title: Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array.
abstract: Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Stephanie A
authors.identifier: http://orcid.org/0000-0002-8713-4583
authors.initials: SA
authors.lastname: Bien
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Genevieve L
authors.identifier: http://orcid.org/0000-0001-7206-8088
authors.initials: GL
authors.lastname: Wojcik
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Niha
authors.initials: N
authors.lastname: Zubair
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gignoux
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Alicia R
authors.identifier: http://orcid.org/0000-0003-0241-3522
authors.initials: AR
authors.lastname: Martin
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jonathan M
authors.identifier: http://orcid.org/0000-0001-8084-1608
authors.initials: JM
authors.lastname: Kocarnik
authors.affiliation: Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Martin
authors.affiliation: Department of Genetics, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Steven
authors.identifier: http://orcid.org/0000-0001-8539-5416
authors.initials: S
authors.lastname: Buyske
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Haessler
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Walker
authors.affiliation: Cancer Prevention Institute of California, Fremont, California, United States of America.
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Mariaelisa
authors.initials: M
authors.lastname: Graff
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.
authors.forename: Lucy
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Genetics, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Tara
authors.initials: T
authors.lastname: Matise
authors.affiliation: Division of Intramural Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: James
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lucia
authors.identifier: http://orcid.org/0000-0002-4414-3236
authors.initials: L
authors.lastname: Hindorff
authors.affiliation: Department of Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Kooperberg
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
mesh_terms: D000483:Alleles; D000886:Anthropometry; D002874:Chromosome Mapping; D005006:Ethnicity / Q000235:genetics*; D059472:Exome; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D014481:United States