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

Autor: Deepti Jain, Alex P. Reiner, Kent D. Taylor, Jean Morrison, Timothy A. Thornton, Diane D. Chen, Jerome I. Rotter, Ruth J. F. Loos, Yun Li, Yukio Nakamura, Cecilia A. Laurie, Paul L. Auer, Sharon R. Browning, George Papanicolaou, Kari E. North, Brian L. Browning, Claudia Schurmann, Lisa M. Brown, Tamar Sofer, Chani J. Hodonsky, Caitlin P. McHugh, Cathy C. Laurie, Ursula M. Schick, Ryo Kurita, Nathan Pankratz, Yongmei Liu, Daniel E. Bauer
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Cancer Research
Erythrocytes
Genome-wide association study
beta-Globins
Biochemistry
Hemoglobins
Animal Cells
Red Blood Cells
Solute Carrier Family 12
Member 2
Copy-number variation
Genetics (clinical)
Genetics
Sex Chromosomes
medicine.diagnostic_test
Chromosome Biology
X Chromosomes
Genomics
Hispanic or Latino
Female
RNA
Long Noncoding
Cellular Types
Research Article
Proteasome Endopeptidase Complex
lcsh:QH426-470
Quantitative Trait Loci
Mean corpuscular hemoglobin
Locus (genetics)
Biology
Quantitative trait locus
Polymorphism
Single Nucleotide
Chromosomes
03 medical and health sciences
alpha-Globins
Genome-Wide Association Studies
medicine
Humans
Hemoglobin
Allele
1000 Genomes Project
Molecular Biology
Alleles
Ecology
Evolution
Behavior and Systematics
Homeodomain Proteins
Blood Cells
Tumor Suppressor Proteins
Biology and Life Sciences
Proteins
Computational Biology
Human Genetics
Cell Biology
Genome Analysis
lcsh:Genetics
030104 developmental biology
Genetic Loci
Erythrocyte Count
Imputation (genetics)
Genome-Wide Association Study
Zdroj: PLoS Genetics, Vol 13, Iss 4, p e1006760 (2017)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary Red blood cells (RBC) are important for transport of oxygen to tissues throughout the body. Distribution of RBC traits differs by ethnicity and gender, and both genetic and acquired factors likely contribute to these differences. Prior genetic studies have identified physical regions of the genome associated with RBC traits in populations with European, African, and Asian ancestry. These studies have not included individuals with ancestry from the American continents (Amerindian ancestry), such as Hispanics/Latinos. In an analysis of RBC traits in up to 19,608 Hispanics/Latinos, we identified an Amerindian-ancestry genetic association in a known alpha-globin regulatory region. We also identified three new RBC trait associations, including a regulatory variant of SLC12A2 that encodes a RBC membrane ion-transport protein. Experimental disruption of this regulatory element led to reduced expression of both SLC12A2 and an adjacent long non-coding RNA in human erythroid progenitor cells. These results contribute to understanding the physiology of red blood cells and reinforce the importance of genetic study of diverse ancestry populations, in particular Hispanics/Latinos.
Databáze: OpenAIRE
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