Evaluating the glucose raising effect of established loci via a genetic risk score

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels.

近期的全基因组关联研究已发现多个与血糖水平相关的单核苷酸多态性（single nucleotide polymorphisms, SNPs）。本研究旨在验证一项假说：通过评分方式评估的升高血糖的SNPs的累积效应是否与血糖水平相关。本次分析共纳入来自THISEAS研究的1434名希腊裔参与者，以及来自GOMAP研究的1160名参与者。本研究基于已报道的升高血糖的基因座，构建了遗传风险评分（genetic risk score, GRS），以探究已报道的血糖相关基因座对血糖水平的累积效应。在THISEAS研究中，遗传风险评分与血糖水平（单位：mmol/L）升高呈显著关联（β±标准误：0.024±0.004，P=8.27×10^-7）。在GOMAP研究中，遗传风险评分的效应同样具有统计学显著性（β±标准误：0.011±0.005，P=0.031）。对两项研究开展荟萃分析后发现，遗传风险评分与血糖水平升高呈显著关联（β±标准误：0.019±0.003，P=1.41×10^-9）。此外，SLC30A8、PROX1、MTNR1B、ADRA2A、G6PC2、LPIN3基因座的变异体与血糖水平的关联达到临界统计学显著性（P<0.05）。本研究在希腊人群中验证了已报道的升高血糖变异体的关联信号，并证实了效应方向的一致性（二项符号检验P=6.96×10^-5）。本研究同时证实，已报道的血糖相关基因座的累积效应与血糖水平升高存在显著关联。