Genome-wide interaction studies reveal sex-specific asthma risk alleles.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
Department of Human Genetics ram330@gmail.com nicolae@galton.uchicago.edu.
Rachel A
RA
Myers
Department of Human Genetics.
Nicole M
NM
Scott
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
W James
WJ
Gauderman
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Weiliang
W
Qiu
Department of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Rasika A
RA
Mathias
International Agency for Research on Cancer, Lyon, France.
Isabelle
I
Romieu
Department of Public Health Sciences.
Albert M
AM
Levin
Department of Medicine and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Maria
M
Pino-Yanes
BIO5 Institute, Arizona Respiratory Care Center, University of Arizona, Tucson, AZ 85721, USA.
Penelope E
PE
Graves
National Institute of Public Health of Mexico, Cuernavaca, Morelos, Mexico.
Albino Barraza
AB
Villarreal
Department of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Terri H
TH
Beaty
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Vincent J
VJ
Carey
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Damien C
DC
Croteau-Chonka
Hospital Infantil de Mexico Federico Gómez, Mexico City, Mexico.
Blanca
B
del Rio Navarro
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
Christopher
C
Edlund
National Institute of Public Health of Mexico, Cuernavaca, Morelos, Mexico.
Leticia
L
Hernandez-Cadena
National Institute of Public Health of Mexico, Cuernavaca, Morelos, Mexico.
Efrain
E
Navarro-Olivos
Center for Health Policy and Health Services Research.
Badri
B
Padhukasahasram
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
Muhammad T
MT
Salam
Department of Medicine and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
Dara G
DG
Torgerson
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
David J
DJ
Van den Berg
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
Hita
H
Vora
Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Eugene R
ER
Bleecker
Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Deborah A
DA
Meyers
Center for Health Policy and Health Services Research Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
L Keoki
LK
Williams
BIO5 Institute, Arizona Respiratory Care Center, University of Arizona, Tucson, AZ 85721, USA.
Fernando D
FD
Martinez
Department of Medicine and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
Esteban G
EG
Burchard
Department of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Kathleen C
KC
Barnes
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
Frank D
FD
Gilliland
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Scott T
ST
Weiss
National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
Stephanie J
SJ
London
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Benjamin A
BA
Raby
Department of Human Genetics.
Carole
C
Ober
Department of Human Genetics Department of Statistics and Medicine, University of Chicago, Chicago, IL 60637, USA ram330@gmail.com nicolae@galton.uchicago.edu.
Dan L
DL
Nicolae
D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D044469:Racial Groups / Q000235:genetics; D015203:Reproducibility of Results; D012737:Sex Factors