High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans
High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans
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DOI：
10.1016/j.ajhg.2017.04.007
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发表时间：
2017-05-04
影响因子：
9.8
通讯作者：
Maniatis, Nikolas
中科院分区：
文献类型：
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作者：
Lau, Winston;Andrew, Toby;Maniatis, Nikolas
对 T2D 全基因组关联研究结果的解释具有挑战性。在非洲血统人群中只有很少的基因座被复制，并且所涉及的功能基因的识别在很大程度上仍然不确定。我们使用遗传图谱捕获欧洲和非裔美国人详细的连锁不平衡信息，并将其应用于大型 T2D 病例对照样本，以估计两个人群中假定的功能变异的位置。使用脂肪表达测试复制的 T2D 位置是否是监管热点的证据。我们使用下一代测序和功能注释（包括增强子、转录和染色质修饰）验证了共定位间隔的样本。我们确定了另外 111 个疾病易感地点，其中 93 个是国际大都会，18 个是欧洲特有的。我们发现许多先前已知的信号也是非裔美国人的风险位点。大多数疾病位置似乎通过调节大量（266）个顺式调节基因的表达水平来赋予 T2D 风险，其中大多数不是距离疾病位点最近的基因。对三个大都会位置进行测序提供了候选功能变体，这些变体与细胞特异性染色质结构域和胰岛增强子精确共定位。这些变异具有很大的效应量，并且在人群中很常见。结果表明，通过将这些影响定位在高分辨率遗传图谱上，可以有效整合不同群体中的疾病相关位点、基因表达和细胞特异性调控注释。顺式调控基因提供了对所涉及的复杂分子途径的深入了解，并且可以用作测序和功能分子研究的靶标。
Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations. Replicated T2D locations were tested for evidence of being regulatory hotspots using adipose expression. We validated a sample of our co-location intervals using next generation sequencing and functional annotation, including enhancers, transcription, and chromatin modifications. We identified 111 additional disease-susceptibility locations, 93 of which are cosmopolitan and 18 of which are European specific. We show that many previously known signals are also risk loci in African Americans. The majority of the disease locations appear to confer risk of T2D via the regulation of expression levels for a large number (266) of cis-regulated genes, the majority of which are not the nearest genes to the disease loci. Sequencing three cosmopolitan locations provided candidate functional variants that precisely co-locate with cell-specific chromatin domains and pancreatic islet enhancers. These variants have large effect sizes and are common across populations. Results show that disease-associated loci in different populations, gene expression, and cell-specific regulatory annotation can be effectively integrated by localizing these effects on high-resolution genetic maps. The cis-regulated genes provide insights into the complex molecular pathways involved and can be used as targets for sequencing and functional molecular studies.