The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark.
Eur J Hum Genet. 2018 Jun;26(6):868-875. doi: 10.1038/s41431-018-0109-3. Epub 2018 Feb 26.
We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA) and at estimating the effect of known HbA-associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model. To estimate the effect of known HbA-associated loci, we modeled the effect in the European and Inuit ancestry proportions of the Greenlandic genome (EAPGG and IAPGG, respectively). After correcting for multiple testing, we found no novel significant associations. When we investigated loci known to associate with HbA levels, we found that the lead variant in the GCK locus associated significantly with HbA levels in the IAPGG ([Formula: see text]). Furthermore, for 10 of 15 known HbA loci, the effects in IAPGG were similar to the previously reported effects. Interestingly, the ANK1 locus showed a statistically significant ancestral population differential effect, with opposing directions of effect in the two ancestral populations. In conclusion, we found only 1 of the 15 known HbA loci to be significantly associated with HbA levels in the IAPGG and that two-thirds of the loci showed similar effects in Inuit as previously found in European and East Asian populations. Our results shed light on the genetic effects across ethnicities.
我们之前曾表明，在小型且历史上相对孤立的格陵兰人群中，一种常见的遗传变异会导致 2 型糖尿病（T2D）的风险显著增加。受此启发，我们旨在发现糖化血红蛋白（HbA）的新遗传决定因素，并估计已知 HbA 相关基因座在格陵兰人群中的效应。我们分析了使用 Illumina Cardio-Metabochip 生成的 4049 名格陵兰人的基因型数据。我们通过加性线性混合模型进行发现关联分析。为了估计已知与 HbA 相关的基因座的效应，我们对格陵兰人基因组的欧洲和因纽特祖先比例（EAPGG 和 IAPGG 分别）进行了建模。在进行多重检验校正后，我们没有发现新的显著关联。当我们研究与 HbA 水平相关的已知基因座时，我们发现 GCK 基因座的主要变异与 IAPGG 中的 HbA 水平显著相关([Formula: see text])。此外，对于 15 个已知与 HbA 相关的基因座中的 10 个，IAPGG 中的效应与之前报道的效应相似。有趣的是，ANK1 基因座显示出统计学上显著的祖先群体差异效应，在两个祖先群体中效应的方向相反。总之，我们发现只有 15 个已知的 HbA 基因座中的 1 个与 IAPGG 中的 HbA 水平显著相关，三分之二的基因座在因纽特人中的效应与之前在欧洲和东亚人群中发现的相似。我们的研究结果阐明了跨种族的遗传效应。
