Comparative genetic architectures of schizophrenia in East Asian and European populations

Abstract

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.

Figure 1 ∣. Genetic associations in East Asian populations.

Manhattan plot for schizophrenia genetic associations using East Asian samples (stages 1 and 2; n = 22,778 cases; 35,362 controls).

Figure 2 ∣. Schizophrenia associations in EUR and EAS samples.

Manhattan plot for the schizophrenia genetic associations from the EAS (stages 1 and 2) + EUR meta-analysis (n = 56,418 cases; 78,818 controls).

Figure 3 ∣. Trans-ethnic fine-mapping improves resolution.

a, An association was mapped to a single variant (rs11587347) after adding EAS samples and using the trans-ancestry fine-mapping approach. Regional association plots were generated using http://locuszoom.org/ and LD from 1000 Genomes Project Phase 3 EUR subjects. b, LD with the lead variant (rs11587347). c, The lead variant (rs11587347) has strong association significance in both populations and low heterogeneity across populations. a-c, n (EAS stage 1) = 13,305 cases, 16,244 controls; n (EUR PGC2) = 33,640 cases, 43,456 controls. d, Number of variants in the 95% credible set using the trans-ancestry (EAS+EUR) and published fine-mapping approaches (EUR only).

Figure 4 ∣. Genetic risk prediction accuracy in EAS from EAS or EUR training data.

Polygenic risk scores were computed with GWAS summary statistics from EAS and EUR populations as training sets. EAS risk alleles and weights were computed with a leave-one-out meta-analysis approach across the 13 stage 1 samples. Error bars indicate the 95% confidence interval. LD panel for clumping is from EUR and EAS 1000 Genomes Phase 3 samples. a, Case/control variance explained in EAS samples by variants from EAS and EUR training data with a P-value more significant than the threshold. b, Case/control variance explained by the n most significant independent variants. a-b, For EAS stage 1: 13,305 cases and 16,244 controls; For EUR 33,640 cases and 43,456 controls.