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Rare Variants Play Outsized Role in Human Height

NEW YORK (GenomeWeb) – An international team led by investigators in Canada, the UK, and the US has identified dozens of rare or low-frequency genetic contributors to human height, including versions of some variants suspected of affecting adult height by close to an inch.

"The genes affected by these genetic variations modulate, among other things, bone and cartilage development, and growth hormone production and activation," co-senior author Guillaume Lettre, a researcher affiliated with the University of Montreal and the Montreal Heart Institute, said in a statement.

As they reported in Nature today, Lettre and his colleagues did a meta-analysis of relatively rare variants assessed with the ExomeChip array in more than half a million individuals. Searching for variants that corresponded to height, the investigators narrowed in on 83 coding variants, each present in less than 5 percent of the population.

In contrast to the hundreds of common variants identified in prior genome-wide association studies, the team estimated that low-frequency variants in STC2, IHH, and other genes had relatively pronounced height effects — patterns that the collaborators followed up on in more detail with functional experiments in mice.

"Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways," the authors wrote.

As a model for other complex human traits and conditions, the team set out to see if it could identify genes and pathways that are relevant to human height by searching the low-frequency end of the variant spectrum. Nearly 700 common variants have been implicated in human height already, the authors explained, but much of the trait's heritability remains unexplained.

"The idea was that if we could understand the genetics of human height, we could then apply this knowledge to develop genetic tools to predict other traits or the risk of developing common diseases," Lettre added.

For the first stage of their study, the researchers analyzed genotyping data for 458,927 individuals of European, African, South Asian, East Asian, Hispanic, and Saudi Arabian ancestry. In this cohort, and a validation group that included another 252,501 individuals, they narrowed in on more than 600 variants with apparent ties to the individuals' adult height.

The team went on to whittle that set down to 83 non-synonymous or splice site variants that were rare or present at low frequencies in the participants, including variants in genes implicated in growth disorders and uncommon variants falling close to SNPs linked to height in the past.

Consistent with the potential importance of rare variants in the trait, the authors noted that alleles found at lower frequency appeared to have increasing impacts on height.

"Our results agree with a model based on accumulating theoretical and empirical evidence that suggest that variants with strong phenotypic effects are more likely to be deleterious, and therefore rare," they wrote.

Using gene-based analyses, functional experiments in mice, and other follow-up work, the team explored the biological basis of these associations, highlighting height roles from skeletal growth-related genes, hormone signaling pathways, and other processes.

"[O]ur findings provide strong evidence that rare and low-frequency coding variants contribute to the genetic architecture of height, a model complex human trait," they noted. "This conclusion has implications for the prediction of complex human phenotypes in the context of precision medicine initiatives."