Dataset Information

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

ABSTRACT: The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

SUBMITTER: DiCorpo D

PROVIDER: S-EPMC9334637 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

DiCorpo Daniel D Gaynor Sheila M SM Russell Emily M EM Westerman Kenneth E KE Raffield Laura M LM Majarian Timothy D TD Wu Peitao P Sarnowski Chloé C Highland Heather M HM Jackson Anne A Hasbani Natalie R NR de Vries Paul S PS Brody Jennifer A JA Hidalgo Bertha B Guo Xiuqing X Perry James A JA O'Connell Jeffrey R JR Lent Samantha S Montasser May E ME Cade Brian E BE Jain Deepti D Wang Heming H D'Oliveira Albanus Ricardo R Varshney Arushi A Yanek Lisa R LR Lange Leslie L Palmer Nicholette D ND Almeida Marcio M Peralta Juan M JM Aslibekyan Stella S Baldridge Abigail S AS Bertoni Alain G AG Bielak Lawrence F LF Chen Chung-Shiuan CS Chen Yii-Der Ida YI Choi Won Jung WJ Goodarzi Mark O MO Floyd James S JS Irvin Marguerite R MR Kalyani Rita R RR Kelly Tanika N TN Lee Seonwook S Liu Ching-Ti CT Loesch Douglas D Manson JoAnn E JE Minster Ryan L RL Naseri Take T Pankow James S JS Rasmussen-Torvik Laura J LJ Reiner Alexander P AP Reupena Muagututi'a Sefuiva MS Selvin Elizabeth E Smith Jennifer A JA Weeks Daniel E DE Xu Huichun H Yao Jie J Zhao Wei W Parker Stephen S Alonso Alvaro A Arnett Donna K DK Blangero John J Boerwinkle Eric E Correa Adolfo A Cupples L Adrienne LA Curran Joanne E JE Duggirala Ravindranath R He Jiang J Heckbert Susan R SR Kardia Sharon L R SLR Kim Ryan W RW Kooperberg Charles C Liu Simin S Mathias Rasika A RA McGarvey Stephen T ST Mitchell Braxton D BD Morrison Alanna C AC Peyser Patricia A PA Psaty Bruce M BM Redline Susan S Shuldiner Alan R AR Taylor Kent D KD Vasan Ramachandran S RS Viaud-Martinez Karine A KA Florez Jose C JC Wilson James G JG Sladek Robert R Rich Stephen S SS Rotter Jerome I JI Lin Xihong X Dupuis Josée J Meigs James B JB Wessel Jennifer J Manning Alisa K AK

Communications biology 20220728 1

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly ass ...[more]

PMID: 35902682

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Project description:Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Dataset Information

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

Publications

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

Similar Datasets

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