Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics

Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variatio...

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Published in:BMC genomics Vol. 21; no. 1; pp. 228 - 14
Main Authors: Hodonsky, Chani J., Baldassari, Antoine R., Bien, Stephanie A., Raffield, Laura M., Highland, Heather M., Sitlani, Colleen M., Wojcik, Genevieve L., Tao, Ran, Graff, Marielisa, Tang, Weihong, Thyagarajan, Bharat, Buyske, Steve, Fornage, Myriam, Hindorff, Lucia A., Li, Yun, Lin, Danyu, Reiner, Alex P., North, Kari E., Loos, Ruth J. F., Kooperberg, Charles, Avery, Christy L.
Format: Journal Article
Language:English
Published: London BioMed Central 14.03.2020
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
African Americans
Animal Genetics and Genomics
Biomedical and Life Sciences
Black or African American - genetics
Blood cell traits
Combined-phenotype analysis
Diversity
Erythrocytes
Erythrocytes - metabolism
Female
Genes
Genetic aspects
Genetic research
Genetics, Population
Genome-wide association studies
Genome-Wide Association Study - methods
Genomics
GWAS
Hispanic or Latino - genetics
Human and rodent genomics
Humans
Identification and classification
Life Sciences
Male
Microarrays
Microbial Genetics and Genomics
Minority & ethnic groups
Multi-ethnic
Multifactorial Inheritance
Phenotype
Phenotypes
Plant Genetics and Genomics
Pleiotropy
Polymorphism, Single Nucleotide
Power (Philosophy)
Proteomics
Quantitative trait loci
Quantitative Trait, Heritable
Red blood cells
Research Article
Sequence Analysis, DNA
Single nucleotide polymorphisms
United States - ethnology
White People - genetics
United States
Multi-ethnic
Combined-phenotype analysis
Pleiotropy
GWAS
Blood cell traits
Diversity
ISSN:1471-2164, 1471-2164
Online Access:Get full text
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Summary:Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n  = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal ( p  < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci ( HFE , KIT , HBS1L/MYB , CITED2/FILNC1 , ABO , HBA1/2 , and PLIN4/5 ). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.
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ISSN:1471-2164
1471-2164
DOI:10.1186/s12864-020-6626-9