title: Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yingleong
authors.initials: Y
authors.lastname: Chan
authors.forename: Oddgeir L
authors.initials: OL
authors.lastname: Holmen
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.forename: Aki S
authors.initials: AS
authors.lastname: Havulinna
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.forename: Kirsti
authors.initials: K
authors.lastname: Kvaløy
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Thutrang T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Cristen
authors.initials: C
authors.lastname: Willer
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001827:Body Height / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019655:Quantitative Trait, Heritable; D035781:Siblings