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Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.

TitleGenome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.
Publication TypePublication
Year2017
AuthorsHodonsky CJ, Jain D, Schick UM, Morrison JV, Brown L, McHugh CP, Schurmann C, Chen DD, Liu YMei, Auer PL, Laurie CA, Taylor KD, Browning BL, Li Y, Papanicolaou G, Rotter JI, Kurita R, Nakamura Y, Browning SR, Loos RJF, North KE, Laurie CC, Thornton TA, Pankratz N, Bauer DE, Sofer T, Reiner AP
JournalPLoS Genet
Volume13
Issue4
Paginatione1006760
Date Published2017 04
ISSN1553-7404
Keywordsalpha-Globins, beta-Globins, Erythrocyte Count, Erythrocytes, Female, genome-wide association study, Hemoglobins, Hispanic Americans, Homeodomain Proteins, Humans, Male, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, RNA, Long Noncoding, Solute Carrier Family 12, Member 2, Tumor Suppressor Proteins
Abstract

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 harboring 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.

DOI10.1371/journal.pgen.1006760
Alternate JournalPLoS Genet
PubMed ID28453575
PubMed Central IDPMC5428979
Grant ListU01 HG007417 / HG / NHGRI NIH HHS / United States
K08 DK093705 / DK / NIDDK NIH HHS / United States
P01 GM099568 / GM / NIGMS NIH HHS / United States
R01 HL129132 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
T32 GM081062 / GM / NIGMS NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
MS#: 
0296
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
ECI: 
Yes
Manuscript Status: 
Published and Public