Genetic studies of body mass index yield new insights for obesity biology

Adam E Locke, Bratati Kahali, Sonja I Berndt, Anne E Justice, Tune H Pers, Felix R Day, Corey Powell, Sailaja Vedantam, Martin L Buchkovich, Jian Yang, Damien C Croteau-Chonka, Tonu Esko, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Zoltán Kutalik, Jian'an Luan, Reedik Mägi, Joshua C Randall, Thomas W WinklerAndrew R Wood, Tsegaselassie Workalemahu, Jessica D Faul, Jennifer A Smith, Jing Hua Zhao, Wei Zhao, Jin Chen, Rudolf Fehrmann, Åsa K Hedman, Juha Karjalainen, Ellen M Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L Bolton, Jennifer L Bragg-Gresham, Steven Buyske, Ayse Demirkan, Guohong Deng, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Anuj Goel, Jian Gong, Anne U Jackson, Aaron Isaacs, Andrew Wong, Kevin B Jacobs, LifeLines Cohort Study

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Original languageEnglish
Pages (from-to)197-206
Number of pages10
JournalNature
Volume518
Issue number7538
DOIs
Publication statusPublished - 12 Feb 2015
Externally publishedYes

Keywords

  • Adipogenesis/genetics
  • Adiposity/genetics
  • Age Factors
  • Body Mass Index
  • Continental Population Groups/genetics
  • Energy Metabolism/genetics
  • Europe/ethnology
  • Female
  • Genetic Predisposition to Disease/genetics
  • Genome-Wide Association Study
  • Glutamic Acid/metabolism
  • Humans
  • Insulin/metabolism
  • Insulin Secretion
  • Male
  • Obesity/genetics
  • Polymorphism, Single Nucleotide/genetics
  • Quantitative Trait Loci/genetics
  • Synapses/metabolism

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