First Genome-Wide Association Study in an Australian Aboriginal Population Provides Insights into Genetic Risk Factors for Body Mass Index and Type 2 Diabetes
<div><p>A body mass index (BMI) >22kg/m<sup>2</sup> is a risk factor for type 2 diabetes (T2D) in Aboriginal Australians. To identify loci associated with BMI and T2D we undertook a genome-wide association study using 1,075,436 quality-controlled single nucleotide polymorphisms (SNPs) genotyped (Illumina 2.5M Duo Beadchip) in 402 individuals in extended pedigrees from a Western Australian Aboriginal community. Imputation using the thousand genomes (1000G) reference panel extended the analysis to 6,724,284 post quality-control autosomal SNPs. No associations achieved genome-wide significance, commonly accepted as P<5x10<sup>-8</sup>. Nevertheless, genes/pathways in common with other ethnicities were identified despite the arrival of Aboriginal people in Australia >45,000 years ago. The top hit (rs10868204 <i>P</i><sub>genotyped</sub> = 1.50x10<sup>-6</sup>; rs11140653 P<sub>imputed_1000G</sub> = 2.90x10<sup>-7</sup>) for BMI lies 5’ of <i>NTRK2</i>, the type 2 neurotrophic tyrosine kinase receptor for brain-derived neurotrophic factor (BDNF) that regulates energy balance downstream of melanocortin-4 receptor (MC4R). PIK3C2G (rs12816270 P<sub>genotyped</sub> = 8.06x10<sup>-6</sup>; rs10841048 P<sub>imputed_1000G</sub> = 6.28x10<sup>-7</sup>) was associated with BMI, but not with T2D as reported elsewhere. BMI also associated with <i>CNTNAP2</i> (rs6960319 P<sub>genotyped</sub> = 4.65x10<sup>-5</sup>; rs13225016 P<sub>imputed_1000G</sub> = 6.57x10<sup>-5</sup>), previously identified as the strongest gene-by-environment interaction for BMI in African-Americans. The top hit (rs11240074 P<sub>genotyped</sub> = 5.59x10<sup>-6</sup>, P<sub>imputed_1000G</sub> = 5.73x10<sup>-6</sup>) for T2D lies 5’ of <i>BCL9</i> that, along with <i>TCF7L2</i>, promotes beta-catenin’s transcriptional activity in the WNT signaling pathway. Additional hits occurred in genes affecting pancreatic (<i>KCNJ6</i>, <i>KCNA1</i>) and/or GABA (<i>GABRR1</i>, <i>KCNA1</i>) functions. Notable associations observed for genes previously identified at genome-wide significance in other populations included <i>MC4R</i> (P<sub>genotyped</sub> = 4.49x10<sup>-4</sup>) for BMI and <i>IGF2BP2</i> P<sub>imputed_1000G</sub> = 2.55x10<sup>-6</sup>) for T2D. Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.</p></div
