title: First genome-wide association study in an Australian aboriginal population provides insights into genetic risk factors for body mass index and type 2 diabetes.
abstract: A body mass index (BMI) >22kg/m2 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<5x10-8. 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 Pgenotyped = 1.50x10-6; rs11140653 Pimputed_1000G = 2.90x10-7) for BMI lies 5' of NTRK2, 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 Pgenotyped = 8.06x10-6; rs10841048 Pimputed_1000G = 6.28x10-7) was associated with BMI, but not with T2D as reported elsewhere. BMI also associated with CNTNAP2 (rs6960319 Pgenotyped = 4.65x10-5; rs13225016 Pimputed_1000G = 6.57x10-5), previously identified as the strongest gene-by-environment interaction for BMI in African-Americans. The top hit (rs11240074 Pgenotyped = 5.59x10-6, Pimputed_1000G = 5.73x10-6) for T2D lies 5' of BCL9 that, along with TCF7L2, promotes beta-catenin's transcriptional activity in the WNT signaling pathway. Additional hits occurred in genes affecting pancreatic (KCNJ6, KCNA1) and/or GABA (GABRR1, KCNA1) functions. Notable associations observed for genes previously identified at genome-wide significance in other populations included MC4R (Pgenotyped = 4.49x10-4) for BMI and IGF2BP2 Pimputed_1000G = 2.55x10-6) for T2D. Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia; Cambridge Institute for Medical Research, Department of Medicine, and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fakiola
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Francis
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Syn
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.
authors.forename: Elizabeth S H
authors.initials: ES
authors.lastname: Scaman
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia; Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Subiaco, Western Australia, 6008, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Davis
authors.affiliation: Ngangganawili Aboriginal Health Service, Wiluna, Western Australia, 6646, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Miles
authors.affiliation: Ngangganawili Aboriginal Health Service, Wiluna, Western Australia, 6646, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: McLeay
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia; Cambridge Institute for Medical Research, Department of Medicine, and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia / Q000208:ethnology; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors