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Am J Hematol. 2018 Jun 15. doi: 10.1002/ajh.25161. [Epub ahead of print]

Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.

Author information

1
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC.
2
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
3
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY.
4
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
5
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.
6
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, the Netherlands.
7
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT.
8
Department of Statistics and Biostatistics, Hill Center, Rutgers, The State University of New Jersey, 110 Frelinghuysen Rd. Piscataway, NY.
9
Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX.
10
Division of Genomic Medicine, National Human Genome Research Institute, National institutes of Health, Bethesda, MD.
11
Departments of Medicine, University of Washington, Seattle, WA.
12
Department of Epidemiology, University of Washington, Seattle, WA.
13
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI.
14
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
15
Department of Biostatistics, University of North Carolina, Chapel Hill, NC.
16
Carolina Population Center, University of North Carolina, Chapel Hill, NC.

Abstract

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10-4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10-7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

KEYWORDS:

Genomics; RBC traits; fine-mapping; generalization; trans-ethnic meta-analysis

PMID:
29905378
PMCID:
PMC6300146
[Available on 2019-12-15]
DOI:
10.1002/ajh.25161
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