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Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.

ABSTRACT: Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.

SUBMITTER: Huyghe JR

PROVIDER: S-EPMC3727235 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.

Huyghe Jeroen R JR Jackson Anne U AU Fogarty Marie P MP Buchkovich Martin L ML Stančáková Alena A Stringham Heather M HM Sim Xueling X Yang Lingyao L Fuchsberger Christian C Cederberg Henna H Chines Peter S PS Teslovich Tanya M TM Romm Jane M JM Ling Hua H McMullen Ivy I Ingersoll Roxann R Pugh Elizabeth W EW Doheny Kimberly F KF Neale Benjamin M BM Daly Mark J MJ Kuusisto Johanna J Scott Laura J LJ Kang Hyun Min HM Collins Francis S FS Abecasis Gonçalo R GR Watanabe Richard M RM Boehnke Michael M Laakso Markku M Mohlke Karen L KL

Nature genetics 20121223 2

Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males u ...[more]

PMID: 23263489

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Project description:Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF?<?0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF?=?0.06%; p.Gly71Arg], rs144398951 [MAF?=?0.06%; p.Ile215Val], rs35003977 [MAF?=?0.78%; p.Val225Gly], and rs57307513 [MAF?=?0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P?=?2.34?×?10(-34), P?=?7.02?×?10(-34), and P?=?8.27?×?10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P?=?1.98?×?10(-26); rs2070959, p.Thr181Ala, P?=?2.87?×?10(-27); and rs1105879, p.Arg184Ser, P?=?3.27?×?10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P?=?3.21?×?10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

Dataset Information

Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.

Publications

Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.

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