Ancestry-Specific Associations Identified in Genome-Wide Combined-Phenotype Study of Red Blood Cell Traits Emphasize Benefits of Diversity in Genomics

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Citation

Hodonsky, Chani J.; Baldassari, Antoine R.; Bien, Stephanie A.; Raffield, Laura M.; Highland, Heather M.; Sitlani, Colleen M.; Wojcik, Genevieve L.; Tao, Ran; Graff, Mariaelisa; & Tang, Weihong, et al. (2020). Ancestry-Specific Associations Identified in Genome-Wide Combined-Phenotype Study of Red Blood Cell Traits Emphasize Benefits of Diversity in Genomics. BMC Genomics, 21(1), 228. PMCID: PMC7071748

Abstract

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.

URL

https://doi.org/10.1186/s12864-020-6626-9

Reference Type

Journal Article

Year Published

2020

Journal Title

BMC Genomics

Author(s)

Hodonsky, Chani J.
Baldassari, Antoine R.
Bien, Stephanie A.
Raffield, Laura M.
Highland, Heather M.
Sitlani, Colleen M.
Wojcik, Genevieve L.
Tao, Ran
Graff, Mariaelisa
Tang, Weihong
Thyagarajan, Bharat
Buyske, Steven G.
Fornage, Myriam
Hindorff, Lucia A.
Li, Yun
Lin, Dan-Yu
Reiner, Alexander P.
North, Kari E.
Loos, Ruth J. F.
Kooperberg, Charles L.
Avery, Christy L.

Article Type

Regular

PMCID

PMC7071748

Data Set/Study

Population Architecture using Genomics and Epidemiology (PAGE) Study

Continent/Country

United States of America

State

Nonspecific

Race/Ethnicity

African-American
Hispanic/Latinx
European American

ORCiD

Avery - 0000-0002-1044-8162
Highland - 000-0002-3583-8239
Graff - 0000-0001-6380-1735