02 September 2012

Near and far, nature and nurture

Study examines the genetic architecture of gene activity in twins to functionally link genes involved in human disease

The MuTHER logo.

The MuTHER logo.


A new study points the way to discover genetic variants that affect human health. It is the first study to use unique sets of samples from twins that mean the team can unpick the relative contributions of genetic variants in the genome and the environment in controlling activity of key genes.

The team’s method enabled them to establish a functional link for more than 350 putative disease-causing genetic variants, including cancer, skin disease, immune system disease and obesity, to a specific gene. Their study also shows the way in which new approaches will be able to uncover the ‘missing’ variants important for human disease.

Genetic researchers have, since the decoding of the human genome, identified thousands of genetic variants associated with human disease. In many cases, these variants are relatively common in human populations (perhaps one in twenty people), but their effects are often rather slight. These statistical associations often involve multiple genes and both the genes and variants that are the direct cause of the disease remain, for the most part, unknown.

In this project, the team looked at the effects that genetic variants had on activity of thousands of genes in three tissue types from more than 850 twins. Twin studies - use both identical twins which are genetically identical and non-identical twins - can help to tease out the role of genes and the role of environment: if two people are genetically identical, differences in disease development is most likely to be due to environmental influences.

They hoped to uncover genetic variants that drove different levels of activity of one or more genes. These variants could be important in development of disease.

"We generated the most precise estimates to date of how heritable gene activity is in humans, and this was made possible by using the twins," says Elin Grundberg, lead analyst in the study, from the Wellcome Trust Sanger Institute and King’s College London. "We found that variants that lie close to genes, called cis variants, account for 30-36 per cent of the genetic component in gene activity."

“Identifying variants which control the activity of many genes is a greater challenge than we anticipated but we are developing appropriate tools to uncover them and understand their contribution to disease.”

Dr Panos Deloukas

The team measured the activity of thousands of genes in three tissues - skin, adipose and cell lines derived from blood: these tissues are important for disease from eczema to cancer. They then looked to see if different levels of activity were associated with different genetic variants in the human genome. They looked at variants that lay close to each gene, called cis variants, as well as those that lay elsewhere, called trans variants.

They found thousands of regions in the genome where gene activity was different in the tissue samples. For 358 of these, they found a candidate association between the genetic variant, the altered gene activity and a disease, homing in on the causative gene.

The twin samples enabled them to look in more detail at inheritance of variants that affect gene activity. They estimate that about half of the genetic effects remain to be uncovered, residing in variants that are relatively rare in humans.

"This is the first time that anyone has looked at the contribution of genetic and non-genetic factors to gene activity in tissues from twins, a set of samples that allow us to unpick the genetics of human disease," says Tim Spector, Head of the Department of Twin Research, from King’s College London. "We are grateful to all the volunteers in the TwinsUK study: without them and their altruistic gift, we wouldn’t be able to make these advances in this way. For the first time we are able to quantify the contribution of rare regulatory variants to gene expression levels." says Emmanouil Dermitzakis, Louis-Jeantet Professor of Genetics, University of Geneva Medical School. "This is a great step in elucidating the identity and contribution of such rare regulatory variants to complex disease risk"

Importantly, the twins sample set and the associated issue studies meant the team could uncover in greater depth the influence of variants at a distance - trans variants - on gene activity. Such variants tend to be master regulators of gene activity, affecting many genes, but also tend to be active in one tissue, suggesting each tissue has a set of such regulators.

The results are from the MuTHER (Multiple Tissue Human Expression Resource) project, and the research was led by Panos Deloukas from the Wellcome Trust Sanger Institute, Tim Spector from the Department of Twin Research and Genetic Epidemiology at King’s College London, Mark McCarthy from the Wellcome Trust Centre for Human Genetics, University of Oxford, and Emmanouil Dermitzakis from the Department of Genetic Medicine and Development at the University of Geneva Medical School, Switzerland.

The team’s experiments provide the foundation and set the requirements for new discovery of trans variants. To tease out these important variants - as well as the rarer cis variants close to genes - will need more samples than used or, indeed, expected.

"Identifying variants which control the activity of many genes is a greater challenge than we anticipated but we are developing appropriate tools to uncover them and understand their contribution to disease," comments Panos Deloukas, Senior Group Leader, from the Wellcome Trust Sanger Institute. "Modern human genetics combined with samples donated by the participants in studies such as TwinsUK is making great strides towards finding the genetic culprits behind human disease. We are in a period of rich discovery and we must ensure these are made available as widely as we can, to drive the search for new diagnostics and treatments."

The data are available for the three tissues can be accessed through the browsable Genevar tool at the Sanger Institute website.

Notes to Editors

Publication details

  • Mapping cis- and trans-regulatory effects across multiple tissues in twins.

    Grundberg E, Small KS, Hedman ÅK, Nica AC, Buil A, Keildson S, Bell JT, Yang TP, Meduri E, Barrett A, Nisbett J, Sekowska M, Wilk A, Shin SY, Glass D, Travers M, Min JL, Ring S, Ho K, Thorleifsson G, Kong A, Thorsteindottir U, Ainali C, Dimas AS, Hassanali N, Ingle C, Knowles D, Krestyaninova M, Lowe CE, Di Meglio P, Montgomery SB, Parts L, Potter S, Surdulescu G, Tsaprouni L, Tsoka S, Bataille V, Durbin R, Nestle FO, O'Rahilly S, Soranzo N, Lindgren CM, Zondervan KT, Ahmadi KR, Schadt EE, Stefansson K, Smith GD, McCarthy MI, Deloukas P, Dermitzakis ET, Spector TD and Multiple Tissue Human Expression Resource (MuTHER) Consortium

    Nature genetics 2012;44;10;1084-9


The MuTHER Study was funded by a program grant from the Wellcome Trust and by core funding for the Wellcome Trust Centre for Human Genetics. Additional funding came from the European Community’s Seventh Framework Programme grant agreement, ENGAGE project and grant agreement HEALTH-F4-2007-201413, the Swiss National Science Foundation, the Louis-Jeantet Foundation and a US National Institutes of Health-National Institute of Mental Health (NIMH) grant (GTEx project). Additional details on the funding for the participating studies and investigators are provided at the Nature Genetics website.

Participating Centres

A full list of participating centres can be found at the Nature Genetics website.

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.


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The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.


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