Analysis of clinically relevant variants from ancestrally diverse Asian genomes
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...
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| Format: | Journal Article |
| Language: | English |
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2023
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| Online Access: | https://hdl.handle.net/10356/168639 |
| _version_ | 1826128955084636160 |
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| author | Chan, Sock Hoai Bylstra, Yasmin Teo, Jing Xian Kuan, Jyn Ling Bertin, Nicolas Gonzalez-Porta, Mar Hebrard, Maxime Tirado-Magallanes, Roberto Tan, Joanna Hui Juan Jeyakani, Justin Li, Zhihui Chai, Jin Fang Chong, Yap Seng Davila, Sonia Goh, Liuh Ling Lee, Eng Sing Wong, Eleanor Wong, Tien Yin Prabhakar, Shyam Liu, Jianjun Cheng, Ching-Yu Eisenhaber, Birgit Karnani, Neerja Leong, Khai Pang Sim, Xueling Yeo, Khung Keong Chambers, John Campbell Tai, E-Shyong Tan, Patrick Jamuar, Saumya S. Ngeow, Joanne Lim, Weng Khong |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Chan, Sock Hoai Bylstra, Yasmin Teo, Jing Xian Kuan, Jyn Ling Bertin, Nicolas Gonzalez-Porta, Mar Hebrard, Maxime Tirado-Magallanes, Roberto Tan, Joanna Hui Juan Jeyakani, Justin Li, Zhihui Chai, Jin Fang Chong, Yap Seng Davila, Sonia Goh, Liuh Ling Lee, Eng Sing Wong, Eleanor Wong, Tien Yin Prabhakar, Shyam Liu, Jianjun Cheng, Ching-Yu Eisenhaber, Birgit Karnani, Neerja Leong, Khai Pang Sim, Xueling Yeo, Khung Keong Chambers, John Campbell Tai, E-Shyong Tan, Patrick Jamuar, Saumya S. Ngeow, Joanne Lim, Weng Khong |
| author_sort | Chan, Sock Hoai |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:33:19Z |
| format | Journal Article |
| id | ntu-10356/168639 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:33:19Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1686392023-06-18T15:38:56Z Analysis of clinically relevant variants from ancestrally diverse Asian genomes Chan, Sock Hoai Bylstra, Yasmin Teo, Jing Xian Kuan, Jyn Ling Bertin, Nicolas Gonzalez-Porta, Mar Hebrard, Maxime Tirado-Magallanes, Roberto Tan, Joanna Hui Juan Jeyakani, Justin Li, Zhihui Chai, Jin Fang Chong, Yap Seng Davila, Sonia Goh, Liuh Ling Lee, Eng Sing Wong, Eleanor Wong, Tien Yin Prabhakar, Shyam Liu, Jianjun Cheng, Ching-Yu Eisenhaber, Birgit Karnani, Neerja Leong, Khai Pang Sim, Xueling Yeo, Khung Keong Chambers, John Campbell Tai, E-Shyong Tan, Patrick Jamuar, Saumya S. Ngeow, Joanne Lim, Weng Khong Lee Kong Chian School of Medicine (LKCMedicine) National Cancer Centre Singapore Duke-NUS Medical School National Healthcare Group Polyclinics Precision Health Research Singapore (PRECISE) Institute of Molecular and Cellular Biology, A*STAR Science::Medicine Epidemiology Genetic Variation 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. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This study made use of data generated as part of the Singapore National Precision Medicine program funded by the Industry Alignment Fund (Pre-Positioning) (IAF-PP: H17/01/ a0/007). The participating study cohorts were supported by the following funding sources: (1) HELIOS study by grants from a Strategic Initiative at Lee Kong Chian School of Medicine, the Singapore Ministry of Health (MOH) under its Singapore Translational Research Investigator Award (NMRC/STaR/0028/2017) and the IAF-PP: H18/01/a0/016, (2) GUSTO study by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore MOH’s National Medical Research Council (NMRC) Singapore (NMRC/TCR/004-NUS/2008, NMRC/TCR/ 012-NUHS/2014) with additional funding