title: 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.
  
  
  RESULTS
  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.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Granell
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: A John
authors.initials: AJ
authors.lastname: Henderson
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: UK National Institute for Health Research Bristol Nutrition Biomedical Research Unit in Nutrition, Diet and Lifestyle, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, United Kingdom; School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Ness
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Jonathan A C
authors.initials: JA
authors.lastname: Sterne
mesh_terms: D050154:Adiposity; D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D015992:Body Mass Index; D001835:Body Weight; D002648:Child; D004739:England / Q000453:epidemiology; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D020641:Polymorphism, Single Nucleotide