Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort

• Published in: Journal of psychiatric research Vol. 44; no. 12; pp. 748 - 753
• Main Authors: Athanasiu, Lavinia, Mattingsdal, Morten, Kähler, Anna K., Brown, Andrew, Gustafsson, Omar, Agartz, Ingrid, Giegling, Ina, Muglia, Pierandrea, Cichon, Sven, Rietschel, Marcella, Pietiläinen, Olli P.H., Peltonen, Leena, Bramon, Elvira, Collier, David, Clair, David St, Sigurdsson, Engilbert, Petursson, Hannes, Rujescu, Dan, Melle, Ingrid, Steen, Vidar M., Djurovic, Srdjan, Andreassen, Ole A.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.09.2010; Elsevier
• Subjects: ACSM1; Adult and adolescent clinical studies; ANK3; Ankyrins - genetics; Biological and medical sciences; Bipolar disorder; Coenzyme A Ligases - genetics; Cohort Studies; Data processing; Discovery; Europe - epidemiology; Female; Genes; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Male; Medical sciences; Mental disorders; Norway; Norway - epidemiology; PLAA; Polymorphism, Single Nucleotide - genetics; Proteins - genetics; Psychiatric genetics; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Reference Values; Replication; Retrospective Studies; Schizophrenia; Schizophrenia - epidemiology; Schizophrenia - genetics; Single-nucleotide polymorphism; Surrogates; Susceptibility; White People; Norway; Europe; GWAS; APT; ACSM1; Schizophrenia; PRIME-MD; RYR3; PCLO; RELN; SCID-I; SNP; Genome-wide association study; PHACTR1; DISC1; Psychiatric genetics; FWER; OPCML; ACSM; GAF-F; OR; GLUDP5; cPLA2; WNT7A; NRG1; ANK3; FMO3; ANO4; GAF; OTOR; PCA; RRAGC; TOP; GAF-S; LD; CDH13; PLAA; FMO6P; single nucleotide polymorphism; family-wise error rate; phosphatase and actin regulator 1; odds ratio; Thematic Organized Psychosis Research; Structured Clinical Interview for DSM-IV-TR axis I disorders; Global Assessment of Function of mental disorders symptoms; ryanoid receptor 3; cadherin 13; linkage disequilibrium; neuregulin 1; acyl-CoA synthetase medium-chain family member 1; Global Assessment of Function of mental disorders functions; ankyrin 3; disrupted in schizophrenia 1; ras-related GTP binding C; wingless-type MMTV integration site family, member 7A; Primary Care Evaluation of Mental Disorders; flavin-containing monooxygenase 6; opioid binding protein/cell adhesion molecule-like; phospholipase A2-activating protein; Affymetrix Power Tools; anocatmin 4; otoraplin; cytosolic phospholipase A2; flavin-containing monooxygenase 3; piccolo; Global Assessment of Function of mental disorders; glutamate dehydrogenase pseudogene 5; genome-wide association study; reelin; principal component analysis; Psychosis; Genetic variant; Genetics; Genetic determinism; Norwegian
• ISSN: 0022-3956; 1879-1379; 1879-1379
• DOI: 10.1016/j.jpsychires.2010.02.002

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.