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A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

ABSTRACT: Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.

SUBMITTER: Choi J

PROVIDER: S-EPMC10411914 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

Choi Jaeyong J Kim Sungjae S Kim Juhyun J Son Ho-Young HY Yoo Seong-Keun SK Kim Chang-Uk CU Park Young Jun YJ Moon Sungji S Cha Bukyoung B Jeon Min Chul MC Park Kyunghyuk K Yun Jae Moon JM Cho Belong B Kim Namcheol N Kim Changhoon C Kwon Nak-Jung NJ Park Young Joo YJ Matsuda Fumihiko F Momozawa Yukihide Y Kubo Michiaki M Kim Hyun-Jin HJ Park Jin-Ho JH Seo Jeong-Sun JS Kim Jong-Il JI Im Sun-Wha SW

Science advances 20230809 32

Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects ...[more]

PMID: 37556544

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Project description:The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB1 exposed. AFB1-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB1-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB1-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

Dataset Information

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

Publications

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

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