Q2. What future works have the authors mentioned in the paper "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution" ?
By providing new insights into the regulation of body fat distribution, the present study raises a number of issues for future investigation. Efforts to tackle overall obesity through therapeutic or lifestyle-based modulation of overall energy balance have proved extremely challenging to implement, and the manipulation of processes associated with more beneficial patterns of fat distribution offers an alternative perspective for future drug discovery. From the genetic perspective, resequencing, dense-array genotyping and fine-mapping approaches will be required to characterize causal variants at the loci the authors have identified and to support further discoveries that may account for the substantial proportion of genetic variance unexplained by their findings.
Q3. How many SNPs were examined in the discovery stage?
In the discovery stage, up to 2,850,269 imputed and genotyped SNPs were examined in 32 GWAS comprising up to 77,167 participants informative for anthropometric measures of body fat distribution.
Q4. What is the role of the waist circumference in obesity?
WHR is of particular interest as a measure of body fat distribution because it integrates the adverse metabolic risk associated with increasing waist circumference with the more protective role of gluteal fat deposition with respect to diabetes, hypertension and dyslipidemia5,6.
Q5. How many women were included in the discovery and follow-up studies?
These analyses included up to 108,979 women (42,735 in the discovery stage and 66,244 in the follow up) and 82,483 men (34,601 in the discovery and 47,882 in the follow up).
Q6. What was the effect size of the LY86 locus on the WHR?
After adding an interaction term of SNP with BMI into the model, the authors observed that BMI modified the WHR association at the LY86 locus (P for interaction = 9.5 × 10−5), with a larger WHR effect among obese individuals compared to non-obese individuals(Supplementary Note).
Q7. What was the effect size of the ten loci in the discovery analysis?
Of the ten loci shown to be associated with BMI in previous GWAS14,15,18, only two showed nominally significant (P < 0.05) associations for BMI-adjusted WHR in the discovery analysis (FTO, rs8050136, P = 0.03, n = 77,074; TMEM18, rs6548238, P = 3.0 × 10−3, n = 77,016).
Q8. What is the significance of the WHR association in fat depots?
To determine whether genes within the WHR-associated loci showed evidence of differential transcription in distinct fat depots, the authors compared expression levels in gluteal or abdominal SAT in 49 individuals.
Q9. How much of the variance in WHR was explained by the 14 loci?
These 14 loci explain 1.34% of the variance in WHR (after adjustment for BMI and age) in women but only 0.46% of the variance in WHR in men.
Q10. What is the primary objective of genetic discovery efforts?
The primary objective of genetic discovery efforts is to characterize the specific mechanisms involved in regulating the trait of interest.
Q11. How many SNPs were evaluated in the discovery phase?
The authors selected SNPs representing the top 16 independent (defined as being located >1 Mb apart) regions of association (discovery P < 1.4 × 10−6; Table 1) and evaluated them in 29 additional, independent studies (comprising up to 113,636 individuals) using a mixture of in silico data and de novo genotyping.
Q12. What is the relationship between the WHR-associated loci and metabolic traits?
To identify potential functional connections and pathway relationships between genes mapping at the WHR-associated loci, the authors focused on the 95 genes located in a 2-Mb interval centered around each of the 48 independent SNPs that attained P < 1.0 × 10−5 in the WHR discovery studies.