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A Genome-Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Lookup NU author(s): Professor Heather Cordell

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Abstract

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P = 5 x 10(-8)) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 x 10(-6); GABRB1: rs10517178/rs1372491, P = 4.19 x 10(-6)) and 14q13 (PRKD1: rs10144903, 3.92 x 10(-6)), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex = 2.06 x 10(-5); KCTD8: rs4407541, Padj-agesex = 1.42 x 10(-4); GABRB1: rs10517178/rs1372491, Padj-agesex = 0.027; 14q13 PRKD1: rs10144903, Padj-agesex = 6.95 x 10(-5)). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj-agesex = 0.030) and rs2055942 (Padj-agesex = 0.022) atCOX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined = 3 x 10(-4)) and at KCTD8 (rs4695718: Padj-agesex-combined = 2 x 10(-4)). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex = 0.031; Padj-agesex-combined = 2 x 10(-4)). These genes may provide important functional leads in understanding disease pathogenesis in this population.

Publication metadata

Author(s): Al Safar HS, Cordell HJ, Jafer O, Anderson D, Jamieson SE, Fakiola M, Khazanehdari K, Tay GK, Blackwell JM

Publication type: Article

Publication status: Published

Journal: Annals of Human Genetics

Year: 2013

Volume: 77

Issue: 6

Pages: 488-503

Print publication date: 01/11/2013

ISSN (print): 0003-4800

ISSN (electronic): 1469-1809

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/ahg.12036

DOI: 10.1111/ahg.12036

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