Analysis of clinically relevant variants from ancestrally diverse Asian genomes

• Main Authors: 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
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Medicine; Epidemiology; Genetic Variation
• Online Access: https://hdl.handle.net/10356/168639
• Institution: Nanyang Technological University

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.