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In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of ~1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
Schizophrenia is a common disorder caused by the interaction of multiple genetic and environmental factors, but its etiology has proved difficult to determine1. In particular, genetic research has been hindered by the largely nonmendelian patterns of familial transmission and the lack of disease-specific neuropathological features or biomarkers2. Although the heritability of schizophrenia is high (~80%), nongenetic factors likely also considerably modify disease risk3, further complicating the identification of susceptibility genes. Genome-wide linkage analyses have identified several chromosomal regions thought to harbor schizophrenia genes, but only a few overlap across studies4,5. To identify the potential loci underlying these signals, well over 1,000 studies have been published claiming or refuting genetic association between putative schizophrenia genes and affection status, onset age and/or certain endophenotypes. Currently, about 150 genetic association studies are published each year, at increasing pace (Supplementary Fig. 1 online). Despite these efforts, no single gene or genetic variant has been established as a bona fide schizophrenia susceptibility gene, at least not with the confidence accorded to other genes associated with susceptibility to complex disease, such as APOE in Alzheimer's disease6 or CFH in...