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

Summary 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 × 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, Padj‐agesex = 2.06 × 10−5; KCTD8: rs4407541, Padj‐agesex = 1.42 × 10−4; GABRB1: rs10517178/rs1372491, Padj‐agesex = 0.027; 14q13 PRKD1: rs10144903, Padj‐agesex = 6.95 × 10−5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj‐agesex = 0.030) and rs2055942 (Padj‐agesex = 0.022) at COX7B2/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 × 10−4) and at KCTD8 (rs4695718: Padj‐agesex‐combined = 2 × 10−4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj‐agesex = 0.031; Padj‐agesex‐combined = 2 × 10−4). These genes may provide important functional leads in understanding disease pathogenesis in this population.