We examined associations between six common polymorphisms in the GH/IGF axis and measures of anthropometric and physical capability phenotypes in seven UK cohorts comprising a total of 13,364 adults aged between 52 and 90 years. To our knowledge this is the largest investigation into polymorphisms in the axis and physical capability. The polymorphisms chosen are either functional or have been robustly associated with age-related phenotypes in GWAS. Among the 48 genotype association tests conducted in the main analysis there were few important associations observed. We found evidence for associations between d3GHR and anthropometry, with carriers of at least one exon-3 deletion having lower weight, BMI and a trend towards lower WHR. After adjusting for age and sex we found evidence for an association with physical capability for only one of the polymorphisms, with the minor allele of rs2665802 (GH1) being associated with increased ability to balance for at least 5 s. On the whole, the associations for physical capability were similar in males and females, between the physically active and inactive and after additionally adjusting for height and weight. These findings suggest that these polymorphisms are not important contributors to physical capability in older adults.
GWAS in Asian populations have found associations between SNPs around IGF1
, including rs35767, and height 
. However, to-date, little evidence has emerged from GWAS supporting highly significant associations between common polymorphisms in the six genes that we investigated in the GH/IGF axis and measures of anthropometry in Europeans 
. Although, it is possible that SNPs in these six genes may significantly modify the effects on lean body mass of SNPs in other genes that are relevant to the GH/IGF axis 
. We observed no association between rs35767 (IGF1
) and measures of body size, consistent with other studies on European populations 
. A previous investigation in elderly men and women found no consistent associations between rs35767 (IGF1
) and measures of body composition and walk times, grip strength and timed chair stand 
. We did not observe poorer measures of physical capability among carriers of the risk allele for prostate cancer for rs7127900 near IGF2 
. Other smaller studies had found no association between rs2854744 (IGFBP3
) and measures of adult body size in women of European ancestry (n
, or muscle phenotypes in response to strength training in older adults (n
. Unlike a previous study (n
, we did not observe associations between rs2665802 (GH1
) and height in either sex, nor were associations reported with height or BMI elsewhere (sample sizes ranged between 293 and 1003) 
. Our results suggested that the minor allele of rs2665802 (GH1
) was associated with better ability to balance for at least 5 s. The allele has also been associated with lower colorectal cancer 
and mortality risk in females 
, though the null findings observed for the other measures of physical capability would suggest that rs2665802 (GH1
) does not substantially influence measures of physical capability. In addition, a study of 169 athletes and 155 controls suggests that it is not associated with athletic status 
. Our meta-analysis provided some evidence for lower weight and BMI among carriers of the exon-3 deletion of GHR
. Although few specific investigations into the d3GHR polymorphism on population-based studies of adults have been conducted, smaller studies have found no associations with measures of body size (sample sizes ranged between 100 and 831) 
; however, one study observed associations between its haplotypic block and BMI 
. We therefore contacted the GIANT Consortium 
to look up associations between tag SNPs of d3GHR and BMI. No associations were observed in per minor allele models for BMI for any of the five available SNPs, for example, for rs4590183 the data suggested a p-value of 0.98 in an analysis of 123,863 participants, suggesting our observed associations for d3GHR with weight and BMI were false positives.
It is an important finding that this investigation does not provide evidence for a substantial role of these common polymorphisms in the GH/IGF axis and measures of physical capability given the statistical power of this multi-cohort study. Sample size calculations for the quantitative traits for 80% power at the 5% significance level estimated that around 7000 individuals would be required to detect a beta coefficient of 0.07 z-score units under a dominant model for a polymorphism with a MAF of 0.19 or for 0.05 z-score units under an additive model using a MAF of 0.35. For example, there was sufficient power to detect a difference in grip strength of around 0.8 kg under a dominant model for rs7127900 (IGF2), assuming a standard deviation of 11. This allows the inference that any associations between the polymorphisms and physical capability traits are very small.
Deviation from the HWE condition was detected for d3GHR in two of the larger studies, NSHD and HCS. However, the only suggested associations for d3GHR were with weight and BMI, which were found to be in opposite directions for these studies (Table S6
, Figure S1
), indicating that, although exclusion is not recommended 
, excluding these two studies would not substantially affect the overall pooled results. Furthermore, whilst we observed four deviations from HWE altogether, around two statistically significant tests would be expected given the 42 (6 polymorphisms×7 studies) HWE tests performed.
Whilst the choice of polymorphisms within our candidate genes were primarily based on robust associations observed with age-related traits 
, or functional evidence 
, additional polymorphisms in these genes may be useful for exploring further the influence of common polymorphisms in the GH/IGF axis on measures of physical capability.
The results of this large, multi-cohort investigation do not support the hypothesis that these common polymorphisms in the GH/IGF axis contribute substantially to objectively measured physical capability in older adults.