Human Molecular Genetics Advance Access first published online on October 31, 2009
This version [Corrected Proof] published online on November 12, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp504
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Life course variations in the associations between FTO and MC4R gene variants and body size
1 MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College London, London WC1B 5JU, UK and 2 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital Box 285, Cambridge CB2 0QQ, UK
* To whom correspondence should be addressed at: MRC Unit for Lifelong Health and Ageing, 33 Bedford Place, London WC1B 5JU, UK. Tel: +44 2076705713; Fax: +44 2075801501; Email: r.hardy{at}nshd.mrc.ac.uk
Received July 22, 2009; Revised September 24, 2009; Accepted October 29, 2009
The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2–20 years) or adulthood (20–53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003–0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08–0.19), and then weakened during adulthood (–0.003 SDS/A-allele/year, –0.005 to –0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001–0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07–0.18), and weakened during adulthood (–0.002 SDS/C-allele/year, –0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.