Study Finds Gene Variants Governing Human Height
Researchers from more than 200 institutions in the U.S. and Europe have identified hundreds of genetic variants that in total account for roughly 10 percent of the inherited variation in human height.
The consortium of researchers, named GIANT for Genetic Investigation of ANthropometric Traits, combined data from more than 180,000 individuals, including millions of genetic results from each of 46 separate studies in the U.S., Canada, Europe and Australia. Using this data, they were able to identify hundreds of genetic variants associated with height located in at least 180 different spots in the genome.
The study revealed that these variants consistently cluster around genes from at least six different biological pathways, many of which are located near genes already known to be involved in skeletal growth syndromes. However, others implicate previously unrecognized genetic growth regulators, suggesting new areas for biological research on human height.
“Height clearly has a lot to do with genetics – shorter parents tend to have shorter children, and taller parents tend to have taller children,” said Joel Hirschhorn of Children’s Hospital Boston, the Broad Institute and Harvard Medical School and a co-senior author of a report about the study.
“This paper is the biggest step forward to date in understanding which of the genetic variants that differ between people account for our differences in height,” he said.
To search for genes affecting height, Hirschhorn and colleagues used something called genome-wide association (GWA) studies. Such studies sample millions of sites of genetic variation in large groups of people, and then analyze the data to search for consistent differences associated with any of the variants in the genome.
When studying large enough populations, these variants can point to genes that contribute to traits such as height, which vary widely among people for many different genetic reasons.
“A good bit of the genetic differences in height is going to be explained by common variants that individually have very small effects,” said Hirschhorn.
“We all carry many different variants that each make us slightly taller or shorter.”
The study found that at least 19 locations in the genome had multiple variants independently associated with height, suggesting that the nearby genes are significant in regulating childhood growth and may account for a considerable fraction of existing height-related variation.
The GIANT GWA study of height, which discovered more genetic variants influencing a trait than any prior genetic study, demonstrates the value of GWA studies with large populations.
“With enough statistical power, you can identify lots of loci, and clearly relevant biological pathways emerge that were not evident in smaller studies,” said Hirschhorn.
The study also has implications in the role of rare versus common genetic variants. Many scientists believe that genetic variants that alter gene function and influence diseases or traits are rare (occurring in 1 percent or less of the population), since natural selection would tend to eliminate them from the general population.
“What we show is that for at least some cases, it’s the common variant that has the effect,” says Hirschhorn.
“More importantly, they cluster in consistent areas near or within particular genes that highlight biological pathways – they’re not randomly strewn across the genome.”
Despite the large number of genetic regions identified by the study, the fraction of variation in height explained by these loci is only about 10 percent.
“Genome-wide association studies are very powerful tools, but even so, we are still some way short of understanding the full details of how differences in our genomes influence common human traits such as height,” said Timothy Frayling PhD of the University of Exeter (UK), co-senior author of the report.
“Complex traits such as height are proving even more complex than we had first thought. We will need even more powerful tools and different approaches if we are to understand fully the differences between individuals,” he said.
Height is a classic model for genetic research on complex traits because it is easily measured and varies greatly from person to person. And unlike Mendelian genetics where a single inherited gene determines whether a pea is green or yellow, height has many gradations and is the sum product of multiple genes.
“If we can understand the genetics of height, it will help us understand how other polygenic traits are inherited,” said Hirschhorn.
The GIANT study was published in the September 29 advance online edition of the journal Nature.