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

Abstract

SummaryTwenty 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 × 10 −8 ) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 × 10 −6 ; GABRB1: rs10517178/rs1372491, P = 4.19 × 10 −6 ) and 14q13 (PRKD1: rs10144903, 3.92 × 10 −6 ), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, P adj-agesex = 2.06 × 10 −5 ; KCTD8: rs4407541, P adj-agesex = 1.42 × 10 −4 ; GABRB1: rs10517178/rs1372491, P adj-agesex = 0.027; 14q13 PRKD1: rs10144903, P adj-agesex = 6.95 × 10 −5 ). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P adj-agesex = 0.030) and rs2055942 (P adj-agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P adj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P adj-agesex-combined = 3 × 10 −4 ) and at KCTD8 (rs4695718: P adj-agesex-combined = 2 × 10 −4 ). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P adj-agesex = 0.031; P adj-agesex-combined = 2 × 10 −4 ). These genes may provide important functional leads in understanding disease pathogenesis in this population.

Genetic risk variants for metabolic traits in Arab populations

“…Few that have been reported include: (i) a T2DM case-control study on Saudi Arabian population that validated only some ( WFS1, JAZF1, SLC30A8, CDKN2A/B, TCF7L2, KCNQ1, HMG20A, HNF4A and DUSP9 ) of the T2DM genes implicated in European population3; however, the study was not adjusted for population stratification. (ii) a T2DM case-control study on Lebanese population that replicated only two ( CDKAL1 and TCF7L2 ) of the genes implicated in European population4; and (iii) a study from the United Arab Emirates5 on an extended pedigree (consisting of 178 Arab individuals) that implicated association of KCTD8, COX7B2 and GABRA4 genes with T2DM for the first time; the implicated markers have not so far been replicated in any other population.…”

First Genome-Wide Association Study in an Australian Aboriginal Population Provides Insights into Genetic Risk Factors for Body Mass Index and Type 2 Diabetes

“…Previous studies in China have demonstrated association between polymorphisms at GABRR1 and diabetic cataract [63]. Recently we also demonstrated that polymorphisms in both GABA-A and GABA-B receptor pathway genes are associated with T2D in an extended family from the United Arab Emirates [85]. GABA-A receptors act as inhibitory neurotransmitters in the central nervous system.…”

Identification and Validation of a Novel Metabolism‑Related Prognostic Signature in Hepatocellular Carcinoma

“…Liang et al reported that the single nucleotide polymorphism (SNPs) of the cytochromooxidase VIIb 2(COX7B2) gene was associated with familial nasopharyngeal carcinoma [33]. A study by Al et al revealed that COX7B2 is a susceptibility gene for type 2 diabetes in an extended Arab family [34]. In addition, little is known about the roles of COX7B2 in human cancers and other diseases.…”