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Nat Genet. 2019 Dec;51(12):1670-1678. doi: 10.1038/s41588-019-0512-x. Epub 2019 Nov 18.

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

Lam M1,2,3,4,5,6, Chen CY4,5,7,8,9, Li Z10,11, Martin AR4,5,7, Bryois J12, Ma X13, Gaspar H14, Ikeda M15, Benyamin B16,17,18, Brown BC19,20, Liu R4,5, Zhou W11,21, Guan L22,23,24, Kamatani Y25,26, Kim SW27, Kubo M28, Kusumawardhani AAAA29, Liu CM30,31, Ma H22,23,24, Periyasamy S32,33, Takahashi A26,34, Xu Z35, Yu H22,23,24, Zhu F36,37,38; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Indonesia Schizophrenia Consortium; Genetic REsearch on schizophreniA neTwork-China and the Netherlands (GREAT-CN), Chen WJ30,31,39, Faraone S40, Glatt SJ41, He L11,42,43, Hyman SE5,44, Hwu HG30,31,39, McCarroll SA5,45, Neale BM4,5,7, Sklar P46, Wildenauer DB47, Yu X22,23,24, Zhang D22,23,24, Mowry BJ32,33, Lee J48, Holmans P49, Xu S13,50,51,52, Sullivan PF53, Ripke S4,5,54, O'Donovan MC49, Daly MJ4,5,7,55, Qin S11,56, Sham P57,58, Iwata N15, Hong KS59, Schwab SG60,61, Yue W62,63,64,65, Tsuang M66, Liu J67,68, Ma X69,70,71, Kahn RS72,73,74, Shi Y75,76,77,78, Huang H79,80,81.

Author information

1
Bio-X Institutes, Shanghai Jiao Tong University and Research Division, Institute of Mental Health Singapore, Singapore, Singapore.
2
Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
3
Division of Psychiatry Research, the Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA.
4
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
5
Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Research Division, Institute of Mental Health Singapore, Singapore, Singapore.
7
Department of Medicine, Harvard Medical School, Boston, MA, USA.
8
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
9
Biogen, Cambridge, MA, USA.
10
Biomedical Sciences Institute of Qingdao University, Qingdao Branch of Shanghai Jiao Tong University Bio-X Institutes and the Affiliated Hospital of Qingdao University, Qingdao, China.
11
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
13
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
14
Social Genetic and Developmental Psychiatry, King's College London, London, UK.
15
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
16
Australian Centre for Precision Health, School of Health Sciences, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia.
17
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
18
South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
19
Data Science Institute, Columbia University, New York, NY, USA.
20
New York Genome Center, New York, NY, USA.
21
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
22
Peking University Sixth Hospital and Institute of Mental Health, Beijing, China.
23
National Health Commission Key Laboratory of Mental Health (Peking University), Beijing, China.
24
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
25
Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
26
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
27
Department of Psychiatry, Chonnam National University Medical School, Gwangju, Republic of Korea.
28
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
29
Department of Psychiatry, Cipto Mangunkusumo General Hospital, Universitas Indonesia, Jakarta, Indonesia.
30
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.
31
Department of Psychiatry, National Taiwan University College of Medicine, Taipei, Taiwan.
32
Queensland Brain Institute The University of Queensland, Brisbane, Queensland, Australia.
33
Queensland Center for Mental Health Research, The University of Queensland, Wacol, Queensland, Australia.
34
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
35
Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands.
36
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
37
Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
38
Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
39
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
40
The State University of New York, Syracuse, NY, USA.
41
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
42
Shanghai Center for Women and Children's Health, Shanghai, China.
43
Baoan Maternal and Child Health Hospital, Jinan University, Shenzhen, China.
44
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
45
Department of Genetics, Harvard Medical School, Boston, MA, USA.
46
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
47
University of Western Australia, Perth, Western Australia, Australia.
48
Institute of Mental Health, Singapore, Singapore.
49
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine , Cardiff University, Cardiff, UK.
50
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
51
Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
52
Collaborative Innovation Center of Genetics and Development, Shanghai, China.
53
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
54
Department of Psychiatry and Psychotherapy Charité - Universitätsmedizin, Berlin, Germany.
55
Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
56
Collaborative Innovation Center, Jining Medical University, Jining, China.
57
State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China.
58
Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
59
Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
60
Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia.
61
Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
62
Peking University Sixth Hospital and Institute of Mental Health, Beijing, China. dryue@bjmu.edu.cn.
63
National Health Commission Key Laboratory of Mental Health (Peking University), Beijing, China. dryue@bjmu.edu.cn.
64
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. dryue@bjmu.edu.cn.
65
IDG/McGovern Institute for Brain Research at Peking University, Beijing, China. dryue@bjmu.edu.cn.
66
Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, San Diego, CA, USA. mtsuang@ucsd.edu.
67
Human Genetics, Genome Institute of Singapore, Singapore, Singapore. liuj3@gis.astar.edu.sg.
68
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. liuj3@gis.astar.edu.sg.
69
Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. maxiancang@163.com.
70
Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. maxiancang@163.com.
71
Clinical Research Center for Mental Disease of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. maxiancang@163.com.
72
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. rene.kahn@mssm.edu.
73
Behavioral Health System, Icahn School of Medicine at Mount Sinai, New York, NY, USA. rene.kahn@mssm.edu.
74
Department of Psychiatry, Brain Center Rudolf Magnus, UMC Utrecht, Utrecht, the Netherlands. rene.kahn@mssm.edu.
75
Bio-X Institutes, Shanghai Jiao Tong University and Research Division, Institute of Mental Health Singapore, Singapore, Singapore. shiyongyong@gmail.com.
76
Biomedical Sciences Institute of Qingdao University, Qingdao Branch of Shanghai Jiao Tong University Bio-X Institutes and the Affiliated Hospital of Qingdao University, Qingdao, China. shiyongyong@gmail.com.
77
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China. shiyongyong@gmail.com.
78
Department of Psychiatry, First Teaching Hospital of Xinjiang Medical University, Ürümqi, China. shiyongyong@gmail.com.
79
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org.
80
Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org.
81
Department of Medicine, Harvard Medical School, Boston, MA, USA. hhuang@broadinstitute.org.

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.

PMID:
31740837
PMCID:
PMC6885121
[Available on 2020-05-18]
DOI:
10.1038/s41588-019-0512-x
[Indexed for MEDLINE]

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