title: Finding missing heritability in less significant Loci and allelic heterogeneity: genetic variation in human height.
abstract: Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of 'missing' heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10(-8)) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10(-4)) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.
authors.affiliation: Human Genetics Division, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.forename: Guangyun
authors.initials: G
authors.lastname: Sun
authors.forename: Subba Rao
authors.initials: SR
authors.lastname: Indugula
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Dubravka
authors.initials: D
authors.lastname: Havas-Augustin
authors.forename: Natalija
authors.initials: N
authors.lastname: Novokmet
authors.forename: Zijad
authors.initials: Z
authors.lastname: Durakovic
authors.forename: Sasa
authors.initials: S
authors.lastname: Missoni
authors.forename: Ranajit
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Pavao
authors.initials: P
authors.lastname: Rudan
authors.forename: Ranjan
authors.initials: R
authors.lastname: Deka
mesh_terms: D000483:Alleles; D000704:Analysis of Variance; D001827:Body Height / Q000235:genetics*; D016000:Cluster Analysis; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans