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.1 Recent studies implicate rare, large, high-penetrance copy number variants (CNVs) in some cases2, but it is not known what genes or biological mechanisms underlie susceptibility. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended Major Histocompatibility Complex (MHC) region on chromosome 6. We carried out a genome-wide association study (GWAS) 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 (ISC) and SGENE datasets. 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 × 10−9). This region includes a histone gene cluster and several immunity-related genes, possibly implicating etiologic mechanisms involving chromatin modification, transcriptional regulation, auto-immunity 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.

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

“…Recent meta-analyses of combined SNP data from several large genomewide scans suggests a significant association with several markers spanning the HMC region on chromosome 6. 1, 28 This finding and our gene-expression results lead further support to an immune component being involved with schizophrenia risk and functionality.…”

“…Nonetheless, owing to the recent break-through of the development of high-density SNP arrays, several large population-based association studies provide unbiased genome scans in search of schizophrenia susceptibility genes. 1, 28 Various statistically significant markers spanning a region of HMC loci and histone gene cluster on chromosome 6p21.3-22.1, a marker located upstream of the neurograinin gene (NRGN), a marker in intron 4 of transcription factor 4, 1 and markers in genes including CACNA1C, CSF2RB, CACNA1B and DGKI have been identified. 28 These findings are partially consistent with our immune-related findings using expression-genetic approach.…”

Genetic studies of schizophrenia: an update

“…It has long been speculated that the immune system is involved in SCZ, so the finding that the genetic effects are enriched in the MHC region or even in regions outside the MHC that are also involved in acquired immunity is consistent with this hypothesis. After the first GWAS reporting on the MHC region, a total of 30 loci across the whole genome were reported to be associated with SCZ by 2013 [15][16][17][18][19][20][21][22][23][24][25] , including the genes for transcription factor 4 (TCF4), neurogranin (NRGN), and DPYD/MIR317 that are known to play crucial roles in brain development. Of these GWASs, only two used…”

The pursuit of genome-wide association studies: where are we now?

“…On the other hand, for schizophrenia, the association with SNPs located in the major histocompatibility complex region was first demonstrated consistently by three GWAS implicating an immune component in the patho-physiology of the disease. [123][124][125] Several studies of genome-wide associations of structural variations and CNVs with schizophrenia have been quite successful and have also yielded some interesting and insightful findings about the genetic architecture of this complex disease, 126 but they are not reviewed here.…”