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Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.

ABSTRACT: Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

SUBMITTER: Wheeler MM

PROVIDER: S-EPMC9732337 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.

Wheeler Marsha M MM Stilp Adrienne M AM Rao Shuquan S Halldórsson Bjarni V BV Beyter Doruk D Wen Jia J Mihkaylova Anna V AV McHugh Caitlin P CP Lane John J Jiang Min-Zhi MZ Raffield Laura M LM Jun Goo G Sedlazeck Fritz J FJ Metcalf Ginger G Yao Yao Y Bis Joshua B JB Chami Nathalie N de Vries Paul S PS Desai Pinkal P Floyd James S JS Gao Yan Y Kammers Kai K Kim Wonji W Moon Jee-Young JY Ratan Aakrosh A Yanek Lisa R LR Almasy Laura L Becker Lewis C LC Blangero John J Cho Michael H MH Curran Joanne E JE Fornage Myriam M Kaplan Robert C RC Lewis Joshua P JP Loos Ruth J F RJF Mitchell Braxton D BD Morrison Alanna C AC Preuss Michael M Psaty Bruce M BM Rich Stephen S SS Rotter Jerome I JI Tang Hua H Tracy Russell P RP Boerwinkle Eric E Abecasis Goncalo R GR Blackwell Thomas W TW Smith Albert V AV Johnson Andrew D AD Mathias Rasika A RA Nickerson Deborah A DA Conomos Matthew P MP Li Yun Y Þorsteinsdóttir Unnur U Magnússon Magnús K MK Stefansson Kari K Pankratz Nathan D ND Bauer Daniel E DE Auer Paul L PL Reiner Alex P AP

Nature communications 20221208 1

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) t ...[more]

PMID: 36481753

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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 sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.

Publications

Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.

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