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Penetrance of polygenic obesity susceptibility loci across the body mass index distribution: an update on scaling effects

Arkan Abadi, Akram Alyass, Sebastien Robiou du Pont, Ben Bolker, Pardeep Singh, Viswanathan Mohan, Rafael Diaz, James C. Engert, Hertzel C. Gerstein, Sonia S. Anand, David Meyre
doi: https://doi.org/10.1101/225128
Arkan Abadi
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
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Akram Alyass
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
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Sebastien Robiou du Pont
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
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Ben Bolker
2Department of Mathematics and Statistics, McMaster University, Hamilton, ON L8S 4L8 Canada
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Pardeep Singh
3Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8 Canada
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Viswanathan Mohan
4Madras Diabetes Research Foundation, Chennai, India
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Rafael Diaz
5ECLA-Academic Research Organization, Rosario, Argentina
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James C. Engert
6McGill University, Montreal, QC H3A 0G4 Canada
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Hertzel C. Gerstein
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
7Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON L8S 4L8 Canada
8Department of Medicine, McMaster University, Hamilton, ON L8S 4L8 Canada
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Sonia S. Anand
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
7Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON L8S 4L8 Canada
8Department of Medicine, McMaster University, Hamilton, ON L8S 4L8 Canada
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David Meyre
1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8 Canada
3Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8 Canada
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  • For correspondence: mevred@mcmaster.ca
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ABSTRACT

A growing number of single nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effect of these obesity susceptibility loci is uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI/obesity-associated SNPs in 75,230 adults of European ancestry along BMI percentiles using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of 9 SNPs (24%) increased significantly across the sample BMI distribution including, FTO (rs1421085, p=8.69×10−15), PCSK1 (rs6235, p=7.11×10−06), TCF7L2 (rs7903146, p=9.60×10−06), MC4R (rs11873305, p=5.08×10−05), FANCL (rs12617233, p=5.30×10−05), GIPR (rs11672660, p=1.64×−04), MAP2K5 (rs997295, p=3.25×10−04), FTO (rs6499653, p=6.23×10−04) and NT5C2 (rs3824755, p=7.90×10−04). We showed that such increases stem from unadjusted gene interactions that enhanced the effects of SNPs in persons with high BMI. When 125 height-associated were analyzed for comparison, only one (<1%), IGF1 (rs6219, p=1.80×10−04), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-Height, respectively) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p=7.03×10−37, Height: p=0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method to detect such interactions using only the sample outcome distribution.

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Posted November 29, 2017.
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Penetrance of polygenic obesity susceptibility loci across the body mass index distribution: an update on scaling effects
Arkan Abadi, Akram Alyass, Sebastien Robiou du Pont, Ben Bolker, Pardeep Singh, Viswanathan Mohan, Rafael Diaz, James C. Engert, Hertzel C. Gerstein, Sonia S. Anand, David Meyre
bioRxiv 225128; doi: https://doi.org/10.1101/225128
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Penetrance of polygenic obesity susceptibility loci across the body mass index distribution: an update on scaling effects
Arkan Abadi, Akram Alyass, Sebastien Robiou du Pont, Ben Bolker, Pardeep Singh, Viswanathan Mohan, Rafael Diaz, James C. Engert, Hertzel C. Gerstein, Sonia S. Anand, David Meyre
bioRxiv 225128; doi: https://doi.org/10.1101/225128

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