Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

PLAG1 and NCAPG‐LCORL in livestock

“…The genome‐wide significant SNPs in 423 loci together explained 16% of heritability (Wood et al . 2014). In contrast, genetic architecture for stature is simple in domestic animals.…”

“…Human height loci are substantially enriched for regulatory variants (Wood et al . 2014). The bovine QTNs at the PLAG1 locus are regulatory and increased less than two‐fold gene expression (average 1.2‐fold), while the QTL genotype effects on live weight were +19.9 kg ( QQ ), 0 kg ( Qq ) and −23.5 kg ( qq ) and the QTL explained 9.9% of live weight variance of the F2 population (Karim et al .…”

“…The genome‐wide significant single nucleotide polymorphisms (SNPs) explained 16% of heritability and all common variants together captured 60% of heritability (Wood et al . 2014). The study also identified several genes and pathways not previously connected with human skeletal growth (Wood et al .…”

“…The study also identified several genes and pathways not previously connected with human skeletal growth (Wood et al . 2014). …”

Variants fréquents et rares, caractères multigéniques et héritabilité perdue

“…Peut-on ainsi espérer résoudre l'irritant problème de l'héritabilité manquante (missing heritability), auquel deux chroniques ont été consacrées par le passé [2,3] (➜), et qui se manifeste dans ce cas par le fait que les 697 variants connus ne rendent compte à eux tous que de 20 % environ de l'héritabilité de la taille [4] ? Avant d'examiner les conclusions de cet article, il est nécessaire de faire un point d'ensemble sur les différentes classes de variants répertoriés dans le génome humain, à la lumière des études de séquençage à grande échelle qui ont été menées ces dernières années et qui ont largement précisé ce que certains appellent le « variome » humain 1 .…”