
    Huyghe, Jeroen R.
    Minnier, Jessica
    Chang-Claude, Jenny
    Hampe, Jochen
    Harley, John B.
    Visvanathan, Kala
    Curtis, Keith R.
    Offit, Kenneth
    Li, Li
    Le Marchand, Loic
    Vodickova, Ludmila
    Gunter, Marc J.
    Jenkins, Mark A.
    Slattery, Martha L.
    Lemire, Mathieu
    Woods, Michael O.
    Song, Mingyang
    Murphy, Neil
    Lindor, Noralane M.
    Dikilitas, Ozan
    Pharoah, Paul D. P.
    Campbell, Peter T.
    Newcomb, Polly A.
    Milne, Roger L.
    MacInnis, Robert J.
    Castellvi-Bel, Sergi
    Ogino, Shuji
    Berndt, Sonja, I
    Bezieau, Stephane
    Thibodeau, Stephen N.
    Gallinger, Steven J.
    Zaidi, Syed H.
    Harrison, Tabitha A.
    Keku, Temitope O.
    Hudson, Thomas J.
    Vymetalkova, Veronika
    Moreno, Victor
    Martin, Vicente
    Arndt, Volker
    Wei, Wei-Qi
    Chung, Wendy
    Su, Yu-Ru
    Hayes, Richard B.
    White, Emily
    Vodicka, Pavel
    Casey, Graham
    Gruber, Stephen B.
    Schoen, Robert E.
    Chan, Andrew T.
    Potter, John D.
    Brenner, Hermann
    Jarvik, Gail P.
    Corley, Douglas A.
    Peters, Ulrike
    Hsu, Li
    Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk2020Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 107, nr 3, s. 432-444Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

