Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona 08034, Spain.
ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium; Interuniversity Institute of Bioinformatics in Brussels (IB2), Brussels 1050, Belgium.
Cell Rep. 2021 Oct 12;37(2):109807. doi: 10.1016/j.celrep.2021.109807.
Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.
全基因组关联研究（GWAS）鉴定了数百个与 2 型糖尿病（T2D）相关的信号。为了深入了解其潜在的分子机制，我们创建了转化人类胰腺胰岛基因型组织表达资源（TIGER），汇集了来自 2020 年地平线联盟 T2DSystems 五个队列的超过 500 个人胰岛基因组数据集。我们使用四个参考面板进行基因型推断，并对队列进行荟萃分析，以提高表达数量性状基因座（eQTL）的覆盖范围，并开发一种跨样本组合等位基因特异性表达的方法（cASE）。我们鉴定了超过 100 万个胰岛 eQTL，其中 53 个与 T2D 信号重叠。其中，降低 T2D 风险一半的低频等位基因增加了 CCND2 的表达。我们鉴定了 8 个 cASE 共定位，其中我们发现了一个与 T2D 相关的 SLC30A8 变体。我们通过 TIGER 门户（http://tiger.bsc.es）提供所有数据，这是一个全面的人类胰岛基因组数据资源，用于阐明遗传变异如何影响胰岛功能，并转化为 T2D 的治疗见解和精准医学。
