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Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.
Tuesday,2021-07-20 14:46 America/Los_Angeles — ecterry
| Title | Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | Hu, Y, Stilp, AM, McHugh, CP, Rao, S, Jain, D, Zheng, X, Lane, J, de Bellefon, SMéric, Raffield, LM, Chen, M-H, Yanek, LR, Wheeler, M, Yao, Y, Ren, C, Broome, J, Moon, J-Y, de Vries, PS, Hobbs, BD, Sun, Q, Surendran, P, Brody, JA, Blackwell, TW, Choquet, H, Ryan, K, Duggirala, R, Heard-Costa, N, Wang, Z, Chami, N, Preuss, MH, Min, N, Ekunwe, L, Lange, LA, Cushman, M, Faraday, N, Curran, JE, Almasy, L, Kundu, K, Smith, AV, Gabriel, S, Rotter, JI, Fornage, M, Lloyd-Jones, DM, Vasan, RS, Smith, NL, North, KE, Boerwinkle, E, Becker, LC, Lewis, JP, Abecasis, GR, Hou, L, O'Connell, JR, Morrison, AC, Beaty, TH, Kaplan, R, Correa, A, Blangero, J, Jorgenson, E, Psaty, BM, Kooperberg, C, Walton, RT, Kleinstiver, BP, Tang, H, Loos, RJF, Soranzo, N, Butterworth, AS, Nickerson, D, Rich, SS, Mitchell, BD, Johnson, AD, Auer, PL, Li, Y, Mathias, RA, Lettre, G, Pankratz, N, Laurie, CC, Laurie, CA, Bauer, DE, Conomos, MP, Reiner, AP |
| Corporate/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
| Journal | Am J Hum Genet |
| Volume | 108 |
| Issue | 5 |
| Pagination | 874-893 |
| Date Published | 2021 05 06 |
| ISSN | 1537-6605 |
| Keywords | Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States |
| Abstract | <p>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.</p> |
| DOI | 10.1016/j.ajhg.2021.04.003 |
| Alternate Journal | Am J Hum Genet |
| PubMed ID | 33887194 |
| PubMed Central ID | PMC8206199 |
| Grant List | R01 HL130733 / HL / NHLBI NIH HHS / United States P01 HL142494 / HL / NHLBI NIH HHS / United States R01 HL136574 / HL / NHLBI NIH HHS / United States K08 HL136928 / HL / NHLBI NIH HHS / United States R01 HL146500 / HL / NHLBI NIH HHS / United States |
ePub date:
21/05