Previous studies have used genome-wide association studies (GWAS) to locate genetic variants. This method rapidly scans across the genomes of large populations for markers that track with a particular trait.
GWAS is successful at finding common genetic variants. However, most of these only alter height by under 1 millimeter. GWAS unsuccessfully captures uncommon genetic variants that may have a larger affect on height.
Another problem is that common genetic variants that track with traits lie outside the protein-coding parts of genes. This positioning makes it harder to find out which genes they affect.
Some genetic variants identified have significant influence on height
In the new study, the investigators decided to use another technology called the ExomeChip in order to overcome some of the issues experienced with GWAS. ExomeChip tested for almost 200,000 known genetic variants that are less common in the 711,428 adults included in the study.
These known variants can be used as a shortcut to work out the genes that are important for particular diseases or traits. Most of these variants had not yet been assessed in previous studies of height.
Out of the 83 uncommon variants identified that affect human height, 51 of them were "low-frequency" variants that are found in less than 5 percent of people, and 32 of them were rare variants found in less than 0.5 percent.
"Of these 83 genetic variations, some influence adult height by more than 2 centimeters, which is enormous," says Guillaume Lettre, a professor at the Université de Montréal's Faculty of Medicine and researcher at the Montreal Heart Institute. "The genes affected by these genetic variations modulate, among other things, bone and cartilage development and growth hormone production and activation," he adds.
Lettre co-led the study with professors Joel Hirschhorn - of Boston's Children's Hospital, MA, and the Broad Institute of MIT and Harvard, and chair of the GIANT Consortium - and Panos Deloukas - of the Queen Mary University of London in the United Kingdom. Almost 280 other research groups were also involved.
The team notes that 27.4 percent of the heritability of height is now accounted for, with most heritability still explained by common genetic variants.
The study also found several genes that could potentially be targeted therapeutically for children with growth problems.
One of the genes, STC2, had DNA changes that significantly affected height. Genetic changes that inactivate the STC2 gene increase the height of individuals who carry them in their DNA by 1-2 cm, by acting on certain growth factors. "In this sense, evaluating whether drugs that block STC2 activity could have an impact on growth seems to us very promising," says Lettre.
Findings could pave way for tools to predict risk of common diseases
"The success of our study was due to our large sample size," says Prof. Deloukas. "Our results suggest that our genetic approach works. We can now start identifying similar genetic variations that may influence the risk of developing common diseases such as diabetes, cancer, schizophrenia, and cardiovascular disease, to name just a few."
Lettre says that adult height was used as a simple trait to understand how information in DNA can explain how individuals are different. "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," he adds.
Precision medicine is an emerging approach that involves customizing treatments and prevention measures to an individual patient. Lettre and colleagues suggest that the findings of the study could help to identify genetic variations that increase a person's risk of developing diseases. If this were the case, pinpointing these variations would be valuable in precision medicine.
"This study has shown that rare protein-altering variants can be helpful at finding some of the important genes, but also that even larger sample sizes will be needed to completely understand the genetic and biologic basis of human growth and other multifactorial diseases."
The GIANT Consortium's future work will focus on a GWAS of height, including more than 2 million people and studies involving sequencing data. "We predict that these more comprehensive studies will continue to enhance our understanding of human growth and how best to attain the biological insights that will inform treatments for common diseases," concludes Hirschhorn.