Two NGI centers, the Center for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing contributed to a landmark paper in Nature about height genes. Scientists from both centers participate in the GIANT consortium. Length is a trait with a strong heritability. This paper is a big step forward in understanding which of the genetic variants that differ between people account for differences in height. Of particular interest was that some of the loci contained sets of genes known to be involved in growth-related processes, and a number of the loci overlapped with those previously linked to other traits and diseases, including bone mineral density, rheumatoid arthritis, type 1 diabetes, psoriasis and obesity. In depth analysis of these results will provide new insights in biological processes affecting health.
Hundreds of common genetic variants across the human genome influence adult height, according to a study of over 180 000 individuals published in the journal 'Nature'. The study itself identifies over a hundred new variants and shows that they are not randomly distributed, but are clustered around genes which have been previously linked to growth.
Scientists have now identified a total of 180 genetic variants which influence height. Today's study, funded by several large national agencies like Wellcome Trust and NIH, and includes funding from the Netherlands Genomics Initiative to the Dutch genome scientists, still only accounts for around 10 per cent of our inherited variation in height, highlighting the challenging nature of unravelling genetics.
Height is a classic 'complex trait' - in other words, a trait that is influenced by a number of different genes and the environment. Over 80 per cent of the variation within a given population is estimated to be attributable to genetic factors; the remainder is influenced by a person's environment, such as their diet.
For this new study, almost three hundred researchers from over a hundred institutions across the globe - part of the appropriately named the Genome-wide Investigation of ANthropometric Traits Consortium or GIANT Consortium - analysed data from the DNA samples of over 180 000 individuals, looking for genetic variants known as single nucleotide polymorphisms - SNPs (pronounced 'snips').
The human genome is made up of more than three billion sub units of DNA, called nucleotides. A substantial part of the variation in DNA sequence between individuals is due to differences in individual nucleotides. These differences are the SNPs. Genome-wide association studies scan the genome looking for SNPs that are common in particular populations - for example, in patients with a particular disease.
Researchers from the GIANT Consortium, including teams from the UK, the USA, Iceland and the Netherlands, identified SNPs associated with influencing height in adults in 180 regions of the genome (known as 'loci'); over a hundred of these regions were identified for the first time.
”This study identified by far the largest number of genetic variants convincingly associated to a human trait. Beyond the large number of newly discovered genetic variants, the greatest leap forward is made towards the understanding of the biological processes controlling human height variation ” says Fernando Rivadeneira, Erasmus MC Senior Scientist and also co-lead first author of the paper.
“A part of the genetically determined differences in height is now shown to be explained by hundreds of common variants that individually have small but genuine effects,” says André Uitterlinden, Professor of Complex Genetics at Erasmus MC.
"For common traits, we have reached the stage where only giant global consortia can provide enough power to track the underlying biology, and the Netherlands' researchers are wellcome collaborators with their large and well-typed biobanks" says professor Gertjan van Ommen, director of the Center for Medical Systems Biology (CMSB). "Researchers of the Netherlands Genomics Initiative centers CMSB and Netherlands Consortium for Healthy Ageing (NCHA), have contributed to this landmark paper, from VU University Amsterdam, Erasmus MC Rotterdam and Leiden University Medical Center ".
The researchers found that the loci were not distributed randomly across the genome, but that they clustered within genomic loci and in biological pathways. Twenty-one were found near certain genes known to influence abnormal skeletal growth in rare cases. This suggests that the SNPs were linked to these genes, possibly being involved in their regulation.
Of particular interest was that some of the loci contained sets of genes known to be involved in growth-related processes, and a number of the loci overlapped with those previously linked to other traits and diseases, including bone mineral density, rheumatoid arthritis, type 1 diabetes, psoriasis and obesity.
"We are now starting to find actual evidence supporting the involvement of height genes in the occurrence of human disease, which provides some insight to those epidemiological studies, linking some of these diseases and height," says Dr Fernando Rivadeneira, from Erasmus Medical Center, The Netherlands. "In-depth analysis of the way in which common variants in genes have modest effects on people's height will provide important insight into understanding the causes of human diseases."
"We have found clues to how genes related to growth are being regulated by nearby genetic variants as well as identifying new candidates that may play a role in growth," adds Dr Mike Weedon from the Peninsula Medical School, University of Exeter. "Given the number of loci we have found that contain genes known to be involved in growth, we can assume that those loci not found near known height-related genes could provide potential clues to important and novel biological processes."
Despite the number of DNA samples analysed in this study, the researchers believe that they have only found around a quarter of those genetic variants which could feasibly be identified using genome-wide association studies. "Twin studies indicate that the heritability of human height is at least 80%", says Dorret Boomsma. To find the remainder will require larger studies and, very likely, a more detailed analysis of different types of variation in the genome, including variants that are rare or complex, such as repetitive or missing sections.
"Genome-wide association studies are very powerful tools, but even so, we are still some way short of understanding the full details of how differences in our genomes influence common human traits such as height," says Professor Tim Frayling, also from the Peninsula Medical School. "Complex traits such as height are proving even more complex than we had first thought. We will need even more powerful tools and different approaches if we are to understand fully the differences between individuals
Karol Estrada, first starred author of the Nature paper: “This gigantic study identified by far the largest number of genetic variants convincingly associated to a human trait. Beyond the large number of newly discovered genetic variants, the greatest leap forward is made towards the understanding of the biological processes controlling human height variation.”
To Center for Medical Systems Biology
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