Do the diverse phenotypes of Prader-Willi syndrome reflect extremes of covariation in typical populations?

Abstract

The phenotypes of human imprinted neurogenetic disorders can be hypothesized as extreme alterations of typical human phenotypes. The imprinted neurogenetic disorder Prader-Willi syndrome (PWS) features covarying phenotypes that centrally involve altered social behaviors, attachment, mood, circadian rhythms, and eating habits, that can be traced to altered functioning of the hypothalamus. Here, we conducted analyses to investigate the extent to which the behavioral variation shown in typical human populations for a set of PWAS-associated traits including autism spectrum cognition, schizotypal cognition, mood, eating, and sleeping phenotypes shows covariability that recapitulates the covariation observed in individuals with PWS. To this end, we collected data from 296 typical individuals for this set of phenotypes, and showed, using principal components analysis, evidence of a major axis reflecting key covarying PWS traits. We also reviewed the literature regarding neurogenetic syndromes that overlap in their affected traits with PWS, to determine their prevalence and properties. These findings demonstrate that a notable suite of syndromes shows phenotypic overlap with PWS, implicating a large set of imprinted and non-imprinted genes, some of which interact, in the phenotypes of this disorder. Considered together, these findings link variation in and among neurogenetic disorders with variation in typical populations, especially with regard to pleiotropic effects mediated by the hypothalamus. This work also implicates effects of imprinted gene variation on cognition and behavior in typical human populations.