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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.

SUBMITTER: Lam M

PROVIDER: S-EPMC6885121 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Comparative genetic architectures of schizophrenia in East Asian and European populations.

Lam Max M Chen Chia-Yen CY Li Zhiqiang Z Martin Alicia R AR Bryois Julien J Ma Xixian X Gaspar Helena H Ikeda Masashi M Benyamin Beben B Brown Brielin C BC Liu Ruize R Zhou Wei W Guan Lili L Kamatani Yoichiro Y Kim Sung-Wan SW Kubo Michiaki M Kusumawardhani Agung A A A AAAA Liu Chih-Min CM Ma Hong H Periyasamy Sathish S Takahashi Atsushi A Xu Zhida Z Yu Hao H Zhu Feng F Chen Wei J WJ Faraone Stephen S Glatt Stephen J SJ He Lin L Hyman Steven E SE Hwu Hai-Gwo HG McCarroll Steven A SA Neale Benjamin M BM Sklar Pamela P Wildenauer Dieter B DB Yu Xin X Zhang Dai D Mowry Bryan J BJ Lee Jimmy J Holmans Peter P Xu Shuhua S Sullivan Patrick F PF Ripke Stephan S O'Donovan Michael C MC Daly Mark J MJ Qin Shengying S Sham Pak P Iwata Nakao N Hong Kyung S KS Schwab Sibylle G SG Yue Weihua W Tsuang Ming M Liu Jianjun J Ma Xiancang X Kahn René S RS Shi Yongyong Y Huang Hailiang H

Nature genetics 20191118 12

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 ...[more]

PMID: 31740837

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Project description:To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (πc). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for πc differences related to hematological and metabolic traits (hematological fold-enrichment = 4.45, p = 2.15 × 10-7; metabolic fold-enrichment = 4.05, p = 4.01 × 10-6). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median πc = 0.15%, EAS-metabolic median πc = 0.18%) with the strongest πc difference with respect to respiratory traits (EAS-respiratory median πc = 0.50%; hematological-p = 2.26 × 10-3; metabolic-p = 3.48 × 10-3). In EUR, pairwise comparisons showed multiple πc differences related to the endocrine category (fold-enrichment = 5.83, p = 4.76 × 10-6), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median πc = 0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median πc = 0.50%; p = 1.19 × 10-4). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p = 2.18 × 10-4; EUR endocrine-gastrointestinal p = 6.80 × 10-4). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.

Dataset Information

Comparative genetic architectures of schizophrenia in East Asian and European populations.

Publications

Comparative genetic architectures of schizophrenia in East Asian and European populations.

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