Analyses were performed in a collection from the Avon Longitudinal Study of Parents and Children (ALSPAC, mean age 15.5yrs) and in a replication cohort of adults from the UK Adult Twin Registry (TwinsUK, mean age 50.9yrs). A compound phenotype was generated by subtracting standardised BMI from standardised fasting plasma glucose to yield a continuously distributed variable where positive values were indicative of “healthier” adiposity status relative to glucose, zero was indicative of matching adiposity/glucose status and negative values were indicative of “healthier” glucose status relative to adiposity.
Genomewide analysis of this trait in ALSPAC (n=2584) gave evidence of association at the G6PC2 locus where each additional T allele at the well-known variant rs560887 was related to a -0.25(SE 0.04, p=3.9e-10) change in standardised disparity score. This was replicated in TwinsUK (n=2599)(-0.11(SE 0.04, p=0.003)) and a meta-analysis gave a joint p-value 6.1e-11. This signal was also seen when using DXA derived fat mass in place of BMI (meta-analysis p=4.4e-10) and, as anticipated, with an inverted beta coefficient when replacing glucose status with HOMA_b.
This work illustrates how derived phenotypes can be used as indicators of disparity between adiposity and glycaemic traits. Using a standardised disparity score allows a powerful analysis of metabolic features avoiding the costly procedure of defining MONW and MHO by threshold. Results are in line with the carriage of additional T alleles at G6PC2(rs560887) being associated with improved glycaemic profile. Work here did not yield signals of variants showing independent contributions to adiposity; this likely the result of genetic architecture and the causal effect that BMI has on many downstream, causal effects.
|Publication status||Published - 2014|
|Event||American Society of Human Genetics 64th Annual Meeting - San Diego, United States|
Duration: 18 Oct 2014 → 22 Oct 2014
|Conference||American Society of Human Genetics 64th Annual Meeting|
|Period||18/10/14 → 22/10/14|
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Polly E Eccleston (Other), Simon H Atack (Other) & D A G Williams (Manager)