title: Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma.
abstract: Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10(-6); OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10(-8) and 4.09 × 10(-8), respectively) and MTHFR in the African ancestry sample (P=1.72 × 10(-6)). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the 'missing heritability' of asthma.
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Igartua
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Myers
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA.
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: 1] Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA [2] CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid 28029, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Pino-Yanes
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Celeste
authors.initials: C
authors.lastname: Eng
authors.affiliation: Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Graves
authors.affiliation: Department of Public Health Science, Henry Ford Health System, Detroit, Michigan 48202, USA.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Levin
authors.affiliation: Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Del-Rio-Navarro
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Jackson
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
authors.forename: Oren E
authors.initials: OE
authors.lastname: Livne
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21224, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.affiliation: School of Nursing, University of Michigan, Ann Arbor, Michigan 48202, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Huntsman
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Salam
authors.affiliation: International Agency for Research on Cancer, Lyon 69372, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Romieu
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mourad
authors.affiliation: 1] Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA [2] Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Gern
authors.affiliation: 1] Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA [2] Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Annah
authors.initials: A
authors.lastname: Wyss
authors.affiliation: 1] Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA [2] Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27607, USA.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hoppin
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.affiliation: 1] Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA [2] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Esteban G
authors.initials: EG
authors.lastname: Burchard
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: W James
authors.initials: WJ
authors.lastname: Gauderman
authors.affiliation: Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.affiliation: 1] Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts 2115, USA [2] Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, Massachusetts 2115, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts 2115, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: 1] Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan 48202, USA [2] Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, USA.
authors.forename: L Keoki
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.affiliation: 1] Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA [2] Departments of Medicine and Statistics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Nicolae
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D001249:Asthma / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D000094524:Gasdermins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins; C410230:tamalin protein, human