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

Autor: Hodonsky CJ; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA. ch2um@virginia.edu.; University of Virginia Center for Public Health Genomics, 1355 Lee St, Charlottesville, VA, 22908, USA. ch2um@virginia.edu., Baldassari AR; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA., Bien SA; Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA., Raffield LM; Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA., Highland HM; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA., Sitlani CM; University of Washington, 1730 Minor Ave, Ste 1360, Seattle, WA, 98101, USA., Wojcik GL; Stanford University School of Medicine, 291 Campus Dr, Stanford, CA, 94305, USA., Tao R; Vanderbilt University, 2525 West End Ave #1100, Nashville, TN, 37203, USA., Graff M; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA., Tang W; University of Minnesota, 420 Delaware St SE, Minneapolis, MN, 55455, USA., Thyagarajan B; University of Minnesota, 420 Delaware St SE, Minneapolis, MN, 55455, USA., Buyske S; Rutgers University, 683 Hoes Ln W, Piscataway, NJ, 08854, USA., Fornage M; University of Texas Houston, 7000 Fannin Street, Houston, TX, 77030, USA., Hindorff LA; National Human Genome Research Institute, 31 Center Dr, Bethesda, MD, 20894, USA., Li Y; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA., Lin D; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA., Reiner AP; Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.; University of Washington, 1705 NE Pacific St, Seattle, WA, 98195, USA., North KE; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA., Loos RJF; Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY, 10029, USA., Kooperberg C; University of Washington, 1705 NE Pacific St, Seattle, WA, 98195, USA., Avery CL; University of North Carolina Gillings School of Public Health, 135 Dauer Dr, Chapel Hill, NC, 27599, USA.
Jazyk: angličtina
Zdroj: BMC genomics [BMC Genomics] 2020 Mar 14; Vol. 21 (1), pp. 228. Date of Electronic Publication: 2020 Mar 14.
DOI: 10.1186/s12864-020-6626-9
Abstrakt: 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.
Databáze: MEDLINE
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