Genetic control of body weight by the human brain proteome
Eloi Gagnon,
Arnaud Girard,
Émilie Gobeil,
Jérôme Bourgault,
Christian Couture,
Patricia L. Mitchell,
Claude Bouchard,
Angelo Tremblay,
Patrick Mathieu,
Andréanne Michaud,
Louis Pérusse,
Benoit J. Arsenault
Affiliations
Eloi Gagnon
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Arnaud Girard
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Émilie Gobeil
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Jérôme Bourgault
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Christian Couture
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Patricia L. Mitchell
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
Claude Bouchard
Pennington Biomedical Research Center, Baton Rouge, LA, USA
Angelo Tremblay
Department of Kinesiology, Faculty of Medicine, Université Laval, Québec, QC, Canada; School of Nutrition, Université Laval, Québec, QC, Canada
Patrick Mathieu
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada; Department of Surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada
Andréanne Michaud
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada; School of Nutrition, Université Laval, Québec, QC, Canada
Louis Pérusse
Department of Kinesiology, Faculty of Medicine, Université Laval, Québec, QC, Canada; School of Nutrition, Université Laval, Québec, QC, Canada
Benoit J. Arsenault
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada; Corresponding author
Summary: Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with body weight but the biological relevance of most remains unexplored. Given the critical role of the brain in body weight regulation, we set out to determine whether genetic variants linked with body mass index (BMI) could be mapped to brain proteins. Using genetic colocalization, we mapped 25 loci from the largest BMI GWAS (n = 806,834) to brain protein concentrations obtained from publicly available datasets. We also performed a proteome-wide Mendelian randomization on 696 brain proteins followed by genetic colocalization and identified 35 additional brain proteins. Only a minority of these proteins (<30%) had a colocalization signal with cortex gene expression levels, highlighting the value of moving beyond gene expression levels and examining brain protein levels. In conclusion, we identified 60 unique proteins expressed in the brain that may be critical regulators of body weight in humans.
