title: Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity.
abstract: In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada INSERM UMR 1190, Department of Nutrition, University of Lille, CHRU Lille, Lille, 59000, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Pigeyre
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors.forename: Fereshteh T
authors.initials: FT
authors.lastname: Yazdi
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
authors.forename: Yuvreet
authors.initials: Y
authors.lastname: Kaur
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada meyred@mcmaster.ca.
authors.forename: David
authors.initials: D
authors.lastname: Meyre
mesh_terms: D044127:Epigenesis, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D056186:Metagenomics; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D020738:Leptin
keywords: epigenetics; genetics; leanness; metagenomics; obesity and body fat distribution; pathophysiology; personalized medicine