The international Genetic Investigation of Anthropometric Traits (GIANT) Consortium has uncovered 83 new DNA changes that affect human height, some rare but some adjusting height by more than 2 centimeters. The 700,000-plus-person study also found several genes pointing to previously unknown biological pathways involved in skeletal growth.
In 2014, GIANT, studying roughly 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 powerful method called genome-wide association study (GWAS), which rapidly scans across the genomes of large populations for markers that track with a particular trait. GWAS are good at finding common genetic variants, but nearly all of the identified variants alter height by less than 1 mm (less than 1/20 of an inch). GWAS studies are not as good at capturing uncommon genetic variants, which can have larger effects. Finally, the common variants that track with traits tend to lie mostly outside the protein-coding parts of genes, making it harder to figure out which genes they affect.
So in the new study, the GIANT investigators used a different technology: 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 (an initial 460,000 people and about 250,000 more to validate the findings), the investigators identified 83 uncommon variants associated with adult height: 51 "low-frequency" variants (found in less than 5 percent of people) and 32 rare variants (found in less than 0.5 percent).
With these new findings, 27.4 percent of the heritability of height is now accounted for (up from 20 percent in earlier studies), with most heritability still explained by common variants.