| Literature DB >> 33887194 |
Yao Hu1, Adrienne M Stilp2, Caitlin P McHugh2, Shuquan Rao3, Deepti Jain2, Xiuwen Zheng2, John Lane4, Sébastian Méric de Bellefon5, Laura M Raffield6, Ming-Huei Chen7, Lisa R Yanek8, Marsha Wheeler9, Yao Yao3, Chunyan Ren3, Jai Broome2, Jee-Young Moon10, Paul S de Vries11, Brian D Hobbs12, Quan Sun13, Praveen Surendran14, Jennifer A Brody15, Thomas W Blackwell16, Hélène Choquet17, Kathleen Ryan18, Ravindranath Duggirala19, Nancy Heard-Costa20, Zhe Wang21, Nathalie Chami21, Michael H Preuss21, Nancy Min22, Lynette Ekunwe22, Leslie A Lange23, Mary Cushman24, Nauder Faraday25, Joanne E Curran19, Laura Almasy26, Kousik Kundu27, Albert V Smith16, Stacey Gabriel28, Jerome I Rotter29, Myriam Fornage30, Donald M Lloyd-Jones31, Ramachandran S Vasan32, Nicholas L Smith33, Kari E North34, Eric Boerwinkle11, Lewis C Becker35, Joshua P Lewis18, Goncalo R Abecasis16, Lifang Hou31, Jeffrey R O'Connell18, Alanna C Morrison11, Terri H Beaty36, Robert Kaplan10, Adolfo Correa22, John Blangero19, Eric Jorgenson17, Bruce M Psaty37, Charles Kooperberg1, Russell T Walton38, Benjamin P Kleinstiver39, Hua Tang40, Ruth J F Loos21, Nicole Soranzo41, Adam S Butterworth42, Debbie Nickerson9, Stephen S Rich43, Braxton D Mitchell18, Andrew D Johnson7, Paul L Auer44, Yun Li45, Rasika A Mathias46, Guillaume Lettre47, Nathan Pankratz4, Cathy C Laurie2, Cecelia A Laurie2, Daniel E Bauer3, Matthew P Conomos2, Alexander P Reiner48.
Abstract
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.Entities:
Keywords: base editing; red blood cell traits; whole-genome sequencing
Mesh：
Year: 2021 PMID： 33887194 PMCID： PMC8206199 DOI： 10.1016/j.ajhg.2021.04.003
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025