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Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort |
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| Authors: | Lavinia Athanasiu,Morten Mattingsdal,Anna K. Kä hler,Andrew Brown,Omar Gustafsson,Ina Giegling,Sven Cichon,Marcella Rietschel,Leena Peltonen,Elvira Bramon,David St. Clair,Hannes Petursson,Ingrid Melle,Vidar M. Steen,Srdjan Djurovic,Ole A. Andreassen |
| Affiliation: | a Institute of Psychiatry, University of Oslo, P.O. 1130, Blindern, N-0318 Oslo, Norway b Department of Medical Genetics, Oslo University Hospital, Ulleval, Kirkeveien 166, N-0407 Oslo, Norway c Department of Psychiatry, Oslo University Hospital, Ulleval, Kirkeveien 166, N-0407 Oslo, Norway d Bioinformatics Core Facility, Institute of Medical Informatics, Oslo University Hospital, Montebello 0310, Norway e Department of Biostatistics, University of Oslo, Blindern, N-0318 Oslo, Norway f Department of Mathematics, University of Oslo, Blindern, N-0318 Oslo, Norway g Department of Psychiatric Research, Diakonhjemmet Hospital, Postboks 85, Vinderen, N-0319 Oslo, Norway h Division of Molecular and Clinical Neurobiology, Ludwig-Maximilians-University, Munich, Germany i Medical Genetics, GlaxoSmithKline R&D, Verona, Italy j Institute of Human Genetics, Department of Genomics, Life and Brain Centre, University of Bonn, Bonn, Germany k Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, D-52425 Juelich, Germany l Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany m Department for Molecular Medicine, National Public Health Institute, Helsinki, Finland n Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK o The Broad Institute, Cambridge, MA, USA p Division of Psychological Medicine, Institute of Psychiatry, King’s College, London, UK q Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College, London, UK r Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK s Department of General Adult Psychiatry, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland t Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany u Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Norway v Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway |
| Abstract: | We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P < 8.7 × 10−8). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value < 0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities. |
| Keywords: | ACSM, acyl-CoA synthetase medium-chain family member 1 ANK3, ankyrin 3 ANO4, anocatmin 4 APT, Affymetrix Power Tools CDH13, cadherin 13 cPLA2, cytosolic phospholipase A2 DISC1, disrupted in schizophrenia 1 FMO3, flavin-containing monooxygenase 3 FMO6P, flavin-containing monooxygenase 6 FWER, family-wise error rate GAF, Global Assessment of Function of mental disorders GAF-S, Global Assessment of Function of mental disorders symptoms GAF-F, Global Assessment of Function of mental disorders functions GLUDP5, glutamate dehydrogenase pseudogene 5 GWAS, genome-wide association study LD, linkage disequilibrium NRG1, neuregulin 1 OPCML, opioid binding protein/cell adhesion molecule-like OR, odds ratio OTOR, otoraplin PCA, principal component analysis PCLO, piccolo PHACTR1, phosphatase and actin regulator 1 PLAA, phospholipase A2-activating protein RRAGC, ras-related GTP binding C PRIME-MD, Primary Care Evaluation of Mental Disorders RELN, reelin RYR3, ryanoid receptor 3 SCID-I, Structured Clinical Interview for DSM-IV-TR axis I disorders SNP, single nucleotide polymorphism TOP, Thematic Organized Psychosis Research WNT7A, wingless-type MMTV integration site family, member 7A |
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