A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family

Habiba S. Al Safar, Heather J. Cordell, Osman Jafer, Denise Anderson, Sarra E. Jamieson, Michaela Fakiola, Kamal Khazanehdari, Guan K. Tay, Jenefer M. Blackwell

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 × 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) 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 × 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.

Original languageBritish English
Pages (from-to)488-503
Number of pages16
JournalAnnals of Human Genetics
Volume77
Issue number6
DOIs
StatePublished - Nov 2013

Keywords

  • Association analysis
  • Family-based GWAS
  • Type 2 diabetes
  • UAE

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