Analysis of clinically relevant variants from ancestrally diverse Asian genomes

Sock Hoai Chan, Yasmin Bylstra, Jing Xian Teo, Jyn Ling Kuan, Nicolas Bertin, Mar Gonzalez-Porta, Maxime Hebrard, Roberto Tirado-Magallanes, Joanna Hui Juan Tan, Justin Jeyakani, Zhihui Li, Jin Fang Chai, Yap Seng Chong, Sonia Davila, Liuh Ling Goh, Eng Sing Lee, Eleanor Wong, Tien Yin Wong, Shyam Prabhakar, Jianjun Liu, Ching-Yu Cheng, Birgit Eisenhaber, Neerja Karnani, Khai Pang Leong, Xueling Sim, Khung Keong Yeo, John C. Chambers, E-Shyong Tai, Patrick Tan (), Saumya S. Jamuar (), Joanne Ngeow () and Weng Khong Lim ()
Additional contact information
Sock Hoai Chan: National Cancer Centre Singapore
Yasmin Bylstra: SingHealth Duke-NUS Institute of Precision Medicine
Jing Xian Teo: SingHealth Duke-NUS Institute of Precision Medicine
Jyn Ling Kuan: SingHealth Duke-NUS Institute of Precision Medicine
Nicolas Bertin: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Mar Gonzalez-Porta: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Maxime Hebrard: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Roberto Tirado-Magallanes: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Joanna Hui Juan Tan: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Justin Jeyakani: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Zhihui Li: Genome Research Informatics & Data Science Platform, Genome Institute of Singapore, Agency for Science, Technology and Research
Jin Fang Chai: National University of Singapore
Yap Seng Chong: National University of Singapore
Sonia Davila: SingHealth Duke-NUS Institute of Precision Medicine
Liuh Ling Goh: Personalized Medicine Service, Tan Tock Seng Hospital
Eng Sing Lee: Nanyang Technological University
Eleanor Wong: Genome Institute of Singapore, Agency for Science, Technology and Research
Tien Yin Wong: Singapore Eye Research Institute, Singapore National Eye Centre
Shyam Prabhakar: Laboratory of Systems Biology and Data Analytics, Genome Institute of Singapore, Agency for Science, Technology and Research
Jianjun Liu: Human Genomics, Genome Institute of Singapore, Agency for Science, Technology and Research
Ching-Yu Cheng: Singapore Eye Research Institute, Singapore National Eye Centre
Birgit Eisenhaber: Genome Institute of Singapore, Agency for Science, Technology and Research
Neerja Karnani: Human Development, Singapore Institute for Clinical Sciences
Khai Pang Leong: Personalized Medicine Service, Tan Tock Seng Hospital
Xueling Sim: National University of Singapore
Khung Keong Yeo: SingHealth Duke-NUS Institute of Precision Medicine
John C. Chambers: Nanyang Technological University
E-Shyong Tai: National University of Singapore
Patrick Tan: SingHealth Duke-NUS Institute of Precision Medicine
Saumya S. Jamuar: SingHealth Duke-NUS Institute of Precision Medicine
Joanne Ngeow: National Cancer Centre Singapore
Weng Khong Lim: SingHealth Duke-NUS Institute of Precision Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34116-9

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