Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program
Authors: Hu Yao , Stilp Adrienne M. , McHugh Caitlin P. , Rao Shuquan , Jain Deepti , Zheng Xiuwen , Lane John , de Bellefon Sébastian Méric , Raffield Laura M. , Chen Ming-Huei , Yanek Lisa R. , Wheeler Marsha , Yao Yao , Ren Chunyan , Broome Jai , Moon Jee-Young , de Vries Paul S. , Hobbs Brian D. , Sun Quan , Surendran Praveen , Brody Jennifer A. , Blackwell Thomas W. , Choquet Hélène , Ryan Kathleen , Duggirala Ravindranath , Heard-Costa Nancy , Wang Zhe , Chami Nathalie , Preuss Michael H. , Min Nancy , Ekunwe Lynette , Lange Leslie A. , Cushman Mary , Faraday Nauder , Curran Joanne E. , Almasy Laura , Kundu Kousik , Smith Albert V. , Gabriel Stacey , Rotter Jerome I. , Fornage Myriam , Lloyd-Jones Donald M. , Vasan Ramachandran S. , Smith Nicholas L. , North Kari E. , Boerwinkle Eric , Becker Lewis C. , Lewis Joshua P. , Abecasis Goncalo R. , Hou Lifang , O’Connell Jeffrey R. , Morrison Alanna C. , Beaty Terri H. , Kaplan Robert , Correa Adolfo , Blangero John , Jorgenson Eric , Psaty Bruce M. , Kooperberg Charles , Walton Russell T. , Kleinstiver Benjamin P. , Tang Hua , Loos Ruth J.F. , Soranzo Nicole , Butterworth Adam S. , Nickerson Debbie , Rich Stephen S. , Mitchell Braxton D. , Johnson Andrew D. , Auer Paul L. , Li Yun , Mathias Rasika A. , Lettre Guillaume , Pankratz Nathan , Laurie Cathy C. , Laurie Cecelia A. , Bauer Daniel E. , Conomos Matthew P. , Reiner Alexander P. ,   the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: December 2020

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. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these newly 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 3bp indel p.Lys2169del (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis [OMIM 194380], associated with higher 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.