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
| Autor: | Laura M. Raffield, Alex P. Reiner, Andrew D. Johnson, Eric Boerwinkle, Juan M. Peralta, Michael H. Cho, Jiang He, Amanda L. Tapia, Jessica Lasky-Su, Scott T. Weiss, Edwin K. Silverman, Mary Cushman, L. Adrienne Cupples, Robert C. Kaplan, Yue Shan, Lisa R. Yanek, Marguerite R. Irvin, Paul L. Auer, Tanika N. Kelly, Hélène Choquet, Stacey Gabriel, Yun Li, Deepti Jain, Steve Buyske, Sebastian Zöllner, Nicholette D. Palmer, Caitlin P. McHugh, Michelle Daya, Jee-Young Moon, Patricia A. Peyser, Patrick T. Ellinor, Paul S. de Vries, Ruth J. F. Loos, Steven A. Lubitz, Timothy A. Thornton, Donald W. Bowden, Christy L. Avery, Courtney G. Montgomery, Misa Graff, Jonathan D. Rosen, Seung Hoan Choi, Kent D. Taylor, Kathleen C. Barnes, Rasika A. Mathias, George Papanicolaou, Santhi K. Ganesh, Alanna C. Morrison, Maria Argos, Nicholas L. Smith, Stephen S. Rich, Donna K. Arnett, Myriam Fornage, Namrata Gupta, Lewis C. Becker, Madeline H. Kowalski, Jennifer A. Smith, Lu-Chen Weng, Eric Jorgenson, Chani J. Hodonsky, Joshua C. Bis, Kari E. North, Jianwen Cai, Ziyi Hou, Jerome I. Rotter, Susan R. Heckbert, Stephanie A. Bien, John Blangero, Sharon L.R. Kardia, Kerri L. Wiggins, Russell P. Tracy, James G. Wilson, Nathan Pankratz, Huijun Qian, Nauder Faraday, Tao Wang, Bertha Hidalgo, Charles Kooperberg, Hemant K. Tiwari |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Linkage disequilibrium Heredity Genotyping Techniques Social Sciences Genome-wide association study beta-Globins QH426-470 Biochemistry Linkage Disequilibrium 0302 clinical medicine Gene Frequency Sociology Consortia Databases Genetic Genotype Medicine and Health Sciences Precision Medicine Genetics (clinical) Aged 80 and over Genetics education.field_of_study 0303 health sciences 030305 genetics & heredity Hispanic or Latino Hematology Genomics Middle Aged 3. Good health Genetic Mapping Female Research Article Adult Genotyping Population Variant Genotypes Biology Research and Analysis Methods 03 medical and health sciences Genome-Wide Association Studies Humans Genetic Predisposition to Disease Hemoglobin 1000 Genomes Project Molecular Biology Techniques education Molecular Biology Allele frequency Alleles Ecology Evolution Behavior and Systematics Aged 030304 developmental biology Genetic association Whole Genome Sequencing Haplotype Computational Biology Biology and Life Sciences Proteins Human Genetics Genome Analysis United States Black or African American Minor allele frequency Genetics Population Haplotypes Genetic Loci 030217 neurology & neurosurgery Imputation (genetics) Genome-Wide Association Study |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 15, Iss 12, p e1008500 (2019) |
| Popis: | 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 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. Author summary Admixed African and Hispanic/Latino populations remain understudied in genetic studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project for imputation in ~21,600 individuals of African ancestry (AAs) and ~21,700 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the 1000 Genomes Project and Haplotype Reference Consortium reference panels. Analysis of quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using current reference panels due to lower imputation quality. Our findings demonstrate the power of TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations. |
| Databáze: | OpenAIRE |
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