Whole Genome Sequence Association Analysis of Fasting Glucose and Fasting Insulin Levels in Diverse Cohorts from the NHLBI TOPMed Program
Authors: DiCorpo Daniel , Gaynor Sheila M , Russell Emily M , Westerman Kenneth E , Raffield Laura M , Majarian Timothy D , Wu Peitao , Sarnowski Chloé , Highland Heather M , Jackson Anne ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hasbani Natalie R , de Vries Paul S , Brody Jennifer A , Hidalgo Bertha , Guo Xiuqing , Perry James A , O’Connell Jeffrey R , Lent Samantha , Montasser May E , Cade Brian E , Jain Deepti , Wang Heming , D’Oliveira Albanus Ricardo , Varshney Arushi , Yanek Lisa R , Lange Leslie , Palmer Nicholette D , Almeida Marcio , Peralta Juan M , Aslibekyan Stella , Baldridge Abigail S , Bertoni Alain G , Bielak Lawrence F , Chen Chung-Shiuan , Chen Yii-Der Ida , Choi Won Jung , Goodarzi Mark O , Floyd James S , Irvin Marguerite R , Kalyani Rita R , Kelly Tanika N , Lee Seonwook , Liu Ching-Ti , Loesch Douglas , Manson JoAnn E , Pankow James S , Rasmussen-Torvik Laura J , Reiner Alexander P , Selvin Elizabeth , Smith Jennifer A , Weeks Daniel E , Xu Huichun , Yao Jie , Zhao Wei , Parker Stephen , Alonso Alvaro , Arnett Donna K , Blangero John , Boerwinkle Eric , Correa Adolfo , Cupples L. Adrienne , Curran Joanne E , Duggirala Ravindranath , He Jiang , Heckbert Susan R , Kardia Sharon LR , Kim Ryan W , Kooperberg Charles , Liu Simin , Mathias Rasika A , McGarvey Stephen T , Mitchell Braxton D , Morrison Alanna C , Peyser Patricia A , Psaty Bruce M , Redline Susan , Shuldiner Alan R , Taylor Kent D , Vasan Ramachandran S , Viaud-Martinez Karine A , Florez Jose C , Wilson James G , Sladek Robert , Rich Stephen S , Rotter Jerome I , Lin Xihong , Dupuis Josée , Meigs James B , Wessel Jennifer , Manning Alisa K 
Published: January 2021

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 theG6PC2locus 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 theSLC30A8locus. 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 nearROBO1andPTPRT, and common variants nearMTNR1B, GCK, GCKR, FOXA2, APOB, TCF7L2, andADCY5. 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.