provided by SICS and IAF-PP: H17/01/a0/005, (3) SEED study by NMRC/CIRG/1417/2015, NMRC/CIRG/ 1488/2018, NMRC/OFLCG/004/2018, (4) MEC study by NMRC grant 0838/2004, BMRC grant 03/1/27/18/216, 05/1/21/19/425, 11/1/21/19/678 to NUS and National University Health System (NUHS) Singapore, (5) PRISM cohort study by NMRC/CG/M006/2017_NHCS, NMRC/STaR/ 0011/2012, NMRC/STaR/0026/2015, EYE ACP-PRISM PRECISION MEDICINE INITIATIVE FUND 05/FY2020/EX/06-A41, Lee Foundation and Tanoto Foundation, (6) TTSH cohort study by NMRC/CG12AUG2017 and CGAug16M012. Additional funding support includes grants under National Research Foundation Singapore administered by the Singapore Ministry of Health’s National Medical Research Council to the following individuals: National Precision Medicine Programme (NPM) PHASE II FUNDING (MOH-000588) to W.K.L., National Medical Research Council Singapore Clinician-Scientist Award (NMRC/CSA-INV/0017/2017, MOH000654) to J.N., National Medical Research Council Singapore ClinicianScientist Award (CSAINV21Jun-0003) to S.S.J., and Clinician-Scientist Award Senior Investigator (NMRC/CSA-SI/0012/2017) to C-Y.C; as well as funding from Agency for Science, Technology, and Research (A*STAR) of Singapore to J. Liu 2023-06-13T02:12:55Z 2023-06-13T02:12:55Z 2022 Journal Article Chan, S. H., Bylstra, Y., Teo, J. X., Kuan, J. L., Bertin, N., Gonzalez-Porta, M., Hebrard, M., Tirado-Magallanes, R., Tan, J. H. J., Jeyakani, J., Li, Z., Chai, J. F., Chong, Y. S., Davila, S., Goh, L. L., Lee, E. S., Wong, E., Wong, T. Y., Prabhakar, S., ...Lim, W. K. (2022). Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nature Communications, 13(1), 6694-. https://dx.doi.org/10.1038/s41467-022-34116-9 2041-1723 https://hdl.handle.net/10356/168639 10.1038/s41467-022-34116-9 36335097 2-s2.0-85141355514 1 13 6694 en IAF-PP: H17/01/ a0/007 NMRC/STaR/0028/2017 IAF-PP: H18/01/a0/016 NMRC/TCR/004-NUS/2008 NMRC/TCR/ 012-NUHS/2014 IAF-PP: H17/01/a0/005 NMRC/CIRG/1417/2015 NMRC/CIRG/ 1488/2018 NMRC/OFLCG/004/2018 NMRC-0838/2004 BMRC (03/1/27/18/216, 05/1/21/19/425, 11/1/21/19/678) NMRC/CG/M006/2017_NHCS NMRC/STaR/ 0011/2012 NMRC/STaR/0026/2015 05/FY2020/EX/06-A41 NMRC/CG12AUG2017 CGAug16M012.G (MOH-000588) NMRC/CSA-INV/0017/2017 MOH000654 CSAINV21Jun-0003 NMRC/CSA-SI/0012/2017 Nature Communications © 2022 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Medicine Epidemiology Genetic Variation Chan, Sock Hoai Bylstra, Yasmin Teo, Jing Xian Kuan, Jyn Ling Bertin, Nicolas Gonzalez-Porta, Mar Hebrard, Maxime Tirado-Magallanes, Roberto Tan, Joanna Hui Juan Jeyakani, Justin Li, Zhihui Chai, Jin Fang Chong, Yap Seng Davila, Sonia Goh, Liuh Ling Lee, Eng Sing Wong, Eleanor Wong, Tien Yin Prabhakar, Shyam Liu, Jianjun Cheng, Ching-Yu Eisenhaber, Birgit Karnani, Neerja Leong, Khai Pang Sim, Xueling Yeo, Khung Keong Chambers, John Campbell Tai, E-Shyong Tan, Patrick Jamuar, Saumya S. Ngeow, Joanne Lim, Weng Khong Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title | Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title_full | Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title_fullStr | Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title_full_unstemmed | Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title_short | Analysis of clinically relevant variants from ancestrally diverse Asian genomes |
| title_sort | analysis of clinically relevant variants from ancestrally diverse asian genomes |
| topic | Science::Medicine Epidemiology Genetic Variation |
| url | https://hdl.handle.net/10356/168639 |
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