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Nat Commun. 2015 Jan 16;6:5965. doi: 10.1038/ncomms6965.

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma.

Author information

1
Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 425, Chicago, Illinois 60637, USA.
2
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA.
3
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.
4
Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA.
5
Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA.
6
Department of Public Health Science, Henry Ford Health System, Detroit, Michigan 48202, USA.
7
Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
8
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA.
9
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21224, USA.
10
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
11
School of Nursing, University of Michigan, Ann Arbor, Michigan 48202, USA.
12
International Agency for Research on Cancer, Lyon 69372, France.
13
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.
14
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.
15
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.
16
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.
17
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.
18
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.
19
Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts 2115, USA.
20
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.
21
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.

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.

PMID:
25591454
PMCID:
PMC4309441
DOI:
10.1038/ncomms6965
[Indexed for MEDLINE]
Free PMC Article

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