Genome-wide association study identifies five new schizophrenia loci.
paper
Cited
Public
- Authors
- Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium
- Year
- 2011
- Journal
- Nature genetics
- PMID
- 21926974
- DOI
- 10.1038/ng.940
- PMCID
- PMC3303194
We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 Γ 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 Γ 10(-9)), ANK3 (rs10994359, P = 2.5 Γ 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 Γ 10(-9)).
Manhattan plot for stages 1 and 2. Standard βlog10 P plot of the study results. For the stage 1 results, 16 regions with one or more SNP achieving P < 10β6 are highlighted in color and labeled with the name of the nearest gene. SNPs selected for stage 2 replication are highlighted, with the resulting combined P value after replication (that is, after incorporation of stage 2 results) indicated by the large diamonds. Blue highlighting indicates SNPs that were less significantly associated after replication, and pink highlighting indicates SNPs that were more significantly associated after replication.
Regional association plots for five new schizophrenia loci. Regional P value plots for each of the five new schizophrenia loci: 1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33. Each plot shows the most associated SNP (key SNP) and its genomic region from the first column of Table 2: stage 1 scan results for each SNP Β± 200 kb to the key SNP are shown. On the x axis is the genomic position, and on the y axis is βlog10 P. Larger SNP symbols indicate higher LD (based on HapMap 3 data) to the key SNP than smaller SNP symbols. Color coding (from red to blue) denotes LD information; see also the legend within the plot.
1β18 of 18
| Name | Type |
|---|---|
| 10q24.32-q24.33 local | variant |
| 18q21.2 local | variant |
| 1p21.3 local | variant |
| 2q32.3 local | variant |
| 6p21.32-p22.1 local | variant |
| 8p23.2 local | variant |
| 8q21.3 local | variant |
| AK094607 local | gene |
| ANK3 | gene |
| bipolar disorder | phenotype |
| C10orf26 local | gene |
| CACNA1C | gene |
| CEU | cohort |
| combined dataset (stages 1 and 2) local | cohort |
| combined stage 1 and 2 analysis local | cohort |
| complex traits | phenotype |
| CSMD1 | gene |
| discovery dataset | cohort |
| GWAS of 622 parent-offspring schizophrenia trios from Bulgaria local | cohort |
| HapMap3 | cohort |
| International schizophrenia Consortium | cohort |
| ITIH3 | gene |
| ITIH4 | gene |
| MAD1L1 local | gene |
| MHC region local | variant |
| MIR137 local | drug |
| MIR137 | gene |
| MMP16 local | gene |
| Multicenter Pedigree replication sample local | cohort |
| neurogenesis | phenotype |
| neuronal maturation | phenotype |
| non-MHC SNPs local | variant |
| Nrgn | gene |
| PCGEM1 local | gene |
| psychiatric traits | phenotype |
| replication sample | cohort |
| rs10226475 local | variant |
| rs10503253 local | variant |
| rs10994359 local | variant |
| rs11191580 local | variant |
| rs1625579 local | variant |
| rs17662626 local | variant |
| rs2021722 local | variant |
| rs2239547 | variant |
| rs4687657 local | variant |
| rs4765905 local | variant |
| rs7004633 local | variant |
| rs7914558 local | variant |
| rs9272105 local | variant |
| schizoaffective disorder | phenotype |
| schizophrenia | phenotype |
| Schizophrenia Psychiatric Genome-Wide Association Study (PGC) local | cohort |
| stage 1 | cohort |
| stage 1 analysis local | cohort |
| stage 2 | cohort |
| stage 2 analysis local | cohort |
| TCF7L2 | gene |
| TSI | cohort |
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