Common variants on chromosome 6p22.1 are associated with schizophrenia

Abstract

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

Figure 1. Chromosome 6p22.1 Genetic association and linkage disequilibrium results in European-ancestry samples

Genome-wide significant evidence for association (P < 5 × 10⁻⁸, threshold shown by solid red line, SNPs by large red diamonds) was observed at 7 SNPs across 209 kb. P-values are shown for all genotyped and imputed SNPs (25,900,000–27,875,000 bp) for the meta-analysis of European-ancestry MGS, ISC and SGENE samples (8,008 cases, 19,077 controls). Red circles indicate other SNPs with P < 5 × 10⁻⁷. Not shown are two SNPs in HLA-DQA1 (6p21.32; lowest P = 6.88 × 10⁻⁸, 32,710,247 bp; see Supplementary Datafile 1). Locations are shown for RefSeq genes and POM121L2. Pairwise LD relationships are shown for 26 SNPs with P < 10⁻⁷ (except that SNPs 5 and 6 are shown, despite slightly larger P-values, to illustrate LD for that segment; and a SNP in strong LD with SNPs 25 and 26 is omitted). LD was computed from MGS European-ancestry genotyped and imputed SNP data. The signal is poorly localized because of strong LD: of the 7 significant SNPs, 7–8 and 9–11 are in nearly perfect LD; they are in or within ~ 30–50 kb of a cluster of 5 histone genes (HIST1H2BJ, HIST1H2AG, HIST1H2BK, HIST1H4I, HIST1H2AH; 27,208,073–27,223,325 bp). These SNPs are in moderately strong LD (r² = 0.52–0.77) with 2 other significant SNPs 70–140 kb away, upstream of PRSS16 (SNP 13) or between PRSS16 and POM121L2 (SNP18). (See Table 2 and Supplementary Figures S10–11 for additional details.)