Contribution of 32 GWAS-identified common variants to severe obesity in European adults referred for bariatric surgery

Abstract

The prevalence of severe obesity, defined as body mass index (BMI) ≥ 35.0 kg/m(2), is rising rapidly. Given the disproportionately high health burden and healthcare costs associated with this condition, understanding the underlying aetiology, including predisposing genetic factors, is a biomedical research priority. Previous studies have suggested that severe obesity represents an extreme tail of the population BMI variation, reflecting shared genetic factors operating across the spectrum. Here, we sought to determine whether a panel of 32 known common obesity-susceptibility variants contribute to severe obesity in patients (n = 1,003, mean BMI 48.4 ± 8.1 kg/m(2)) attending bariatric surgery clinics in two European centres. We examined the effects of these 32 common variants on obesity risk and BMI, both as individual markers and in combination as a genetic risk score, in a comparison with normal-weight controls (n = 1,809, BMI 18.0-24.9 kg/m(2)); an approach which, to our knowledge, has not been previously undertaken in the setting of a bariatric clinic. We found strong associations with severe obesity for SNP rs9939609 within the FTO gene (P = 9.3 × 10(-8)) and SNP rs2815752 near the NEGR1 gene (P = 3.6 × 10(-4)), and directionally consistent nominal associations (P<0.05) for 12 other SNPs. The genetic risk score associated with severe obesity (P = 8.3 × 10(-11)) but, within the bariatric cohort, this score did not associate with BMI itself (P = 0.264). Our results show significant effects of individual BMI-associated common variants within a relatively small sample size of bariatric patients. Furthermore, the burden of such low-penetrant risk alleles contributes to severe obesity in this population. Our findings support that severe obesity observed in bariatric patients represents an extreme tail of the population BMI variation. Moreover, future genetic studies focused on bariatric patients may provide valuable insights into the pathogenesis of obesity at a population level.

Figure 1. The boxplot displays genetic risk scores in bariatric patients compared to normal-weight controls.

The average genetic risk score differentiated well between normal-weight controls group and the bariatric surgery group (P = 8.3×10⁻¹¹).

Figure 2. Results of our logistic regression analysis were compared with the GIANT-extremes results using combined data from obesity class 2 and 3 groups ; in terms of odds ratio (OR) with 95% confidence intervals (CI).

There were no significant differences between the compared OR. See Table 2 for allocated reference numbers of SNPs. The diagonal line represents the expected plotted values for our results, based on the GIANT-extremes results. The SNPs below the diagonal line are those which had a larger effect in our study compared to GIANT-extremes, whereas the SNPs above the diagonal line represent SNPs which had a larger effect in GIANT-extremes compared to our study.

Figure 3. Effect sizes (i.e. changes in BMI) within the bariatric cohort, calculated by using standardized BMI values were compared with the known effect sizes derived from inverse standardized BMI values in the GIANT-BMI meta-analysis (A), and by using unstandardized BMI values (B).

Of note, the FTO marker effect size plotted for the GIANT-BMI data relates to the SNP rs1558902 (SNP rs9939609 in our study). There were no statistically significant differences between the compared effect sizes. See Table 2 for allocated reference numbers of SNPs.