Canalization of the Polygenic Risk for Common Diseases and Traits in the UK Biobank Cohort

Abstract

Since organisms develop and thrive in the face of constant perturbations due to environmental and genetic variation, species may evolve resilient genetic architectures. We sought evidence for this process, known as canalization, through comparison of the prevalence of phenotypes as a function of polygenic score (PGS) across environments in the UK Biobank cohort study. Contrasting seven diseases and three categorical phenotypes with respect to 151 exposures in 408,925 people, the deviation between the prevalence-risk curves was observed to increase monotonically with PGS percentile in one fifth of the comparisons, suggesting extensive PGS×Environment (PGS×E) interaction. After adjustment for the dependency of allelic effect sizes on increased prevalence in the perturbing environment, cases where polygenic influences are greater or less than expected are seen to be particularly pervasive for educational attainment, obesity, and the metabolic condition type-2 diabetes. Inflammatory bowel disease analysis shows fewer interactions but confirms that smoking and some aspects of diet influence risk. Notably, body mass index has more evidence for decanalization (increased genetic influence at the extremes of polygenic risk) whereas waist-to-hip ratio shows canalization, reflecting different evolutionary pressures on the architectures of these weight-related traits. An additional ten percent of comparisons showed evidence for an additive shift of prevalence independent of PGS between exposures. These results provide the first widespread evidence for canalization protecting against disease in humans, and have implications for personalized medicine as well as understanding the evolution of complex traits. The findings can be explored through an R shiny app at https://canalization-gibsonlab.shinyapps.io/rshiny/.

Amplification is the Primary Mode of Gene-by-Sex Interaction in Complex Human Traits

“…At the same time, unlike studies in study systems where the environment can be experimentally manipulated [6][7][8][9][10][11][12][13] , there are but a few cases in which GxE models consistently explain data-such as Genome-Wide Association Study (GWAS) data-better than parsimonious models that assume independent contributions of genetic and environmental factors 2,4,[14][15][16] . This discrepancy may point to a pervasive mediation of polygenic effects by the environment-alongside the inability of our current toolbox to quantify polygenic GxE [17][18][19] .…”

Removal of Exogenous Stimuli Reveals a Canalization of Circadian Physiology in a Vertically Migrating Copepod

“…xiphias proteomes showed signs of canalization of a rhythmic response when exogenous food and photoperiod cues were removed. Canalization can refer to the evolved specificity, or a lack of plasticity, of molecular or phenotypic environmental response and has been observed in a variety of contexts across taxa (e.g., refs − ). The observed maintenance of rhythms in protein abundances suggests an evolutionarily maintained pattern specific to the environment and lifestyle of P.…”

Different genetic architectures of complex traits and their relevance to polygenic score performance in diverse populations

“…For example, some traits are highly canalized, while others show evidence of substantial PGS-by-environment interactions. 70 Epistatic interactions also contribute to the genetic architecture of complex traits, and this information can be incorporated into predictive models. 71 Finally, we note that PGS generated from multi-ancestry cohorts are more likely to yield portable predictions.…”