Common variants and the biological and genomic architecture of human height

The latest from the GIANT collaboration. They are also estimating ~ 10k causal variants in total, with 697 now identified at genome-wide significance. See On the genetic architecture of intelligence and other quantitative traits for related discussion.

With ~1k variants to work with, we can expect progress on the question of whether the ~1 SD group difference in height between north and south europeans is due to selection. Uniformly higher SNP frequencies in the north for variants that slightly increase height would be strong evidence of selection. See Recent human evolution: european height.

Defining the role of common variation in the genomic and biological architecture of adult human height (Nature Genetics doi:10.1038/ng.3097 )

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the 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 60% of heritability. The 697 variants clustered in 423 loci were 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/β-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.

From the discussion section:

It has been argued that the biological information emerging from GWAS will become less relevant as sample sizes increase because, as thousands of associated variants are discovered, the range of impli- cated genes and pathways will lose specificity and cover essentially the entire genome. If this were the case, then increasing sample sizes would not help to prioritize follow-up studies aimed at identifying and understanding new biology and the associated loci would blanket the entire genome. Our study provides strong evidence to the contrary: the identification of many hundred and even thousand associated variants can continue to provide biologically relevant information. In other words, the variants identified in larger sample sizes both display a stronger enrichment for pathways clearly relevant to skeletal growth and prioritize many additional new and relevant genes. Furthermore, the associated variants are often non-randomly and tightly clustered (typically separated by < 250kb), resulting in the frequent presence of multiple associated variants in a locus. The observations that genes and especially pathways are now beginning to be implicated by multiple variants suggests that the larger set of results retain biological specificity but that, at some point, a new set of associated variants will largely highlight the same genes, pathways and biological mechanisms as have already been seen.