Why human height’s messy business

UNC-CHAPEL HILL (US) — It turns out there isn’t a simple “tall” gene or “short” gene. Instead hundreds of genes determine a person’s height, new research shows.

The findings—reported in the journal Nature—also point the way to future studies exploring how these genes combine into biological pathways to affect human growth.

“While we haven’t explained all of the heritability of height with this study, we have confidence that these genes play a role in height and now can begin to learn about the pathways in which these genes play a role,” says study coauthor Karen Mohlke, associate professor of genetics at the University of North Carolina at Chapel Hill (UNC).

The study brought together hundreds of investigators from dozens of countries to identify which genes affect height in almost two hundred thousand different individuals.

“These investigators had once been competing with each other to find height genes, but then realized that the next step was to combine their samples and see what else could be found,” says Mohlke. “The competitors became collaborators to achieve a common scientific goal.”

That pooling of resources was necessary because the scientists knew that height was a complex genetic trait, with possibly a number of genes of small effect each adding up to influence whether a person would be taller or shorter.

In this large study, 46 smaller genome-wide association studies of height were combined and then statistically analyzed, yielding 180 different regions or genetic loci that influence the trait.

“These common gene variants could explain as much as sixteen percent of the variation in height,” says study coauthor Kari North, associate professor of epidemiology at UNC.

The researchers looked to see whether the 180 regions contained more genes that underlie skeletal growth defects than would be expected if those regions were just chosen randomly across the genome. They found that the genes were not random and could in fact point to functional pathways important in influencing height.

Members of the consortium—aptly named GIANT for Genetic Investigation of Anthropometric Traits—are working to uncover the “missing heritability”—the proportion of inherited variation in height that is still unexplained. Because this study looked for common genetic variants, the researchers are now going after rare genetic variants that may also play a role.

“This work is giving the field important insights into skeletal growth, height, and growth defects,” says Mohlke. “And it is also showing us how similar approaches can be taken to look for genes underlying other common traits and diseases relevant to body size, like type 2 diabetes.”

The work, funded by the National Institutes of Health, was led by a team of collaborators that included Gonçalo Abecasis from the University of Michigan and researchers from Harvard University, University of Exeter, and deCODE Genetics in Iceland.

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