Dataset Information

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

ABSTRACT: Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

SUBMITTER: Mikhaylova AV

PROVIDER: S-EPMC8546043 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Mikhaylova Anna V AV McHugh Caitlin P CP Polfus Linda M LM Raffield Laura M LM Boorgula Meher Preethi MP Blackwell Thomas W TW Brody Jennifer A JA Broome Jai J Chami Nathalie N Chen Ming-Huei MH Conomos Matthew P MP Cox Corey C Curran Joanne E JE Daya Michelle M Ekunwe Lynette L Glahn David C DC Heard-Costa Nancy N Highland Heather M HM Hobbs Brian D BD Ilboudo Yann Y Jain Deepti D Lange Leslie A LA Miller-Fleming Tyne W TW Min Nancy N Moon Jee-Young JY Preuss Michael H MH Rosen Jonathon J Ryan Kathleen K Smith Albert V AV Sun Quan Q Surendran Praveen P de Vries Paul S PS Walter Klaudia K Wang Zhe Z Wheeler Marsha M Yanek Lisa R LR Zhong Xue X Abecasis Goncalo R GR Almasy Laura L Barnes Kathleen C KC Beaty Terri H TH Becker Lewis C LC Blangero John J Boerwinkle Eric E Butterworth Adam S AS Chavan Sameer S Cho Michael H MH Choquet Hélène H Correa Adolfo A Cox Nancy N DeMeo Dawn L DL Faraday Nauder N Fornage Myriam M Gerszten Robert E RE Hou Lifang L Johnson Andrew D AD Jorgenson Eric E Kaplan Robert R Kooperberg Charles C Kundu Kousik K Laurie Cecelia A CA Lettre Guillaume G Lewis Joshua P JP Li Bingshan B Li Yun Y Lloyd-Jones Donald M DM Loos Ruth J F RJF Manichaikul Ani A Meyers Deborah A DA Mitchell Braxton D BD Morrison Alanna C AC Ngo Debby D Nickerson Deborah A DA Nongmaithem Suraj S North Kari E KE O'Connell Jeffrey R JR Ortega Victor E VE Pankratz Nathan N Perry James A JA Psaty Bruce M BM Rich Stephen S SS Soranzo Nicole N Rotter Jerome I JI Silverman Edwin K EK Smith Nicholas L NL Tang Hua H Tracy Russell P RP Thornton Timothy A TA Vasan Ramachandran S RS Zein Joe J Mathias Rasika A RA Reiner Alexander P AP Auer Paul L PL

American journal of human genetics 20210927 10

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Prec ...[more]

PMID: 34582791

Similar Datasets

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 sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Publications

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets