Discovery and Mediation Analysis of Cross-Phenotype Associations With 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) among 305,945 White British subjects recruited into the UK Biobank in 2006-2010. We searched for overlapping signals and followed-up on genome-wide-significant cross-phenotype associations by conducting mediation analyses, 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 beta = -0.065kg/m2, 95% confidence interval: -0.087, -0.042; P = 1.30 ×10-8). rs705708 resides in 12q13.2, which harbors nine 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 occurs independently of asthma, with consistent magnitude between men and women and non-asthmatics and asthmatics, irrespectively of age at diagnosis; the asthma-association is stronger for childhood vs. adult asthmatics; and both associations remain after confounder adjustment. This suggests that 12q13.2 displays pleiotropy for asthma and BMI. Upon further characterization, 12q13.2 may provide a target for interventions that simultaneously prevent or treat asthma and obesity.