  • 15.
    Thomas, Minta
    et al.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Sakoda, Lori C.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    Hoffmeister, Michael
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Rosenthal, Elisabeth A.
    Department of Medicine (Medical Genetics), University of Washington Medical Center, WA, Seattle, United States.
    Lee, Jeffrey K.
    Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    van Duijnhoven, Franzel J.B.
    Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands.
    Platz, Elizabeth A.
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, MD, Baltimore, United States.
    Wu, Anna H.
    University of Southern California, Preventative Medicine, CA, Los Angeles, United States.
    Dampier, Christopher H.
    Department of Surgery, University of Virginia Health System, VA, Charlottesville, United States.
    de la Chapelle, Albert
    Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, OH, Columbus, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Joshi, Amit D.
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Burnett-Hartman, Andrea
    Institute for Health Research, Kaiser Permanente Colorado, CO, Denver, United States.
    Gsur, Andrea
    Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
    Lindblom, Annika
    Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Castells, Antoni
    Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
    Win, Aung Ko
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, VIC, Melbourne, Australia.
    Namjou, Bahram
    Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, OH, Cincinnati, United States; University of Cincinnati College of Medicine, OH, Cincinnati, United States; Cincinnati VA Medical Center, OH, Cincinnati, United States.
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tangen, Catherine M.
    SWOG Statistical Center, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    He, Qianchuan
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Li, Christopher I.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Schafmayer, Clemens
    Department of General Surgery, University Hospital Rostock, Rostock, Germany.
    Joshu, Corinne E.
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, MD, Baltimore, United States.
    Ulrich, Cornelia M.
    Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, UT, Salt Lake City, United States.
    Bishop, D. Timothy
    Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
    Buchanan, Daniel D.
    University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, VIC, Parkville, Australia; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, VIC, Parkville, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, VIC, Parkville, Australia.
    Schaid, Daniel
    Department of Health Sciences Research, Mayo Clinic, MN, Rochester, United States.
    Drew, David A.
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States.
    Muller, David C.
    School of Public Health, Imperial College London, London, United Kingdom.
    Duggan, David
    Translational Genomics Research Institute - An Affiliate of City of Hope, AZ, Phoenix, United States.
    Crosslin, David R.
    Department of Bioinformatics and Medical Education, University of Washington Medical Center, WA, Seattle, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Giovannucci, Edward L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, Boston, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States.
    Larson, Eric
    Kaiser Permanente Washington Research Institute, WA, Seattle, United States.
    Qu, Flora
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Mentch, Frank
    Center for Applied Genomics, Children's Hospital of Philadelphia, PA, Philadelphia, United States.
    Giles, Graham G.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, VIC, Melbourne, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, VIC, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Clayton, Australia.
    Hakonarson, Hakon
    Center for Applied Genomics, Children's Hospital of Philadelphia, PA, Philadelphia, United States.
    Hampel, Heather
    Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, OH, Columbus, United States.
    Stanaway, Ian B.
    Department of Medicine (Medical Genetics), University of Washington Medical Center, WA, Seattle, United States.
    Figueiredo, Jane C.
    Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, CA, Los Angeles, United States; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Huyghe, Jeroen R.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Minnier, Jessica
    School of Public Health, Oregon Health & Science University, OR, Portland, United States.
    Chang-Claude, Jenny
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
    Hampe, Jochen
    Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
    Harley, John B.
    Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, OH, Cincinnati, United States; University of Cincinnati College of Medicine, OH, Cincinnati, United States; Cincinnati VA Medical Center, OH, Cincinnati, United States.
    Visvanathan, Kala
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, MD, Baltimore, United States.
    Curtis, Keith R.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Offit, Kenneth
    Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Medicine, Weill Cornell Medical College, NY, United States.
    Li, Li
    Department of Family Medicine, University of Virginia, VA, Charlottesville, United States.
    Le Marchand, Loic
    University of Hawaii Cancer Center, HI, Honolulu, United States.
    Vodickova, Ludmila
    Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
    Gunter, Marc J.
    Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Jenkins, Mark A.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, VIC, Melbourne, Australia.
    Slattery, Martha L.
    Department of Internal Medicine, University of Utah, UT, Salt Lake City, United States.
    Lemire, Mathieu
    PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Canada.
    Woods, Michael O.
    Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
    Song, Mingyang
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States.
    Murphy, Neil
    Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Lindor, Noralane M.
    Department of Health Science Research, Mayo Clinic, AZ, Scottsdale, United States.
    Dikilitas, Ozan
    Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, United States.
    Pharoah, Paul D.P.
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Campbell, Peter T.
    Behavioral and Epidemiology Research Group, American Cancer Society, GA, Atlanta, United States.
    Newcomb, Polly A.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; School of Public Health, University of Washington, WA, Seattle, United States.
    Milne, Roger L.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, VIC, Melbourne, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, VIC, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Clayton, Australia.
    MacInnis, Robert J.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, VIC, Melbourne, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, VIC, Melbourne, Australia.
    Castellví-Bel, Sergi
    Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
    Ogino, Shuji
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Broad Institute of Harvard and MIT, MA, Cambridge, United States; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States; Department of Oncologic Pathology, Dana-Farber Cancer Institute, MA, Boston, United States.
    Berndt, Sonja I.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Bézieau, Stéphane
    Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
    Thibodeau, Stephen N.
    Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, MN, Rochester, United States.
    Gallinger, Steven J.
    Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
    Zaidi, Syed H.
    Ontario Institute for Cancer Research, Toronto, Canada.
    Harrison, Tabitha A.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Keku, Temitope O.
    Center for Gastrointestinal Biology and Disease, University of North Carolina, NC, Chapel Hill, United States.
    Hudson, Thomas J.
    Ontario Institute for Cancer Research, Toronto, Canada.
    Vymetalkova, Veronika
    Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
    Moreno, Victor
    Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain; ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
    Martín, Vicente
    CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Biomedicine Institute (IBIOMED), University of León, León, Spain.
    Arndt, Volker
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Wei, Wei-Qi
    Department of Biomedical Informatics, Vanderbilt University Medical Center, TN, Nashville, United States.
    Chung, Wendy
    Office of Research & Development, Department of Veterans Affairs, DC, Washington, United States; Departments of Pediatrics and Medicine, Columbia University Medical Center, NY, New York, United States.
    Su, Yu-Ru
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Hayes, Richard B.
    Division of Epidemiology, Department of Population Health, New York University School of Medicine, NY, New York, United States.
    White, Emily
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington, WA, Seattle, United States.
    Vodicka, Pavel
    Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
    Casey, Graham
    Center for Public Health Genomics, University of Virginia, VA, Charlottesville, United States.
    Gruber, Stephen B.
    Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Schoen, Robert E.
    Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, PA, Pittsburgh, United States.
    Chan, Andrew T.
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, Boston, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States.
    Potter, John D.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Centre for Public Health Research, Massey University, Wellington, New Zealand.
    Brenner, Hermann
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Jarvik, Gail P.
    Department of Medicine (Medical Genetics), University of Washington Medical Center, WA, Seattle, United States; Genome Sciences, University of Washington Medical Center, WA, Seattle, United States.
    Corley, Douglas A.
    Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    Peters, Ulrike
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington, WA, Seattle, United States.
    Hsu, Li
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Biostatistics, University of Washington, WA, Seattle, United States.
    Response to Li and Hopper2021Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 108, nr 3, s. 527-529Artikel i tidskrift (Refereegranskat)
  • 16. Venken, Tine
    et al.
    Claes, Stephan
    Sluijs, Samuël
    Paterson, Andrew D
    van Duijn, Cornelia
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Del-Favero, Jurgen
    Van Broeckhoven, Christine
    Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population2005Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, nr 2, s. 237-248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers similar to8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) greater than or equal to2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples similar to10 generations ago. In this similar to10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.

  • 17. Williams, N M
    et al.
    Norton, N
    Williams, H
    Ekholm, B
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap.
    Hamshere, M L
    Lindblom, Y
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Psykiatri.
    Chowdari, K V
    Cardno, A G
    Zammit, S
    Jones, L A
    Murphy, K C
    Sanders, R D
    McCarthy, G
    Gray, M Y
    Jones, G
    Holmans, P
    Nimgaonkar, V
    Adolfson, R
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Psykiatri.
    Osby, U
    Terenius, L
    Sedvall, G
    O'Donovan, M C
    Owen, M J
    A systematic genomewide linkage study in 353 sib pairs with schizophrenia.2003Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 73, nr 6, s. 1355-1367Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

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