Journal
PLOS GENETICS
Volume 13, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006760
Keywords
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Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233]
- University of Miami [N01-HC65234]
- Albert Einstein College of Medicine [N01-HC65235]
- Northwestern University [N01-HC65236]
- San Diego State University [N01-HC65237]
- NHLBI [HSN 26220/20054C]
- NIDCR [HHSN268201300005C AM03, MOD03]
- NCATS CTSI [UL1TR000123]
- NIDDK Diabetes Research Center (DRC) [DK063491]
- SOL (Study of Latinos) Grant under the Prime between HHS [HHSB268201200054C]
- NIH
- National Heart, Lung and Blood Institute and Illumina, Inc.
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- Andrea and Charles Bronfman Philanthropies
- Scientific Computing at the Icahn School of Medicine at Mount Sinai
- NIDDK [K08DK093705]
- Doris Duke Charitable Foundation
- Charles H. Hood Foundation
- American Society of Hematology
- Burroughs Wellcome Fund
- Cooley's Anemia Foundation
- [1R01DK101855-01]
- [13GRNT16490017]
- [R01-GM110068]
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Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/ SOL Hispanics/Latinos, including African ancestral alpha-and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 ( which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element har-boring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.
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