Modifying effects such as interactions with environmental factors, other genetic variants, age, sex or other variables may, if substantial, also diminish apparent effect sizes, so detailed analyses of interaction with validated variants may be informative. Finally, other than the MC4R coding region, these loci have not yet been explored thoroughly for additional rare (or common) variants. As such, it is not known whether additional variants at these loci (those causal for the index association or those representing independent causal events) could explain a greater fraction of BMI variation. There are a growing number of examples, including at MC4R, where genes containing common variants associated with a particular phenotype also harbor lower-frequency, higher-penetrance variants with more severe phenotypic consequences16,43-46. Comprehensive sequencing studies in these and other loci (perhaps in individuals with extreme obesity) may represent a path to finding such variants and beginning to explore the relative contributions of common and rare variation to BMI. Discovering additional variants will slowly increase predictive power. However, a greater immediate impact of these studies is the identification of previously unsuspected loci that participate in the biology of body weight regulation, and which may help guide the development of new therapies.
