Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

✍ Scribed by Purcell, Shaun M.; Wray, Naomi R.; Stone, Jennifer L.; Visscher, Peter M.; O'Donovan, Michael C.; Sullivan, Patrick F.; Sklar, Pamela; Purcell (Leader), Shaun M.; Stone, Jennifer L.; Sullivan, Patrick F.; Ruderfer, Douglas M.; McQuillin, Andrew; Morris, Derek W.; O’Dushlaine, Colm T.; Corvin, Aiden; Holmans, Peter A.; O’Donovan, Michael C.; Sklar, Pamela; Wray, Naomi R.; Macgregor, Stuart; Sklar, Pamela; Sullivan, Patrick F.; O’Donovan, Michael C.; Visscher, Peter M.; Gurling, Hugh; Blackwood, Douglas H. R.; Corvin, Aiden; Craddock, Nick J.; Gill, Michael; Hultman, Christina M.; Kirov, George K.; Lichtenstein, Paul; McQuillin, Andrew; Muir, Walter J.; O'Donovan, Michael C.; Owen, Michael J.; Pato, Carlos N.; Purcell, Shaun M.; Scolnick, Edward M.; St Clair, David; Stone, Jennifer L.; Sullivan, Patrick F.; Sklar (Leader), Pamela; O'Donovan, Michael C.; Kirov, George K.; Craddock, Nick J.; Holmans, Peter A.; Williams, Nigel M.; Georgieva, Lyudmila; Nikolov, Ivan; Norton, N.; Williams, H.; Toncheva, Draga; Milanova, Vihra; Owen, Michael J.; Hultman, Christina M.; Lichtenstein, Paul; Thelander, Emma F.; Sullivan, Patrick; Morris, Derek W.; O'Dushlaine, Colm T.; Kenny, Elaine; Quinn, Emma M.; Gill, Michael; Corvin, Aiden; McQuillin, Andrew; Choudhury, Khalid; Datta, Susmita; Pimm, Jonathan; Thirumalai, Srinivasa; Puri, Vinay; Krasucki, Robert; Lawrence, Jacob; Quested, Digby; Bass, Nicholas; Gurling, Hugh; Crombie, Caroline; Fraser, Gillian; Leh Kuan, Soh; Walker, Nicholas; St Clair, David; Blackwood, Douglas H. R.; Muir, Walter J.; McGhee, Kevin A.; Pickard, Ben; Malloy, Pat; Maclean, Alan W.; Van Beck, Margaret; Wray, Naomi R.; Macgregor, Stuart; Visscher, Peter M.; Pato, Michele T.; Medeiros, Helena; Middleton, Frank; Carvalho, Celia; Morley, Christopher; Fanous, Ayman; Conti, David; Knowles, James A.; Paz Ferreira, Carlos; Macedo, Antonio; Helena Azevedo, M.; Pato, Carlos N.; Stone, Jennifer L.; Ruderfer, Douglas M.; Kirby, Andrew N.; Ferreira, Manuel A. R.; Daly, M

• Book ID: 109898311
• Publisher: Nature Publishing Group
• Year: 2009
• Tongue: English
• Weight: 441 KB
• Volume: 460
• Category: Article
• ISSN: 0028-0836
• DOI: 10.1038/nature08185

✦ Synopsis

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80% 1,2 . We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.We genotyped the International Schizophrenia Consortium (ISC) case-control sample for up to ,1 million single nucleotide polymorphisms (SNPs), augmented by imputed common HapMap SNPs. In the genome-wide association study (GWAS; genomic control l GC 5 1.09; Supplementary Table and Supplementary Figs ), the most associated genotyped SNP (P 5 3.4 3 10 27 ) was located in the first intron of myosin XVIIIB (MYO18B) on chromosome 22. The second strongest association comprised more than 450 SNPs on chromosome 6p spanning the major histocompatibility complex (MHC; Fig. ). There is some evidence for between-site heterogeneity in both allele frequencies and odds ratios (Table ). We observed associations consistent with previous reports in the 22q11.2 deletion region and ZNF804A (ref. 3) (Supplementary Total sample Cochran-Mantel-Haenszel P 5 4 3 10 27 ; Breslow-Day heterogeneity test P 5 0.012 (d.f. 5 6). * SNP failed genotyping quality control in UCL. Allele frequency for UCL based on imputed genotypes. { Frequency is estimated population frequency.