Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to...

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Vydáno v:	PLoS genetics Ročník 15; číslo 12; s. e1008500
Hlavní autoři:	Kowalski, Madeline H., Qian, Huijun, Hou, Ziyi, Rosen, Jonathan D., Tapia, Amanda L., Shan, Yue, Jain, Deepti, Argos, Maria, Arnett, Donna K., Avery, Christy, Barnes, Kathleen C., Becker, Lewis C., Bien, Stephanie A., Bis, Joshua C., Blangero, John, Boerwinkle, Eric, Bowden, Donald W., Buyske, Steve, Cai, Jianwen, Cho, Michael H., Choi, Seung Hoan, Choquet, Hélène, Cupples, L. Adrienne, Cushman, Mary, Daya, Michelle, de Vries, Paul S., Ellinor, Patrick T., Faraday, Nauder, Fornage, Myriam, Gabriel, Stacey, Ganesh, Santhi K., Graff, Misa, Gupta, Namrata, He, Jiang, Heckbert, Susan R., Hidalgo, Bertha, Hodonsky, Chani J., Irvin, Marguerite R., Johnson, Andrew D., Jorgenson, Eric, Kaplan, Robert, Kardia, Sharon L. R., Kelly, Tanika N., Kooperberg, Charles, Lasky-Su, Jessica A., Loos, Ruth J. F., Lubitz, Steven A., Mathias, Rasika A., McHugh, Caitlin P., Montgomery, Courtney, Moon, Jee-Young, Morrison, Alanna C., Palmer, Nicholette D., Pankratz, Nathan, Papanicolaou, George J., Peralta, Juan M., Peyser, Patricia A., Rich, Stephen S., Rotter, Jerome I., Silverman, Edwin K., Smith, Jennifer A., Smith, Nicholas L., Taylor, Kent D., Thornton, Timothy A., Tiwari, Hemant K., Tracy, Russell P., Wang, Tao, Weiss, Scott T., Weng, Lu-Chen, Wiggins, Kerri L., Wilson, James G., Yanek, Lisa R., Zöllner, Sebastian, North, Kari E., Auer, Paul L., Raffield, Laura M., Reiner, Alexander P., Li, Yun
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.12.2019 Public Library of Science (PLoS)
Témata:	Adult Aged Aged, 80 and over Alleles beta-Globins - genetics Biology and Life Sciences Black or African American - genetics Cardiac arrhythmia College campuses Computational Biology - methods Databases, Genetic Environmental science Epidemiology Female Gene Frequency Gene mapping Genetic Predisposition to Disease Genetics, Population Genome-Wide Association Study Genomes Genomics Genotypes Genotyping Genotyping Techniques Haplotypes HBB gene Health sciences Hematocrit Hemoglobin Hispanic or Latino - genetics Hospitals Humans Linkage Disequilibrium Male Medical research Medicine Medicine and Health Sciences Middle Aged Population genetics Population studies Precision medicine Precision Medicine - methods Public health Research and Analysis Methods Social Sciences United States Whole genome sequencing Whole Genome Sequencing - methods United States North Carolina New York United States > US California Alabama Ann Arbor Michigan Michigan Los Angeles California Colorado Texas Massachusetts Northern California Maryland Baltimore Maryland
ISSN:	1553-7404, 1553-7390, 1553-7404
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Shrnutí:	Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
Bibliografie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 LMR, APR and YL also contributed equally to this work. Edwin K Silverman and Michael H Cho have received grant support from GSK, MHC has received consulting fees from Genentech. Scott T. Weiss and Kathleen C. Barnes received royalties from UpToDate. Patrick T. Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases, and has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics and Novartis. Steven A Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics, Bristol Myers Squibb / Pfizer. Other authors declared no conflicts of interest. Membership in Trans-Omics for Precision Medicine Consortium and the Hematology & Hemostasis Working Group are listed in supplemental files.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1008500