14 October 2022

Genes and growth

The search for genetic factors determining the growth of Europeans is coming to an end

Elena Kleshchenko, PCR.news

One of the largest studies of the genetic determinants of human growth has been completed; its results are published in Nature. The authors used the genetic data of almost 5.4 million people to search for variants associated with differences in height, and showed that they had reached a "saturation point" — more data would not allow new variants to be discovered, at least for populations of European origin. This is a new stage in our understanding of the inheritance of complex traits, the Nature observer notes.

Some diseases, such as cystic fibrosis or Huntington's disease, are caused by changes in one or more specific genes. Once these genes are identified, it is assumed that the cause is clear (although there may be difficulties caused by, for example, incomplete penetrance). For states of a more complex nature, which are determined by many factors, a special approach was developed in 2005 — genome-wide association search (GWAS). Comparing the genomes of a large number of people allows us to identify multiple genetic variants associated with differences in the trait of interest.

Early GWAS usually involved several thousand people, and such a study could explain only about 5% of the differences in height between people. "Missing heritability" — the contribution of factors not detected by GWAS at early stages — included rare variants, intergenic interactions, small effects of individual variants, which are nevertheless significant. There was a fundamental question whether it was possible to get a complete picture of the genetics of a complex trait.

Human growth is largely inherited, and this trait is easy to quantify (as opposed to intelligence or predisposition to cardiovascular diseases), so the genetics of growth is actively studied. An analysis of about 250,000 people conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium in 2014 revealed about 700 growth-related variants, which were thought to explain about 36% of the trait's heritability. A 2018 meta-analysis covering data from about 700,000 people found 712 loci associated with growth.

Millions of human genomes are currently being studied in thousands of GWAS. The authors of the new study wondered whether a large sample size could reveal the missing heritability. The 281 GWAS of the GIANT consortium and the company 23andMe, which they used, mainly presented data from people of European origin (4 million out of 5.4).

The 12 111 variants of single nucleotide substitutions (SNPs) found by the authors are grouped into segments covering 21% of the genome. For example, 25 SNPs associated with growth are localized within 100 bp of each other on chromosome 15 next to the ACAN gene, mutations in which were found in the syndromes of stunting and skeletal dysplasia.

According to previous estimates, heritability, which in principle is explained by all variants detected by GWAS, can reach 50%. Indeed, the SNPs identified by the authors can explain more than 40% of the variations in height.

Thus, the possibilities of GWAS in the study of growth genetics are almost exhausted, at least for European populations. This important result motivates the achievement of "saturation" for other signs and diseases, and then the identification of the genes underlying these associations and the elucidation of the mechanisms of their action.

This study, like other GWAS, did not fully cover human genetic variations, in particular, the huge genetic diversity of Africa was not investigated. For participants of African descent from the United States and the United Kingdom, the identified genetic variants can explain only 5-12% of the differences in height (compared to 40% in people of European descent). As has been repeatedly noted, research is needed that fully reflects the genetic diversity of all human populations.

Article by Yengo et al. A saturated map of common genetic variants associated with human height is published in the journal Nature.

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