These GEITP pages often discuss genotype-phenotype associations of multifactorial traits. Today’s multifactorial trait is “extreme obesity” (but we might consider it like other complex phenotypes such as height, type-2 diabetes, adverse drug response, or toxic effects of an environmental toxicant). Severe obesity, defined as body mass index (BMI) of 40 kg/ m2 or greater, is a rapidly growing public health issue — currently affecting 8% of American adults. Inherited susceptibility to obesity can, in rare cases, be attributed to a large-effect mutation that perturbs energy homeostasis or fat deposition [e.g. genetic inactivation of the melanocortin-4 receptor (MC4R) gene].
A recent genome-wide association study (GWAS) quantified the relationship between each of 2.1 million common genetic variants and BMI in >300,000 individuals; none of the individual variants accounted for a large proportion of the trait. The strongest association was noted for a common variant at the FTO locus (alpha-ketoglutarate-dependent dioxygenase); the risk allele is associated with a statistically robust, but clinically modest, increase in weight of ~1 kg per inherited risk allele. Obtaining meaningful predictive power — thus requires “an aggregation of information from many common variants into a polygenic score.” However, previous efforts to create an effective polygenic score for obesity have had only modest success. This ‘‘polygenic’’ model paradigm is similar to other complex diseases in which polygenic inheritance (involving many common genetic variants, each having small-effect) accounts for the majority of inherited susceptibility.
Authors [see attached article] used recently developed computational algorithms and large datasets to derive, validate, and test a robust polygenic predictor of BMI and obesity. This genome-wide polygenic score (GPS) integrates all available common variants into a single
quantitative measure of inherited susceptibility. GPS identifies a subset of the adult population that is at substantial risk of severe obesity — in some cases equivalent to rare monogenic mutations.
Authors tested this predictor in >300,000 individuals ranging from birth to middle age. Among middle-aged adults, they observed a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles (population divided into tenths). In a longitudinal birth cohort, minimal differences in birthweight were noted across score deciles, but a significant GPS gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to a complex disease, and other multifactorial traits, appears to afford new opportunities for clinical prevention and automatic assessment. 🙂
Cell 18 Apr 2o19; 177: 587–596