Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance ( p <5×10 −28 ), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score ( WAS ), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals ( p <0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced ( p <10 −6 ) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme. Author Summary Although there are many loci in the human genome that have been discovered to be significantly associated with height, it is unclear if these loci have similar effects in extremely tall and short individuals. Here, we examine hundreds of extremely tall and short individuals in two population-based cohorts to see if these known height determining loci are as predictive as expected in these individuals. We found that these loci are generally as predictive of height as expected in these individuals but that they begin to be less predictive in the most extremely short individuals. We showed that this result is consistent with models that not only include the common variants but also multiple low frequency genetic variants that substantially decrease height. However, this result is also consistent with non-additive genetic effects or rare non-genetic factors that substantially decrease height. This finding suggests the possibility of a major role of low frequency variants, particularly in individuals with extreme phenotypes, and has implications on whole-genome or whole-exome sequencing efforts to discover rare genetic variation associated with complex traits.
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