Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population.
Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population.
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DOI：
10.1007/s00439-020-02222-7
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发表时间：
2021-03
期刊：
影响因子：
5.3
通讯作者：
Thanaraj TA
中科院分区：
文献类型：
--
作者：
Hebbar P;Abubaker JA;Abu-Farha M;Alsmadi O;Elkum N;Alkayal F;John SE;Channanath A;Iqbal R;Pitkaniemi J;Tuomilehto J;Sladek R;Al-Mulla F;Thanaraj TA
虽然阿拉伯人口的代谢紊乱患病率很高，但尚未纳入确定代谢特征遗传风险位点的全球研究。确定这种主要以欧洲为中心的既定风险位点的可转移性对于将研究工具/资源和全球研究产生的药物靶点转移到广泛的种族人群至关重要。此外，考虑到阿拉伯人等具有血缘关系和高度近亲繁殖特征的人群，可以确定新的风险位点。我们将两个科威特阿拉伯队列（n = 1434和1298）的已发表GWAS数据估算到1000个基因组计划单倍型，并对与13种代谢性状的关联进行荟萃分析。我们将观察到的关联信号与代谢性状的关联信号进行了比较。我们的研究强调了来自9个不同基因的70种变体，其中一些已经与代谢紊乱建立了联系。通过放宽全基因组显著性阈值，我们从11个代谢性状基因中鉴定出“新的”风险变异。许多新的风险变异关联信号被观察到在全基因组显著性或边缘。此外，在我们的研究中验证了来自187个基因的349个先前建立的变体。观察到风险变异体对多个代谢性状的多效性效应。精细定位显示rs7838666/CSMD 1 rs 1864163/CETP和rs 112861901/[INTS 10，LPL]是影响空腹血糖和高密度脂蛋白水平的候选因果变异。计算功能分析确定了围绕几个变体的各种基因调控信号。这项研究扩大了现有GWAS的人口祖先多样性，并阐明了代谢紊乱的种族群体中的新变体。本文的在线版本（10.1007/s 00439 -020-02222-7）包含补充材料，可供授权用户使用。
While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified ‘novel’ risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders. The online version of this article (10.1007/s00439-020-02222-7) contains supplementary material, which is available to authorized users.
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影响因子：
5.2
作者：
Hebbar, Prashantha;Abubaker, Jehad Ahmed;Thanaraj, Thangavel Alphonse
通讯作者：
Thanaraj, Thangavel Alphonse
影响因子：
2.2
作者：
Fahed AC;El-Hage-Sleiman AK;Farhat TI;Nemer GM
通讯作者：
Nemer GM
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
1.7
作者：
Adeyemo, A.;Rotimi, C.
通讯作者：
Rotimi, C.