Comparative genetic architectures of schizophrenia in East Asian and European populations
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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.
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Risk-flagging models for schizophrenia trained on European populations have reduced performance in East Asian populations.
“In the field of mental health, specifically concerning schizophrenia, a meta-analysis found that risk-flagging models trained on European populations have reduced performance in East Asian populations [88].”
From Barriers to and facilitators of artificial intelligence adoption in health care: scoping review (2024) · cites this paper as [88]
Previous studies found that population diversity may improve fine-mapping resolution.
“Previous studies have found that population diversity may improve fine-mapping resolution38,39”
From Shared genetic architectures of educational attainment in East Asian and European populations (2024) · cites this paper as [38]
A previous genome-wide association study reported 176 genomic loci containing common alleles associated with schizophrenia.
“A recent genome-wide association study (GWAS) reported 176 genomic loci containing common alleles associated with schizophrenia9”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [9]
For almost all cohorts, PRS had more explanatory power when based on risk alleles from the larger combined-ancestry GWAS than from the matched-ancestry GWAS, and this effect was strongest for non-European samples.
“For almost all cohorts, PRS had more explanatory power based on risk alleles derived from the larger combined ancestry GWAS than from the matched ancestry GWAS; given the ancestry specific sample sizes, unsurprisingly9, this effect was strongest for the non-EUR samples”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [9]
PRS explained most variance in liability in cohorts of European ancestry and in samples likely to include the most severe cases, such as hospitalised patients or those treated with clozapine.
“PRS explained most variance in liability in cohorts of European ancestry (again a result of the ancestry composition of the GWAS9) and in samples which by ascertainment likely include the most severe cases (hospitalised patients or those treated with clozapine)”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [9]
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- Authors
- Schizophrenia Working Group of the Psychiatric Genomics Consortium, Lam, M., Indonesia Schizophrenia Consortium, Genetic REsearch on schizophreniA neTwork-China and the Netherlands (GREAT-CN), Chen, C.-Y., Li, Z., Martin, A. R., Bryois, J., Ma, X., Gaspar, H., Ikeda, M., Benyamin, B., Brown, B. C., Liu, R., Zhou, W., Guan, L., Kamatani, Y., Kim, S.-W., Kubo, M., Kusumawardhani, A. A. A. A., Liu, C.-M., Ma, H., Periyasamy, S., Takahashi, A., Xu, Z., Yu, H., Zhu, F., Chen, W. J., Faraone, S., Glatt, S. J., He, L., Hyman, S. E., Hwu, H.-G., McCarroll, S. A., Neale, B. M., Sklar, P., Wildenauer, D. B., Yu, X., Zhang, D., Mowry, B. J., Lee, J., Holmans, P., Xu, S., Sullivan, P. F., Ripke, S., O’Donovan, M. C., Daly, M. J., Qin, S., Sham, P., Iwata, N., Hong, K. S., Schwab, S. G., Yue, W., Tsuang, M., Liu, J., Ma, X., Kahn, R. S., Shi, Y., & Huang, H.
- Affiliations
- Broad Institute (US)
- Qingdao University (CN)
- Karolinska Institutet (SE)
- Shanghai Institute of Nutrition and Health (CN)
- Fujita Health University (JP)
- The University of Queensland (AU)
- New York Genome Center (US)
- Shanghai Jiao Tong University (CN)
- Peking University (CN)
- RIKEN Center for Integrative Medical Sciences (JP)
- Chonnam National University (KR)
- University of Indonesia (ID)
- National Taiwan University (TW)
- National Cerebral and Cardiovascular Center (JP)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- State University of New York (US)
- SUNY Upstate Medical University (US)
- Jinan University (CN)
- Icahn School of Medicine at Mount Sinai (US)
- The University of Western Australia (AU)
- Institute of Mental Health (SG)
- Cardiff University (GB)
- Chinese Academy of Sciences (CN)
- University of North Carolina at Chapel Hill (US)
- University of Hong Kong (HK)
- Samsung Medical Center (KR)
- University of Wollongong (AU)
- University of California San Diego (US)
- National University of Singapore (SG)
- University Medical Center Utrecht (NL)
- Corresponding author
- Ma, Xixian
- Yue, Weihua
- Tsuang, Ming
- Liu, Jianjun
- Ma, Xiancang
- Kahn, René S.
- Shi, Yongyong
- Huang, Hailiang
- ORCID
- Lam, Max
- Chen, Chia-Yen
- Li, Zhiqiang
- Martin, Alicia R.
- Bryois, Julien
- Ma, Xixian
- Gaspar, Helena
- Ikeda, Masashi
- Benyamin, Beben
- Brown, Brielin C.
- Kamatani, Yoichiro
- Kim, Sung-Wan
- Kubo, Michiaki
- Liu, Chih-Min
- Periyasamy, Sathish
- Takahashi, Atsushi
- Yu, Hao
- Chen, Wei J.
- Faraone, Stephen
- Glatt, Stephen J.
- Hyman, Steven E.
- Hwu, Hai-Gwo
- McCarroll, Steven A.
- Neale, Benjamin M.
- Sklar, Pamela
- Wildenauer, Dieter B.
- Mowry, Bryan J.
- Lee, Jimmy
- Holmans, Peter
- Xu, Shuhua
- Sullivan, Patrick F.
- Ripke, Stephan
- O’Donovan, Michael C.
- Daly, Mark J.
- Qin, Shengying
- Sham, Pak
- Iwata, Nakao
- Hong, Kyung S.
- Schwab, Sibylle G.
- Yue, Weihua
- Tsuang, Ming
- Kahn, René S.
- Shi, Yongyong
- Huang, Hailiang
- Venue
- Nature Genetics
- Published
- 2019-11-18
- Volume
- 51
- Issue
- 12
- Pages
- 1670-1678
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6885121
- OpenAlex
- W2983765585
- Cited by
- 655
- References
- 93
- Citations by year
- 2026: 46 · 2025: 102 · 2024: 103 · 2023: 113 · 2022: 113 · 2021: 94 · 2020: 72 · 2019: 11 · 2018: 1
- FWCI
- 57.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Medical Research Council (MR/P005748/1, MR/L010305/1)
- Japan Society for the Promotion of Science (17H04251)
- National Institute of Mental Health (U01MH109539, U01MH109514, R01MH085521, U01MH109528, R01MH085560, U01MH109536, K99MH117229, U01MH109532)
- National Human Genome Research Institute (U54HG003067)
- National Institute of Allergy and Infectious Diseases (R21AI139012)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK114379)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- schizophrenia, genetic architecture, East Asian ancestry, European ancestry, polygenic risk score, genetic correlation, novel genetic loci, cross-population generalizability, genome-wide association study
- MeSH terms
- Asia, Eastern, Genetics, Population, Humans, Schizophrenia, Case-Control Studies, Polymorphism, Single Nucleotide, White People, Asian People, Genome-Wide Association Study
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