A massive new study, the largest genome-wide association study ever done, has found nearly all the common genetic variants that explain the heritability of height among people of European ancestry, and in the process may have set the framework for future genetic research into other traits and diseases.
Using data from about 5.4 million individuals, almost half of whom were 23andMe customers who consented to participate in research, the study identified 12,111 variants or single nucleotide polymorphisms (SNPs) that help explain differences in height.
“We feel that this is really a milestone,” said Joel Hirschhorn, senior author on the study, an institute member at the Broad, and also a professor of genetics and Concordia Professor of Pediatrics at Boston Children’s Hospital and Harvard Medical School. “We’d been studying height for a while but had only identified a small fraction of common variant heritability. We’re now basically done mapping this heritability to specific genomic regions, and that highlights what increasing sample size can tell us about traits controlled by multiple genes.”
Published in the journal Nature, the study, led by researchers at the Broad Institute and the international Genetic Investigation of ANthropometric Traits (GIANT) Consortium, is the culmination of a multi-year effort to foster collaboration between academic, non-profit, government, and commercial partners. In their effort, the researchers collected, merged, and analyzed numerous independently generated genome-wide association studies into a single data set. In all, there are more than 200 different datasets incorporated into this study, which included contributions from hundreds of scientists from around the world.
The Power of Scale
What they found is important not just because of what it says about height, syndromes, and abnormalities affecting stature, but what it says about the potential of using very, very large amounts of data to generate insights into the genetics of different traits and conditions. Because height is so heritable, and because it is easy to measure someone’s height, it offers a very straightforward way to conduct a genetic study into a trait.
“This study highlights the ability of large-scale genetic studies to reveal the underlying biology of human phenotypes,” said Adam Auton, 23andMe’s Vice President of Human Genetics. 23andMe was one of a long list of institutions and organizations involved in the study.
“With this 5.4 million person study, we’re now at the stage where we’re starting to saturate our genetic understanding of height,” Auton said. “However, for other phenotypes — particularly human diseases — we’re a long way from saturation, and there is a lot we don’t yet understand.”
Heritability of Height
Heritability is the measure of how much our DNA explains the differences in specific traits or conditions. A SNP is a one-letter variation in the genetic code at a single point along the genome. These common variants are associated with differences in everything from traits like the color of our eyes or our height, or our risk for certain diseases.
Along with genetics, one’s environment — diet, for instance — also plays a role in these different traits and conditions. In the case of height, genetics has an outsized role in explaining about 80 percent of the variation. Because researchers included more than twice the number of individuals in this study from the next largest height study, they were able to discern almost all the heritability for height. So, size matters in genetic studies.
Previous height studies were large but just not large enough. According to the authors, this study was big enough to discern almost all of the heritability for height. In finding most of the variants that explain the heritability for height, the authors estimate that they’ve now identified variants that account for 40 percent of all variation in height in people with European ancestry. But they’ve identified only around 10–20 percent of the variation in people of other ancestries.
Also significant is that the study found that the genetic variants associated with height clustered within or near genes or gene regions associated with growth and development. That makes sense, but scientists were not so sure that is what they’d find. Many scientists thought that perhaps the variants they’ve identified could be found randomly sprinkled throughout the genome. But seeing that there is clustering will allow researchers to focus more on the clues around the biology and processes involved in individual traits like height.
In addition, the study illustrates something we already know about genetic research: diversity matters.
Although there were large numbers of individuals – more than a million – with African, Asian, and Latino ancestry included in this study, the vast majority of the data came from people of European ancestry. Some of the variants associated with height were associated with individuals of all different ancestries, but the findings were most applicable to those of European ancestry.
The researchers concluded that their study would benefit from data from a more diverse pool of individuals, especially those of African ancestry since people of African ancestry have the most genetic diversity of all populations. Not only would it improve the predictive power of the models developed to predict height for non-Europeans, it would also help in identifying causal genes and rare variants involved in height.
Read the full paper here.