Discovery and Mediation Analysis of Cross-Phenotype Associations Between Asthma and Body Mass Index in 12q13.2.

Twin studies suggest that shared genetics contributes to the comorbidity of asthma and obesity, but candidate-gene studies provide limited evidence of pleiotropy. We conducted genome-wide association analyses of asthma and body mass index (BMI; weight (kg)/height (m)2)) among 305,945 White British subjects recruited into the UK Biobank in 2006-2010. We searched for overlapping signals and conducted mediation analyses on genome-wide-significant cross-phenotype associations, assessing moderation by sex and age at asthma diagnosis, and adjusting for confounders of the asthma-BMI relationship. We identified a genome-wide-significant cross-phenotype association at rs705708 (asthma odds ratio = 1.05, 95% confidence interval: 1.03, 1.07; P = 7.20 × 10-9; and BMI β = -0.065, 95% confidence interval: -0.087, -0.042; P = 1.30 × 10-8). rs705708 resides on 12q13.2, which harbors 9 other asthma- and BMI-associated variants (all P < 5 × 10-5 for asthma; all but one P < 5 × 10-5 for BMI). Follow-up analyses of rs705708 show that most of the BMI association occurred independently of asthma, with consistent magnitude between men and women and persons with and without asthma, irrespective of age at diagnosis; the asthma association was stronger for childhood versus adult asthma; and both associations remained after confounder adjustment. This suggests that 12q13.2 displays pleiotropy for asthma and BMI. Upon further characterization, 12q13.2 might provide a target for interventions that simultaneously prevent or treat asthma and obesity.