Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx

Background Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization. Results Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up. Conclusions We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach

Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx

Abstract Background Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization. Results Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up. Conclusions We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.http://deepblue.lib.umich.edu/bitstream/2027.42/173856/1/13059_2020_Article_2113.pd

Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

Host-parasite interactio

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

Ricardo Riccio Oliveira. Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Patologia Experimental. Salvador, BA, Brasil, 1 Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA. 2 Department of Epidemiology, Bloomberg School of Public Health, JHU, Baltimore, Maryland 21205, USA. 3 Department of Biostatistics, Bloomberg School of Public Health, JHU, Baltimore, Maryland 21205, USA. 4 Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. 5 Department of Genomic Sciences, University of Washington, Seattle, Washington 98195, USA. 6 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. 7 Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. 8 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. 9 Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA. 10 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid 28029, Spain. 11 Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30322, USA. 12 Center for Human Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA. 13 Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan 48202, USA. 14 Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California 94158, USA. 15 Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan 48202, USA. 16 Centro de Neumologia y Alergias, San Pedro Sula 21102, Honduras. 17 Faculty of Medicine, Centro Medico de la Familia, San Pedro Sula 21102, Honduras. 18 Tropical Medicine Research Institute, The University of the West Indies, St. Michael BB11115, Barbados. 19 Department of Parasitology, Leiden University Medical Center, Leiden 2333ZA, The Netherlands. 20 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. 21 Instituto de Investigaciones Immunologicas, Universidad de Cartagena, Cartagena 130000, Colombia. 22 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. 23 Department of Pediatrics, Northwestern University, Chicago, Illinois 60637, USA. 24 The Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois 60637, USA. 25 Department of Medicine, Northwestern University, Chicago, Illinois 60637, USA. 26 Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, USA. 27 Faculty of Medical Sciences Cave Hill Campus, The University of the West Indies, Bridgetown BB11000, Barbados. 28 Queen Elizabeth Hospital, The University of the West Indies, St. Michael BB11115, Barbados. 29 Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA. 30 Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA. 31 Department of Medicine and Center for Global Health, University of Chicago, Chicago, Illinois 60637, USA. 32 Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. 33 Laborato´rio de Patologia Experimental, Centro de Pesquisas Gonc¸alo Moniz, Salvador 40296-710, Brazil. 34 Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA. 35 Department of Statistics, University of Chicago, Chicago, Illinois 60637, USA. 36 Pulmonary and Critical Care Medicine, Morehouse School of Medicine, Atlanta, Georgia 30310, USA. 37 Department of Medicine, The Brooklyn Hospital Center, Brooklyn, New York 11201, USA. 38 National Human Genome Center, Howard University College of Medicine,Washington DC 20059, USA. 39 Department of Microbiology, Howard University College of Medicine,Washington DC 20059, USA. 40 Institute for Immunological Research, Universidad de Cartagena, Cartagena 130000, Colombia. 41 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, USA. 42 Immunology Service, Universidade Federal da Bahia, Salvador 401110170, Brazil. 43 Facultad de Medicina, Universidad Catolica de Honduras, San Pedro Sula 21102, Honduras. 44 Illumina, Inc., San Diego, California 92122, USA. 45 Knome Inc., Cambridge, Massachusetts 02141, USA. 46 Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. 47 Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 48 Institute for Human Genetics, University of California, San Francisco, San Francisco, California 94143, USA. 49 California Institute for Quantitative Biosciences, University of California, San Francisco, California 94143, USA.Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-03-27T16:01:46Z No. of bitstreams: 1 Mathias_R A continuum of...).pdf: 1498239 bytes, checksum: 19504c57796d4f14f86d677aa4e422fa (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-03-27T16:28:42Z (GMT) No. of bitstreams: 1 Mathias_R A continuum of...).pdf: 1498239 bytes, checksum: 19504c57796d4f14f86d677aa4e422fa (MD5)Made available in DSpace on 2017-03-27T16:28:42Z (GMT). No. of bitstreams: 1 Mathias_R A continuum of...).pdf: 1498239 bytes, checksum: 19504c57796d4f14f86d677aa4e422fa (MD5) Previous issue date: 2016Johns Hopkins University. Department of Medicine. Baltimore, Maryland, USA / Bloomberg School of Public Health JHU. Department of Epidemiology. Baltimore, Maryland, USABloomberg School of Public Health, JHU. Department of Biostatistics. Baltimore, Maryland, USAFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Patologia Experimental. Salvador, BA, Brasil. Múltipla - ver em NotasThe African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry

Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations (vol 10, 880, 2019)

Host-parasite interactio

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry