Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Abstract

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

“…In the last decade, a hundred single-nucleotide polymorphisms (SNP) capable of influencing adult height were identified by genome-wide association studies, including SNPs located near to NPR3 and NPPC genes . Four SNPs (rs2679178, rs749052, rs2580816, rs6717918) located upstream of NPPC and five SNPs surrounding the NPR3 gene (rs6450922, rs1173727, rs3792752, rs10472828, rs10472828) were related to adult height [2,3,4,5,6,7]. Each variant allele was associated with an estimated mean change of around 0.4 cm in height.…”

“…Studies in twins have indicated that the heritability of height is high (∼80%), suggesting that genetic variation is the main determinant of stature [1]. Although rare genetic variants are involved with larger effects on stature, common polymorphisms are significantly associated with height in healthy individuals [2]. Among the identified genes associated with stature, there are several genes that act in the growth plate-promoting endochondral ossification [3].…”

“…Genome-wide association studies identified genetic loci related to human height variability mapped in natriuretic peptide system genes [2,3,4,5,6,7]. Since 1998, C-type natriuretic peptide (CNP) and its receptor (NPR-B) have been implicated as important regulators of endochondral bone growth [8,9].…”

Association Study of GWAS-Derived Loci with Height in Brazilian Children: Importance of <b><i>MAP3K3, MMP24</i></b> and <b><i>IGF1R</i></b> Polymorphisms for Height Variation

“…Specifically, the C allele of rs2282978 (CDK6) and rs2871865 (IGF1R) , the A allele of rs2425019 (MMP24) and the T allele of rs8081612 (MAP3K3) and rs3782415 (SOCS2) were among the SNPs most strongly associated with adult height in Europeans [8,9,10]. Moreover, rs2425019 (MMP24) , rs8081612 (MAP3K3) , rs2871865 (IGF1R) and rs3782415 (SOCS2) were also associated with children's and adolescents' height in other populations (table 1).…”

Pharmacogenomics Related to Growth Disorders

“…In normal individuals adult height is affected by a large number of genes and normal growth hormone (GH) secretion is highly variable [1,2,3]. Growth disorders resulting in short stature arise from a spectrum of different aetiologies including hormone deficiencies, hormone resistance, nutritional insufficiency, chronic disease (e.g.…”