Our meta-analysis of nearly 340,000 individuals identified 97 GWS loci associated with BMI, 56 of which are novel. These loci account for 2.7% of the variation in BMI, and suggest that as much as 21% of BMI variation can be accounted for by common genetic variation. Our analyses provide robust evidence to implicate particular genes and pathways affecting BMI, including synaptic plasticity and glutamate receptor activity—pathways that respond to changes in feeding and fasting, are regulated by key obesity-related molecules such as BDNF and MC4R, and impinge on key hypothalamic circuits30–32. These pathways also overlap with one of the several proposed mechanisms of action of topiramate, a component of one of two weight-loss drugs approved by the US Food and Drug Administration33,34. This observation suggests that the relevant site of action for this drug may be glutamate receptor activity, supporting the idea that these genes and pathways could reveal more targets for weight-loss therapies. BMI-associated loci also overlap with genes and pathways implicated in neurodevelopment (Supplementary Tables 21 and 22). Finally, consistent with previous work and findings from monogenic obesity syndromes, we confirm a role for the CNS—particularly genes expressed in the hypothalamus—in the regulation of body mass.
