Genetics and Epigenetics

The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward

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Subjects

Abstract

Background

Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development.

Methods

We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals.

Results

We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10–9) and substantia nigra (p = 6.8 × 10–7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions.

Conclusions

Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

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Acknowledgements

We thank Endocells for providing the pancreatic beta-cell line, EndoC-βH1. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 23 Novermber 2018. This work was supported by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes] and ANR-10-EQPX-07-01 [LIGAN-PM], to PF), from the European Research Council (ERC GEPIDIAB—294785, to PF; ERC Reg-Seq—715575, to AB), from FEDER (to PF), and from the ‘Région Nord Pas-de-Calais’ (to PF and to FKN). AB was supported by Inserm. The D.E.S.I.R. study has been funded by Inserm contracts with Caisse nationale de l’assurance maladie des travailleurs salariés, Lilly, Novartis Pharma, and Sanofi-Aventis; Inserm (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008); the Association Diabète Risque Vasculaire; the Fédération Française de Cardiologie; La Fondation de France; the Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques/Société Francophone de Diabétologie; the Office national interprofessionnel des vins; Ardix Medical; Bayer Diagnostics; Becton Dickinson; Cardionics; Merck Santé; Novo Nordisk; Pierre Fabre; Roche; and Topcon. The D.E.S.I.R. study group includes: Inserm U1018: B. Balkau, P. Ducimetière, and E. Eschwège; Inserm U367: F. Alhenc-Gelas; CHU D’Angers: Y Gallois and A. Girault; Center de Recherche des Cordeliers, Inserm U1138, Bichat Hospital: F. Fumeron, M. Marre, and R. Roussel; CHU de Rennes: F. Bonnet; CNRS UMR8199, Lille: A. Bonnefond and P. Froguel; Centers d’Examens de Santé: Alençon, Angers, Blois, Caen, Chateauroux, Chartres, Cholet, Le Mans, Orléans, and Tours; Institute de Recherche Médecine Générale: J. Cogneau; General practitioners of the region; Institute Inter-Regional pour la Santé: C. Born, E. Caces, M. Cailleau, O Lantieri, J.G. Moreau, F. Rakotozafy, J. Tichet, and S. Vol.

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Correspondence to Philippe Froguel or Amélie Bonnefond.

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