Abstract
Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.
Highlights
Schizophrenia is a common (~0.6–1%), chronic and debilitating neuropsychiatric syndrome for which most of the variability in liability is attributable to genetic factors (~80%) [1]
We considered a region to be “fine-mapped” if the genomic interval for the reduced credible set was smaller than the corresponding interval for single nucleotide polymorphisms (SNP) with Linkage disequilibrium (LD) r2 ≥ 0.6 to the index SNP
We calculated the genomic control factor (λ) and its value scaled to a sample size of 1000 cases and 1000 controls (λ1000) from genome-wide distributions of test statistics; these values were 1.04 and 1.008 for the admixed African genome-wide association studies (GWAS), and 1.055 and 1.031 for the Latino GWAS, indicating that our results are not likely to be confounded by population substructure
Summary
Schizophrenia is a common (~0.6–1%), chronic and debilitating neuropsychiatric syndrome for which most of the variability in liability is attributable to genetic factors (~80%) [1]. The past decade has seen the successes of psychiatric GWAS abound, including the first definitive demonstration of polygenic influences on schizophrenia risk and its shared basis with bipolar disorder [14], and ever-increasing numbers of robustly associated, replicated SNP associations, culminating in the identification of 108 physically distinct risk loci for schizophrenia [12], a number which has since grown to 145 [16]. This progress can be credited to collaborative enterprise on an unprecedented scale, as exemplified by the Psychiatric Genomics Consortium (PGC), and a philosophy of data sharing that has enabled widespread meta-analysis and replication [17]. Empirical evidence indicates that at least some of this common variant attributable risk is shared between populations of European, East-Asian and African ancestry [14, 22, 23], suggesting that variation predating divergence of European and African populations harbors most of the heritability of schizophrenia
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