For height, DNA is largely destiny. Studies of identical and fraternal twins suggest up to 80% of variation in height is genetic. But the genes responsible have largely eluded researchers. Now, by amassing genome data for 4 million people—the largest such study ever—geneticists have accounted for a major share of this “missing heritability,” at least for people of European ancestry. In this group, they’ve identified nearly 10,000 DNA markers that appear to fully explain the influence of common genetic variants over height.
“This is a genuine landmark,” says Daniel MacArthur of the Garvan Institute of Medical Research in Australia.
If the missing genetic contributors to other traits and diseases can be identified, and extended to other ancestries, the results could “inform new biology and contribute to personalized medicine,” suggests Loïc Yengo of the University of Queensland in St. Lucia, Australia, whose team presented the work online this week at the annual meeting of the American Society of Human Genetics. For example, geneticists could more accurately assess people’s risk of diseases from genome scans. But the study leaves some scientists dissatisfied because it identifies only markers linked to genes that sway height, not the genes.
The mystery of missing heritability dates back to the late 2000s, when researchers began to use new tools to scan human genomes for common markers linked to diseases and traits. They expected the results of these genomewide association (GWA) studies to match evidence from the genetics of twins and families, such as the overwhelming influence in wealthy countries of genes on height, rather than environmental factors such as diet or childhood infections.
But it turned out that each identified marker, which may be in or just near a relevant gene, only contributes slightly to a trait or disease risk, and tallying them up didn’t solve the problem. For height, the first 40 DNA markers linked to the trait explained just 5% of its variation.
A number of possible explanations emerged, including rare gene variants missed by the GWA studies, gene-gene interactions, and that the twin studies were wrong. But Peter Visscher, leader of Yengo’s team, argued it was partly a matter of finding many more common variants with very small effects. He estimated that such variants should account for 40% to 50% of the genetic component of height. Picking out the faint signals would require studying the DNA of a huge number of people, however.
By 2018, Visscher’s team and other members of a global consortium called GIANT had pooled DNA data for 700,000 people and found 3300 common markers that explained 25% of the variation in height. Now, by looking across DNA from 201 GWA studies with 4.1 million participants, GIANT has brought the total to roughly 9900 common markers, accounting for 40% of the variation. Other markers located nearby and likely inherited together account for another 10% of height variability.
That’s still short of the 80% predicted by twin studies. But last year, Visscher’s group drew on whole-genome sequencing data of a smaller number of people to demonstrate that rare variants—those carried by fewer than one in 100 people—should explain another 30% of height’s variation. (The result was released in a March 2019 preprint that the team is revising.)
Some geneticists say they aren’t surprised that heritability gaps can be filled once enough people had their DNA scanned. “It was expected,” says Aravinda Chakravarti of New York University. The problem remains that few of the height-linked DNA markers have been tied to specific genes that clearly alter the trait. “It’s mostly all still ‘missing’ in a biological sense,” says David Goldstein of Columbia University.
The new findings brighten prospects for tracking down those genes, Yengo says. Instead of being scattered randomly across the entire genome, which would make it challenging to ever get a handle on the specific genes and their roles, the 9900 or so markers are confined to only about 30% of the genome. And many cluster in areas known to contain genes involved in growth.