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

TitleWhole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.
Publication TypeJournal Article
Year of Publication2022
AuthorsWheeler, MM, Stilp, AM, Rao, S, Halldórsson, BV, Beyter, D, Wen, J, Mihkaylova, AV, McHugh, CP, Lane, J, Jiang, M-Z, Raffield, LM, Jun, G, Sedlazeck, FJ, Metcalf, GA, Yao, Y, Bis, JB, Chami, N, de Vries, PS, Desai, P, Floyd, JS, Gao, Y, Kammers, K, Kim, W, Moon, J-Y, Ratan, A, Yanek, LR, Almasy, L, Becker, LC, Blangero, J, Cho, MH, Curran, JE, Fornage, M, Kaplan, RC, Lewis, JP, Loos, RJF, Mitchell, BD, Morrison, AC, Preuss, M, Psaty, BM, Rich, SS, Rotter, JI, Tang, H, Tracy, RP, Boerwinkle, E, Abecasis, GR, Blackwell, TW, Smith, AV, Johnson, AD, Mathias, RA, Nickerson, DA, Conomos, MP, Li, Y, Þorsteinsdóttir, U, Magnússon, MK, Stefansson, K, Pankratz, ND, Bauer, DE, Auer, PL, Reiner, AP
JournalNat Commun
Date Published2022 Dec 08
KeywordsBlood Cells, Genome-Wide Association Study, Humans, Whole Genome Sequencing

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.

Alternate JournalNat Commun
PubMed ID36481753
PubMed Central IDPMC9732337
Grant ListR01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL154385 / HL / NHLBI NIH HHS / United States
T32 ES007018 / ES / NIEHS NIH HHS / United States
U01 HG011720 / HG / NHGRI NIH HHS / United States

Similar Publications