Genetic study examines mystery of height heritability

Height is often inherited, but precise genetic factors have long eluded researchers.Credit: Shomos Uddin / Getty

One only needs to look at families to see that size is inherited – and studies of twins and identical families have long confirmed this suspicion. About 80% of the height variation is due to genetics, they suggest. But since the human genome was sequenced almost two decades ago, researchers have struggled to fully identify the genetic factors responsible.

Studies looking for the genes that govern height have identified hundreds of common genetic variants related to the trait. But the results also posed a dilemma: each variant had a minimal effect on height that, together, did not equal the genetic contribution predicted by family studies. This phenomenon, which occurs with many other traits and diseases, has been dubbed missing heritability and has even prompted some researchers to speculate that there is something fundamentally wrong with our understanding of genetics.

Now, a study suggests that most of the missing heritability for height and body mass index (BMI) may, as some researchers suspected, be found in rarer genetic variants that had not been discoveries so far.

“This is a reassuring article because it suggests that there is not something terribly wrong with genetics,” says Tim Spector, genetic epidemiologist at King’s College London. “It’s just that sorting it out is more complex than we thought. »The research has been published1 to the bioRxiv preprint server on March 25.

Search the genome

To research the genetic factors underlying diseases and traits, geneticists turn to mega-research known as genome-wide association studies (GWAS). These scour the genomes of tens of thousands of people – or, increasingly, over a million – looking for single letter changes, or SNPs, in genes that commonly appear in people. suffering from a particular disease or which could explain a common trait such as height.

But GWAS has limits. Because sequencing the entire genome of thousands of people is expensive, the GWASs themselves only scan a strategically selected set of SNPs, perhaps 500,000, in each person’s genome. This is just a glimpse of the roughly six billion nucleotides – the building blocks of DNA – chained together in our genome. In turn, those 500,000 common variants would have been found by sequencing the genomes of a few hundred people, says Timothy Frayling, a human geneticist at the University of Exeter, UK.

A team led by Peter Visscher of the Queensland Brain Institute in Brisbane, Australia, decided to determine whether SNPs rarer than those typically scanned in GWAS could explain the missing heritability for height and BMI. They turned to whole genome sequencing – doing a full 6 billion base read – of 21,620 people. (The authors declined to comment on the prepublication, as it is in the process of being submitted to a journal.)

They relied on the simple, yet powerful principle that all people are related to some extent – albeit distantly – and that DNA can be used to calculate degrees of kinship. Then, information about a person’s height and BMI could be combined to identify common and rare SNPs that could contribute to those traits.

Say, for example, that a pair of third cousins ​​is closer in size than a pair of second cousins ​​is in a different family: this is an indication that the size of the third cousins Is mainly due to genetics, and the extent of that correlation will tell you how much, says Frayling. “They used all the genetic information, which allows you to determine to what extent the kinship was due to rarer things as well as common things.”

As a result, researchers have captured genetic differences that occur in only 1 in 500 people, or even 1 in 5,000.

And using information on common and rare variants, the researchers arrived at roughly the same heritability estimates as shown by studies of twins. For height, Visscher and colleagues estimate heritability to be 79% and for BMI 40%. This means that if you take a large group of people, 79% of the height differences would be due to genes rather than environmental factors, such as nutrition.

Complex processes

The researchers also suggest how previously undiscovered variants could contribute to physical traits. Tentatively, they found that these rare variants were slightly enriched in the protein-coding regions of the genome, and that they had an increased likelihood of disrupting these regions, notes Terence Capellini, evolutionary biologist at Harvard University at Cambridge, Massachusetts. This indicates that rare variants could influence height in part by affecting regions encoding proteins instead of the rest of the genome – the vast majority of which do not include instructions for making proteins, but could influence their expression.

The paucity of variants also suggests that natural selection could eliminate them, possibly because they are harmful in one way or another.

The complexity of heritability means that understanding the roots of many common diseases – necessary if researchers are to develop effective therapies against them – will take significantly more time and money, and could involve sequencing hundreds of thousands or even millions of whole genomes to identify the rare variants that explain a substantial part of the genetic components of diseases.

The study only reveals the total number of rare variants contributing to these common traits – not the important ones, says Spector. “The next step is to determine which of these rare variants are important for the traits or diseases for which you want to get a drug. “

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