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Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

ABSTRACT: South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (n_eff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10^-8 to 5.2 × 10^-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.

SUBMITTER: Loh M

PROVIDER: S-EPMC8991226 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Loh Marie M Zhang Weihua W Ng Hong Kiat HK Schmid Katharina K Lamri Amel A Tong Lin L Ahmad Meraj M Lee Jung-Jin JJ Ng Maggie C Y MCY Petty Lauren E LE Spracklen Cassandra N CN Takeuchi Fumihiko F Islam Md Tariqul MT Jasmine Farzana F Kasturiratne Anuradhani A Kibriya Muhammad M Mohlke Karen L KL Paré Guillaume G Prasad Gauri G Shahriar Mohammad M Chee Miao Ling ML de Silva H Janaka HJ Engert James C JC Gerstein Hertzel C HC Mani K Radha KR Sabanayagam Charumathi C Vujkovic Marijana M Wickremasinghe Ananda R AR Wong Tien Yin TY Yajnik Chittaranjan S CS Yusuf Salim S Ahsan Habibul H Bharadwaj Dwaipayan D Anand Sonia S SS Below Jennifer E JE Boehnke Michael M Bowden Donald W DW Chandak Giriraj R GR Cheng Ching-Yu CY Kato Norihiro N Mahajan Anubha A Sim Xueling X McCarthy Mark I MI Morris Andrew P AP Kooner Jaspal S JS Saleheen Danish D Chambers John C JC

Communications biology 20220407 1

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including ...[more]

PMID: 35393509

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Project description:ObjectivesReliable identification of population-specific variants is important for building the single nucleotide polymorphism (SNP) profile. In this study, genomic variation using allele frequency differences of pharmacologically important genes for Gujarati Indians in Houston (GIH) and Indian Telugu in the U.K. (ITU) from the 1000 Genomes Project vis-à-vis global population data was studied to understand its role in drug response.MethodsJoint genotyping approach was used to derive variants of GIH and ITU independently. SNPs of both these populations with significant allele frequency variation (minor allele frequency ≥ 0.05) with super-populations from the 1000 Genomes Project and gnomAD based on Chi-square distribution with p-value of ≤ 0.05 and Bonferroni's multiple adjustment tests were identified. Population stratification and fixation index analysis was carried out to understand genetic differentiation. Functional annotation of variants was carried out using SnpEff, VEP and CADD score.ResultsPopulation stratification of VIP genes revealed four clusters viz., single cluster of GIH and ITU, one cluster each of East Asian, European, African populations and Admixed American was found to be admixed. A total of 13 SNPs belonging to ten pharmacogenes were identified to have significant allele frequency variation in both GIH and ITU populations as compared to one or more super-populations. These SNPs belong to VKORC1 (rs17708472, rs2359612, rs8050894) involved in Vitamin K cycle, cytochrome P450 isoforms CYP2C9 (rs1057910), CYP2B6 (rs3211371), CYP2A2 (rs4646425) and CYP2A4 (rs4646440); ATP-binding cassette (ABC) transporter ABCB1 (rs12720067), DPYD1 (rs12119882, rs56160474) involved in pyrimidine metabolism, methyltransferase COMT (rs9332377) and transcriptional factor NR1I2 (rs6785049). SNPs rs1544410 (VDR), rs2725264 (ABCG2), rs5215 and rs5219 (KCNJ11) share high fixation index (≥ 0.5) with either EAS/AFR populations. Missense variants rs1057910 (CYP2C9), rs1801028 (DRD2) and rs1138272 (GSTP1), rs116855232 (NUDT15); intronic variants rs1131341 (NQO1) and rs115349832 (DPYD) are identified to be 'deleterious'.ConclusionsAnalysis of SNPs pertaining to pharmacogenes in GIH and ITU populations using population structure, fixation index and allele frequency variation provides a premise for understanding the role of genetic diversity in drug response in Asian Indians.

Dataset Information

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Publications

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

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