First Genome-Wide Association Study in an Australian Aboriginal Population Provides Insights into Genetic Risk Factors for Body Mass Index and Type 2 Diabetes
PLOS ONE
Authors: Anderson, Denise; Cordell, Heather J.; Fakiola, Michaela; Francis, Richard W.; Syn, Genevieve; Scaman, Elizabeth S. H.; Davis, Elizabeth; Miles, Simon J.; McLeay, Toby; Jamieson, Sarra E.; Blackwell, Jenefer M.
Abstract
A body mass index (BMI) >22kg/m(2) 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 P-genotyped = 1.50x10(-6); rs11140653 P-imputed_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 P-genotyped = 8.06x10(-6); rs10841048 P-imputed_1000G = 6.28x10(-7)) was associated with BMI, but not with T2D as reported elsewhere. BMI also associated with CNTNAP2 (rs6960319 P-genotyped = 4.65x10(-5); rs13225016 P-imputed_1000G = 6.57x10(-5)), previously identified as the strongest gene-by-environment interaction for BMI in African-Americans. The top hit (rs11240074 P-genotyped = 5.59x10-6, P-imputed_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 (P-genotyped = 4.49x10(-4)) for BMI and IGF2BP2 P-imputed_1000G = 2.55x10(-6)) for T2D. Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.
Physical mapping of potassium channel gene clusters on mouse chromosomes three and six
GENOMICS
Authors: Street, VA; Tempel, BL
Abstract
Mammalian voltage-gated K channel genes have been divided into four subfamilies (Shaker, Shab, Shal, and Shaw) based on their sequence identity and similarity to related genes in Drosophila. Genetic mapping of the voltage-gated K channel genes has shown that similar multigene clusters exist on mouse Chr 3 and 6 and suggests that the clusters may have arisen through chromosomal duplication. In this report, YAC-based physical maps of the clustered mouse Shaker-like K channel genes have been constructed using restriction endonuclease and yeast chromosome fragmentation approaches. These data define the physical spacing as 5'-Kcna3-(60 kb)-Kcna2-(90 kb)-Kcna8-3' on Chr 3, and as 5'-Kcna6-(80 kb)-Kcna1-(110 kb)-Kcna5-3' on Chr 6, with all genes oriented in a head-to-tail manner within their respective clusters. These detailed physical maps of both K channel gene clusters provide additional support for the idea of an ancient genome tetraploidization event. (C) 1997 Academic Press.
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