Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study

Abstract

Background: Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.

Methods and findings: We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.

Conclusions: Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

Figure 1. Main Mendelian randomization features and results of the study.

(A) depicts the IV assumptions, and (B) shows the two unconfounded associations used to estimate causal effects of BMI on asthma: the association of the allele score with BMI and the association of the allele score with asthma.

Figure 2. Association of BMI at 7½ y of 32 BMI-related SNPs.

The left panel shows the mean BMI (with 95% CI) in groups defined by quintiles of genotype-predicted BMI. The right panel shows the same means and confidence intervals superimposed on the overall distribution of BMI plotted against genotype-predicted BMI.

Figure 3. Forest plot of the individual causal effects on current asthma at 7½ y of 32 BMI-related SNPs.

The SNPs are those previously reported in a meta-analysis that excluded ALSPAC data. rs2287019 and rs4771122 were omitted from the forest plot because IV RRs were not estimable. Also rs10150332, rs10767664, rs10938397, rs1555543, rs206936, rs2112347, rs2287019, rs2890652, rs381029, rs4771122, rs4836133, rs9816226, and rs987237 were excluded because the corresponding SE (of the log RR) was >2.