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First genome-wide association study in an Australian aboriginal population provides insights into genetic risk factors for body mass index and type 2 diabetes.

Anderson D, Cordell HJ, Fakiola M, Francis RW, Syn G, Scaman ES, Davis E, Miles SJ, McLeay T, Jamieson SE, Blackwell JM - PLoS ONE (2015)

Bottom Line: 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.Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.

View Article: PubMed Central - PubMed

Affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.

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.

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Related in: MedlinePlus

Imputation accuracy for 402 genotyped individuals imputed against the 1000G reference panel.Imputation accuracy is measured as average r2 across all autosomes for SNPs of different MAFs (see key).
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pone.0119333.g004: Imputation accuracy for 402 genotyped individuals imputed against the 1000G reference panel.Imputation accuracy is measured as average r2 across all autosomes for SNPs of different MAFs (see key).

Mentions: Recent reports have focused on improving tools for imputation of SNPs based on both the 1000 genomes (1000G) and HapMap project data [23, 65]. It was of particular interest to determine how well 1000G imputation would work for this Australian Aboriginal population, given that most estimates suggest the arrival of Aboriginal people in Australia more than 45,000 years ago [66, 67]. We therefore examined the efficiency of imputing genotypes across the genomes of our study population using 1000G data. High average concordance (92.8%-97.9%) was observed across all chromosomes independently of MAF. Fig. 4 compares the efficiency of imputation across all chromosomes, as measured by imputation r2, for SNPs at different MAF. As expected, r2 is lower for SNPs with MAF 0.01–0.03 (mean r2 77.2–85.4) compared to SNPs with MAF 0.03–0.05 (mean r2 81.5–88.5%) and MAF 0.05–0.5 (mean r2 85.9–90.7%). When examined across individuals, mean imputation accuracy for the 195 individuals of pure Martu ancestry (concordance 94.8; r2 88.8) were not different to measures for the 207 individuals of mixed ethnicity (concordance 95.6; r2 90.0) or to measures across all 402 individuals (concordance 95.2; r2 89.5).


First genome-wide association study in an Australian aboriginal population provides insights into genetic risk factors for body mass index and type 2 diabetes.

Anderson D, Cordell HJ, Fakiola M, Francis RW, Syn G, Scaman ES, Davis E, Miles SJ, McLeay T, Jamieson SE, Blackwell JM - PLoS ONE (2015)

Imputation accuracy for 402 genotyped individuals imputed against the 1000G reference panel.Imputation accuracy is measured as average r2 across all autosomes for SNPs of different MAFs (see key).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356593&req=5

pone.0119333.g004: Imputation accuracy for 402 genotyped individuals imputed against the 1000G reference panel.Imputation accuracy is measured as average r2 across all autosomes for SNPs of different MAFs (see key).
Mentions: Recent reports have focused on improving tools for imputation of SNPs based on both the 1000 genomes (1000G) and HapMap project data [23, 65]. It was of particular interest to determine how well 1000G imputation would work for this Australian Aboriginal population, given that most estimates suggest the arrival of Aboriginal people in Australia more than 45,000 years ago [66, 67]. We therefore examined the efficiency of imputing genotypes across the genomes of our study population using 1000G data. High average concordance (92.8%-97.9%) was observed across all chromosomes independently of MAF. Fig. 4 compares the efficiency of imputation across all chromosomes, as measured by imputation r2, for SNPs at different MAF. As expected, r2 is lower for SNPs with MAF 0.01–0.03 (mean r2 77.2–85.4) compared to SNPs with MAF 0.03–0.05 (mean r2 81.5–88.5%) and MAF 0.05–0.5 (mean r2 85.9–90.7%). When examined across individuals, mean imputation accuracy for the 195 individuals of pure Martu ancestry (concordance 94.8; r2 88.8) were not different to measures for the 207 individuals of mixed ethnicity (concordance 95.6; r2 90.0) or to measures across all 402 individuals (concordance 95.2; r2 89.5).

Bottom Line: 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.Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.

View Article: PubMed Central - PubMed

Affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, 6008, Australia.

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.

Show MeSH
Related in: MedlinePlus