Abstract
BackgroundLocated in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed.ResultsA striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10−7). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28 % reduction in type-2 diabetes risk (OR: 0.72, 95 % CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30 % reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95 % CI: 0.53-0.89, P = 0.0001).ConclusionsIn summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0291-z) contains supplementary material, which is available to authorized users.
Highlights
Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders compared to mainland Australia
Research on the Norfolk pedigree has shown that traits for obesity, dyslipidaemia, blood glucose and hypertension exhibit a substantial genetic component, with heritability estimates ranging from 30 % for systolic blood pressure (SBP) to 63 % for low density lipoproteins (LDL) cholesterol [1, 4, 5]
Genome-wide association study (GWAS) of metabolic traits All 16 heritable blood-based clinical traits were screened for association separately; individual trait GWAS Manhattan plots can be viewed in Additional file 2
Summary
Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. This study examined a large multi-generational pedigree from the isolated population of Norfolk Island to identify genomic variants (SNPs – single nucleotide polymorphisms) associated with routinely collected blood-based clinical traits. Genetic linkage analysis in the Norfolk Island pedigree has successfully identified previously documented regions associated with cardiovascular disease risk traits, the most significant being for SBP on chromosome 1 (1p36) [4]
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