Analysis of Clinically Relevant Variants from Ancestrally Diverse Asian Genomes (Nat Commun, Nov 22)

/ 2022, Latest Happenings, Research / By

Sock Hoai Chan # 1 2 3, Yasmin Bylstra # 4, Jing Xian Teo 4, Jyn Ling Kuan 4, Nicolas Bertin 5, Mar Gonzalez-Porta 5, Maxime Hebrard 5, Roberto Tirado-Magallanes 5, Joanna Hui Juan Tan 5, Justin Jeyakani 5, Zhihui Li 5, Jin Fang Chai 6, Yap Seng Chong 7 8, Sonia Davila 4 9 10, Liuh Ling Goh 11, Eng Sing Lee 3 12, Eleanor Wong 13, Tien Yin Wong 14; SG10K_Health Consortium; Shyam Prabhakar 15, Jianjun Liu 16 17, Ching-Yu Cheng 14 18, Birgit Eisenhaber 13 19, Neerja Karnani 20 21 22, Khai Pang Leong 11 23, Xueling Sim 6, Khung Keong Yeo 4 24 25, John C Chambers 3 26 27, E-Shyong Tai 6 17 25 26, Patrick Tan 28 29 30 31 32, Saumya S Jamuar 33 34 35 36, Joanne Ngeow 37 38 39 40, Weng Khong Lim 41 42 43

Affiliations

  • 1Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore.
  • 2Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
  • 4SingHealth Duke-NUS Institute of Precision Medicine, Singapore, 169609, Singapore.
  • 5Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
  • 6Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore.
  • 7Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
  • 8Singapore Institute for Clinical Sciences, Singapore, 117609, Singapore.
  • 9Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 10SingHealth Duke-NUS Genomic Medicine Centre, Singapore, 168582, Singapore.
  • 11Personalized Medicine Service, Tan Tock Seng Hospital, Singapore, 308433, Singapore.
  • 12National Healthcare Group Polyclinics, Singapore, 138543, Singapore.
  • 13Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
  • 14Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 168751, Singapore.
  • 15Laboratory of Systems Biology and Data Analytics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
  • 16Human Genomics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
  • 17Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
  • 18Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 19Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 138671, Singapore.
  • 20Human Development, Singapore Institute for Clinical Sciences, Singapore, 117609, Singapore.
  • 21Clinical Data Engagement, Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 138671, Singapore.
  • 22Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
  • 23Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, 308433, Singapore.
  • 24Department of Cardiology, National Heart Centre Singapore, Singapore, 169609, Singapore.
  • 25Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 26Precision Health Research Singapore (PRECISE), Singapore, 139234, Singapore.
  • 27Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
  • 28SingHealth Duke-NUS Institute of Precision Medicine, Singapore, 169609, Singapore. patrick.tan@precise.cris.sg.
  • 29Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore. patrick.tan@precise.cris.sg.
  • 30Precision Health Research Singapore (PRECISE), Singapore, 139234, Singapore. patrick.tan@precise.cris.sg.
  • 31Cancer & Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore. patrick.tan@precise.cris.sg.
  • 32Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. patrick.tan@precise.cris.sg.
  • 33SingHealth Duke-NUS Institute of Precision Medicine, Singapore, 169609, Singapore. Saumya.S.Jamuar@singhealth.com.sg.
  • 34SingHealth Duke-NUS Genomic Medicine Centre, Singapore, 168582, Singapore. Saumya.S.Jamuar@singhealth.com.sg.
  • 35Genetics Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore, 229899, Singapore. Saumya.S.Jamuar@singhealth.com.sg.
  • 36Paediatric Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore. Saumya.S.Jamuar@singhealth.com.sg.
  • 37Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore. joanne.ngeow@ntu.edu.sg.
  • 38Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore. joanne.ngeow@ntu.edu.sg.
  • 39Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore. joanne.ngeow@ntu.edu.sg.
  • 40Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, 138673, Singapore. joanne.ngeow@ntu.edu.sg.
  • 41SingHealth Duke-NUS Institute of Precision Medicine, Singapore, 169609, Singapore. wengkhong.lim@duke-nus.edu.sg.
  • 42SingHealth Duke-NUS Genomic Medicine Centre, Singapore, 168582, Singapore. wengkhong.lim@duke-nus.edu.sg.
  • 43Cancer & Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore. wengkhong.lim@duke-nus.edu.sg.
#Contributed equally.

Abstract

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

PMID: 36335097    DOI: 10.1038/s41467-022-34116-9

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