Nearly 30 rare gene variants that decrease people鈥檚 height by up to 7 centimetres, or raise it by up to 5 cm, have been discovered by analysing the genomes of more than 300,000 individuals.
鈥淭he variants I found, they鈥檙e very rare, so less than 1 per cent of individuals carry them, but their effects are very large,鈥� says at the University of Exeter Medical School in the UK.
Height is largely genetically determined, with environmental factors such as nutrition playing only a minor role. By comparing the gene variants in millions of people with their heights, more than 12,000 common gene variants that are linked with stature have already been identified.
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However, these common variants usually only have a small effect, typically raising or lowering height by a millimetre or less.
Common variants have mainly been found by analysing data from so-called DNA chips, which look at sites in the genome where single DNA letters often vary between individuals. Such studies cannot identify rare variants that are not included in the DNA chips.
Now, the number of whole-genome sequences is becoming large enough to identify rare variants that affect height. Hawkes and his colleagues started by analysing the genomes of 200,000 people in the UK Biobank study. They then checked the findings by looking at another 130,000 genomes from two US projects called All of Us and TOPMed. This means their research is based largely on people with European ancestry.
The team found 29 rare variants that have an average effect of about 3 cm, but can add up to 5 cm to someone鈥檚 height or take off 7 cm. Most appear to act by altering the level of activity of genes, rather than altering the proteins encoded by genes.
at the University of Queensland in Australia, who carried out the study that identified 12,000 common variants, says the variants found so far in people of European ancestry explain only about half of the variation that is thought to be genetic.
鈥淭his work is complementary to ours,鈥� says Yengo. 鈥淗owever, the 29 variants identified in this study account for a very limited amount of height variance. So there is still a long way to go before we identify all the rare variants responsible for the missing heritability.鈥�
Tallness is regarded as a desirable attribute in many cultures, so much so that some people pay large sums for that involve breaking both femurs. However, last year at the University of Colorado reported that certain gene variants linked to greater height also increase the risk of some nerve, skin and heart conditions.
鈥淭he mechanism linking height with cardiovascular traits still needs some elucidation, so any relationship of newly discovered height-associated rare variants with cardiovascular traits would likely have to be tested directly,鈥� says Raghavan.
However, some conditions such as varicose veins are probably associated with height at least partially for physical reasons, he says, such as the return of blood from the feet being more physically demanding.
Hawkes says he does not see any immediate medical applications for the latest findings. However, understanding the genetics of height will help us understand the genetics of other traits, too. 鈥淥ur predictions, not just for height but for disease and all kinds of [traits], are going to get better and better,鈥� he says.
In theory, in vitro fertilisation (IVF) clinics could screen embryos for these variants and give parents a choice of having taller children, . The idea of parents choosing their children鈥檚 traits is controversial and in the case of the latest research, only a few per cent of people possess any of these rare variants.
bioRxiv
