Inherited susceptibility to obesity can, in rare cases, be attributed to a large-effect mutation that perturbs energy homeostasis or fat deposition (Barsh et al., 2000). For example, genetic inactivation of the melanocortin 4 receptor (MC4R) gene is associated with obesity in both mouse models and humans (Farooqi et al., 2003; Huszar et al., 1997; Vaisse et al., 1998; Yeo et al., 1998). However, for the vast majority of severely obese individuals, no such monogenic mutation can be identified (Larsen et al., 2005; Stutzmann et al., 2008; Vaisse et al., 2000). Their genetic susceptibility may instead result from the cumulative impact of numerous variants with individually modest effect – a ‘polygenic’ model. This paradigm is similar to other complex diseases in which polygenic inheritance, involving many common genetic variants, accounts for the majority of inherited susceptibility (Golan et al., 2014; International Schizophrenia et al., 2009; Visscher et al., 2012; Yang et al., 2011; Zhu et al., 2015).
