title: Associations between body mass index-related genetic variants and adult body composition: The Fenland cohort study.
abstract: Body mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults.
  
  
  
  Among 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex.
  
  
  
  The BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 × 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 × 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 × 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 × 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 × 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 × 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects.
  
  
  
  In adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: E A D
authors.initials: EA
authors.lastname: Clifton
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: F R
authors.initials: FR
authors.lastname: Day
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: De Lucia Rolfe
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: N G
authors.initials: NG
authors.lastname: Forouhi
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Brage
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.|Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Griffin
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
authors.forename: K K
authors.initials: KK
authors.lastname: Ong
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D001823:Body Composition / Q000235:genetics*; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D004739:England / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012959:Socioeconomic Factors