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Interactions with early-life exposures modulate polygenic risk of wheeze and asthma in preschool-aged children
  • +14
  • Jihoon Choi,
  • Amirtha Ambalavanan,
  • Yang Zhang,
  • Ruixue Dai,
  • Elinor Simons,
  • Hind Sbihi,
  • Sonia Anand,
  • Guillaume Paré,
  • Diana Lefebvre,
  • Stuart Turvey,
  • Piush Mandhane,
  • Allen Becker,
  • Meghan Azad,
  • Theo Moraes,
  • Malcolm Sears,
  • Padmaja Subbarao,
  • Qingling Duan
Jihoon Choi
Queen's University
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Amirtha Ambalavanan
Queen's University Department of Biomedical and Molecular Sciences
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Yang Zhang
Queen's University School of Computing
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Ruixue Dai
The Hospital for Sick Children
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Elinor Simons
University of Manitoba Children's Hospital Research Institute of Manitoba
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Hind Sbihi
The University of British Columbia
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Sonia Anand
McMaster University
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Guillaume Paré
McMaster University
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Diana Lefebvre
McMaster University Faculty of Health Sciences
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Stuart Turvey
The University of British Columbia
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Piush Mandhane
University of Alberta
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Allen Becker
University of Manitoba Children's Hospital Research Institute of Manitoba
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Meghan Azad
University of Manitoba Children's Hospital Research Institute of Manitoba
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Theo Moraes
University of Toronto
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Malcolm Sears
McMaster University
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Padmaja Subbarao
McMaster University
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Qingling Duan
Queen's University
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Abstract

Background: Asthma is a multifactorial disease with numerous associated genetic and environmental risk factors, however, gene-environment interactions are poorly understood in modulating disease risk. This study determines the polygenic effects of multiple genetic loci and interactions with environmental exposures during early infancy on risk of recurrent wheeze and asthma in pre-school aged children. Methods: We conducted genome-wide association studies (GWAS) and applied a thresholding method to calculate genetic risk scores (GRS) of recurrent wheeze and asthma in 2835 children of the CHILD Cohort Study. Recurrent wheeze was defined as two or more episodes in one year between ages 2-5 years and asthma was diagnosed at age 5 years. In addition, we tested for interaction effects between the GRS and environmental exposures on these respiratory outcomes. Results: GWAS identified associations with known asthma loci on chromosome 17q12 - 17q21 (p < 5e-8). GRS analysis determined that the weighted addition of alleles at four childhood-asthma loci correlated with more than 2-fold higher prevalence of recurrent wheeze (p =1.5e-08) and asthma (p = 9.4e-08) between high vs. low GRS groups. In addition, the GRS interacts with breastfeeding (p = 0.02) and traffic air pollution (NO2; p < 0.01) during the first year of life to modulate risk of recurrent wheeze and childhood-onset asthma. Conclusions: This study reports polygenic effects of multiple genetic loci, which interact with early-life exposures, to determine risk of respiratory outcomes during early childhood. Thus, asthma risk may be determined early in infancy when exposures may modulate genetic risk.