The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome and exome arrays, resulting in over 100 associated variants. We extended this work with a high-coverage whole genome sequencing (WGS) analysis from fifteen cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. More than 23,000 non-diabetic individuals from five self-reported race/ethnicities (African, Asian, European, Hispanic and Samoan) were included for each trait. We analyzed 60M variants in race/ethnicity-specific and pooled single variant and rare variant aggregate tests. Twenty-two variants across sixteen gene regions were found significantly associated with FG or FI, eight of which were rare (Minor Allele Frequency, MAF<0.05). Functional annotation from resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. Near the G6PC2 locus we identified a distinct FG signal at rare variant rs2232326 (MAF=0.01) after conditioning on known common variants. Functional annotations show rs2232326 to be disruptive and likely damaging while being weakly transcribed in islets. A pair of FG-associated variants were identified near the SLC30A8 locus. These variants, one of which was rare (MAF=0.001) and Asian race/ethnicity-specific, were shown to be in islet-specific active enhancer regions. Other associated regions include rare variants near ROBO1 and PTPRT, and common variants near MTNR1B, GCK, GCKR, FOXA2, APOB, TCF7L2, and ADCY5. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions down to a minor allele count of 20, creating a foundation for future sequencing-based investigation of glycemic traits.

中文翻译：

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来自NHLBI TOPMed计划的不同队列中的空腹血糖和空腹胰岛素水平的全基因组序列关联分析

空腹血糖（FG）和空腹胰岛素（FI）的遗传决定因素主要通过基因组和外显子组阵列进行了研究，产生了100多个相关变体。我们通过NHLBI精密医学Trans-Omics计划（TOPMed）计划中的15个队列的高覆盖全基因组测序（WGS）分析扩展了这项工作。每个特征都包括来自5个自我报告的种族/民族（非洲，亚洲，欧洲，西班牙裔和萨摩亚）的23,000多名非糖尿病患者。我们分析了种族/民族特异性的6000万个变体，并汇总了单个变体和稀有变体的汇总测试。发现跨越16个基因区域的22个变异与FG或FI显着相关，其中8个罕见（次要等位基因频率，MAF <0.05）。针对每种信号（染色质状态，注释主要成分及其他）编译了包括糖尿病表观基因组图谱等资源的功能注释，以阐明功能变异假设。在调节了已知的常见变体后，在G6PC2位点附近，我们在稀有变体rs2232326（MAF = 0.01）处发现了明显的FG信号。功能注释显示rs2232326具有破坏性，并可能在胰岛中转录较弱时造成破坏。在SLC30A8基因座附近鉴定出一对FG相关变体。这些变体，其中之一是罕见的（MAF = 0.001）和亚洲种族/族裔特异性，显示在胰岛特异性活性增强子区域。其他相关区域包括ROBO1和PTPRT附近的罕见变异，以及MTNR1B，GCK，GCKR，FOXA2，APOB，TCF7L2和ADCY5附近的常见变异。