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/m2, 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/m2) 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/m2); 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.

Genetic studies of body mass index yield new insights for obesity biology

“…We first focused on the 64 genes in associated loci with more than one consistent line of supporting evidence. As expected, many of these genes overlap with CNS processes, including synaptic function, cell–cell adhesion, and glutamate signalling ( ELAVL4, GRID1, CADM2, NRXN3, NEGR1 and SCG3 ), cause monogenic obesity syndromes ( MC4R, BDNF, BBS4 and POMC ), or function in extreme/early onset obesity in humans and mouse models ( SH2B1 and NEGR1 ) 6,28,29 . Other genes with several lines of supporting evidence are related to insulin secretion and action, energy metabolism, lipid biology, and/or adipogenesis (TCF7L2, GIPR, IRS1, FOXO3, ASB4, RPTOR, NPC1, CREB1, FAM57B, APOBR and HSD17B12 ), encode RNA binding/processing proteins ( PTBP2, ELAVL4, CELF1 and possibly RALYL ), are in the MAP kinase signalling pathway ( MAP2K5 and MAPK3 ), or regulate cell proliferation or cell survival ( FAIM2, PARK2 and OLFM4 ).…”

rs4771122 Predicts Multiple Measures of Long-Term Weight Loss After Bariatric Surgery

“…In the replication sample, each copy of the G allele was associated with 2.14 greater percent weight lost at the nadir (compared to 4.72 greater percent weight lost at the nadir in our study) (9). The nominal association of rs4771122 G allele with greater BMI at baseline aligns with the Speilotes et al (5) obesity GWAS where the G allele was associated with higher BMI, but is dissimilar to a Finnish study of nearly 1000 bariatric surgery patents that did not find rs4771122 and several other obesity GWAS SNPs to be associated with BMI in patients considering bariatric surgery (11). …”

A single FTO gene variant rs9939609 is associated with body weight evolution in a multiethnic extremely obese population that underwent bariatric surgery

“…The influence of the rs9939609 SNP on morbidly obese patients who underwent bariatric surgery have been previously studied (21,22,(26)(27)(28)(29)(30)(31) . However, the influence of the rs9939609 SNP in the evolution of weight loss or weight regain have not been reported.…”