Contribution of 32 GWAS-identified common variants to severe obesity in European adults referred for bariatric surgery.
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.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Reedik
R
Mägi
Sean
S
Manning
Ahmed
A
Yousseif
Andrea
A
Pucci
Ferruccio
F
Santini
Efthimia
E
Karra
Giorgia
G
Querci
Caterina
C
Pelosini
Mark I
MI
McCarthy
Cecilia M
CM
Lindgren
Rachel L
RL
Batterham
D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D050110:Bariatric Surgery; D015992:Body Mass Index; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008131:London; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009767:Obesity, Morbid / Q000208:ethnology / Q000235:genetics* / Q000601:surgery; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012017:Referral and Consultation; D044465:White People / Q000235:genetics
D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; C485559:NEGR1 protein, human; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human