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

CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Inserm U1190, EGID, CHU Lille, University of Lille, Lille, France. Department of Diabetology, Endocrinology and Nutrition, DHU-FIRE, HUPNVS, AP-HP, Paris, France. Paris Diderot-Sorbonne Paris Cité University, Paris, France. Centre de Recherche des Cordeliers, Inserm U1138, Paris, France. Inserm U1018, Center for Research in Epidemiology and Population Health, Villejuif, France. University Paris-Saclay, Villejuif, France. University Paris-Sud, Villejuif, France. CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France. p.froguel@imperial.ac.uk. Department of Genomics of Common Disease, Imperial College of London, London, UK. p.froguel@imperial.ac.uk. CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France. amelie.bonnefond@inserm.fr. Department of Genomics of Common Disease, Imperial College of London, London, UK. amelie.bonnefond@inserm.fr.

International journal of obesity (2005). 2020;(2):539-543
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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.