A tall order: 83 new gene variants associated with height

The Genetic Investigation of Anthropometric Traits (GIANT) consortium has completed its largest study to date, uncovering 83 new DNA changes that affect human height. The study involved more than 300 researchers across five continents — including three researchers from The University of Western Australia (UWA) — and over 700,000 participants, with its findings published in the journal Nature.

In 2014, a GIANT study of around 250,000 people brought the total number of known genetic variants to nearly 700, in more than 400 spots in the genome. This effort involved a genome-wide association study (GWAS), which rapidly scans across the genomes of large populations for markers that track with a particular trait. GWAS is good at finding common genetic variants, but nearly all of the identified variants alter height by less than 1 mm and tend to lie mostly outside the protein-coding parts of genes, making it harder to figure out which genes they affect. It is not as good at capturing uncommon genetic variants, which can have larger effects.

In the new study, the GIANT investigators used a different technology called the ExomeChip, which tested for a catalogue of nearly 200,000 known variants that are less common and that alter the function of protein-coding genes. These variants point more directly to genes and can be used as a shortcut to figuring out which genes are important for a specific disease or trait. Most had not been assessed in prior genetic studies of height.

Using ExomeChip data from a total of 711,428 adults, the investigators identified 83 uncommon variants associated with adult height — 51 ‘low frequency’ variants (found in less than 5% of people) and 32 rare variants (found in less than 0.5%) — with 24 of these variants found to affect height by more than 1 cm and some by more than 2 cm. Furthermore, the rare variants pointed to dozens of genes as important for skeletal growth, many of which had not previously been connected with such a thing.

One gene of particular interest, STC2, had two different DNA changes that both had larger effects on height. Though the variants are quite rare (0.1% frequency), people with either of these changes were 1–2 cm taller than non-carriers. Further investigations suggested that the variants influence height by affecting the availability of growth factors in the blood.

“The STC2 protein serves as a brake on human height, validating it as a potential drug target for short stature,” said Dr Joel Hirschhorn, chair of the GIANT Consortium.

With these new findings, 27.4% of the heritability of height is now accounted for — up from 20% in earlier studies — with most heritability still explained by common variants. But despite these advances, some readers may still have one question: why study height in the first place?

“It’s important we study height because height is a human trait which is 80% heritable,” said Associate Professor Craig Pennell from UWA. “What we learn from studying height and where genetics play a very large role can then be translated to study the genetics of human disease.

“Our data provides strong evidence that rare genetic variants play a substantial role in regulating height — this has implications in the prediction of complex human disease such as diabetes, cancer, schizophrenia and cardiovascular disease. This is also is important in a new era of precision medicine.

“Understanding what components are responsible for how humans grow will have a tremendous impact in helping us understand disease, work to develop treatments and cures, and to work out which people may be at risk of developing particular diseases.”

Image credit: Lauren Solomon, Broad Communications.