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

Authors

  • Habiba S. Al Safar,

    1. Centre for Forensic Science, The University of Western Australia, Crawley, Western, Australia
    2. Khalifa University of Science, Technology & Research, Biomedical Department, Abu Dhabi, United Arab Emirates
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  • Heather J. Cordell,

    1. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
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  • Osman Jafer,

    1. Molecular Biology and Genetics Laboratory, Central Veterinary Research Laboratory, Dubai, United Arab Emirates
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  • Denise Anderson,

    1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia
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  • Sarra E. Jamieson,

    1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia
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  • Michaela Fakiola,

    1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia
    2. Cambridge Institute for Medical Research and Department of Medicine, School of Clinical, Medicine University of Cambridge, Cambridge, UK
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  • Kamal Khazanehdari,

    1. Molecular Biology and Genetics Laboratory, Central Veterinary Research Laboratory, Dubai, United Arab Emirates
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  • Guan K. Tay,

    1. Centre for Forensic Science, The University of Western Australia, Crawley, Western, Australia
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    • Equal contributions

  • Jenefer M. Blackwell

    Corresponding author
    1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia
    2. Cambridge Institute for Medical Research and Department of Medicine, School of Clinical, Medicine University of Cambridge, Cambridge, UK
    • Centre for Forensic Science, The University of Western Australia, Crawley, Western, Australia
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    • Equal contributions


Corresponding author: Professor Jenefer M. Blackwell, Telethon Institute for Child Health Research, PO Box 855, West Perth, 6872, Western Australia. Tel: 61 8 9489 7910; Fax: 61 8 9489 7770; Email: jblackwell@ichr.uwa.edu.au

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.

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