3rd April 2009

The lowdown on height genes

New study begins to uncover the skeletal basis of variation in height

scan

High-resolution desitometric scan. The team carried out high-resolution internal scans to measure femur, spinal and hip-axis length.

A new study has delved deeper than ever before into understanding the genetic basis of adult human height. The study is the first of its kind, using exploratory statistical analyses to uncover how 17 genetic variants that are implicated in human height affect the length of particular skeletal components of the body, used as a proxy for height subcomponents.

The research opens the door to a better understanding of the developmental pathways that contribute to human height. Four of the variants that the team described as associated with height had not previously been identified.

Researchers at the Wellcome Trust Sanger Institute led an international consortium of investigators from Canada, Israel, the Netherlands and UK to study approximately 20,000 individuals, searching for regions in the genome that were associated with differences in height. By looking through 300,000 known SNPs - single letter changes in genetic code - the team found 17 regions that contributed to human height. To understand better how variation at these regions contributed to height, the team took skeletal measurements of the spine, leg and hip-axis, to determine the specific effects of these genetic markers on the length of skeletal size measurements.

"The statistical analysis of height subcomponents poses challenges due to the high correlation among the different traits," explains Dr Nicole Soranzo, Sanger Institute researcher and lead author on the study. "There have been a handful of genome-wide association studies that have concentrated on height in the past, but the impact of variants on the different skeletal subcomponents of height has never been investigated. The study begins to clear a path for research that goes beyond looking at associations, to look at biological processes involved in differential height components."

" The study begins to clear a path for research that goes beyond looking at associations, to look at biological processes involved in differential height components "

Dr Nicole Soranzo

Genetic regions that play a role in increased human height have, in the past, been uncovered in genome-wide association studies. Height is relatively easy to measure simply and accurately. However, to look at the contribution of individual skeletal components is considerably more complicated.

"Overall height can mask differences in the skeletal components: researchers need to tease apart the contribution of genetic loci to each of these components. Our study is a first attempt towards this goal but much larger samples will be needed to accomplish it," explains Dr Panos Deloukas, senior investigator at the Sanger Institute and coordinator of the consortium. "The final upper or lower body size of humans might be the result of independent growth pathways that need to be understood."

The team wanted to elucidate how the 17 variants strongly associated with adult height impacted on the length of individual skeletal components. To measure the length of the skeletal components the team used data from high-resolution densitometric scans of human bones. Nine of the variants were associated with increased trunk length; approximately 5% of the variance in femur length was explained by a combination of all of the variants. Seven of the variants influenced hip-axis length, which is a known predictor for osteoporosis in humans.

The height of an individual is composite of many genetic influences and each genetic region identified so far adds less than half a centimetre to the height of the individual carrying the underlying variant. In total the 17 regions, reported in this study, account for approximately 2-3% of the variance in height of the sample. The four novel height loci discovered bring the total number of genes implicated in human height to 47. These genes appear to be involved in a variety of processes: from DNA replication to intercellular signalling, cell division and skeletal development.

"The array of gene functions underlying the determination of human height are already starting to show links to several human diseases," says Dr Fernando Rivadeneira, Assistant Professor at the Erasmus MC and co-lead author on the study. "For instance, our current finding on GDF5 - one of the genes associated with hip-axis length - provides further understanding to our previous finding, where we found GDF5 associated with osteoarthritis and bone fracture susceptibility. Similarly, many other height loci with demonstrated overgrowth functions have a known role in human cancers. In-depth analysis of the way in which common variants in genes have modest effects on people's height can provide important insights into understanding the causes of human diseases."

As well as developing new methodological principles for study in this area, the researchers' findings could lead to the discovery of medically important genetic regions for several human diseases. More research and replication using larger samples will strengthen the results and might lead to a more developed understanding of clinical effects.

"This exciting area of research is ripe for further investigation," explains Professor Tim Spector, Director of the TwinsUK project at Kings College London. "We are beginning to understand the genetic basis, not just of human height, but of how individual bones develop. This research underscores the importance of using highly characterised human populations and will help understand musculoskeletal disease in humans."

Notes to Editors

Publication details

  • Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

    Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S, Estrada K, Pols HA, Williams FM, McArdle WL, van Meurs JB, Loos RJ, Dermitzakis ET, Ahmadi KR, Hart DJ, Ouwehand WH, Wareham NJ, Barroso I, Sandhu MS, Strachan DP, Livshits G, Spector TD, Uitterlinden AG and Deloukas P

    PLoS genetics 2009;5;4;e1000445

Funding

This study is funded by the Wellcome Trust and the Netherlands Organization for Scientific Research.

Collaborating Institutions

  • Human Genetics Department, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  • Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, Kings College London, Lambeth Palace Rd, London, UK
  • Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  • Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
  • Sackler Faculty of Medicine, Tel Aviv University, Israel
  • Department of Medicine, Jewish General Hospital, McGill University, Montreal, Canada
  • Department of Haematology of Cambridge & NHS Blood and Transplant (NHSBT), Cambridge, UK
  • Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
  • ALSPAC Laboratory, Department of Social Medicine, University of Bristol, UK
  • Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
  • Division of Community Health Sciences, St George's, University of London, London, UK

Department of Twin Research and Genetic Epidemiology

The Department of Twin Research and Genetic Epidemiology (DTR) encompasses the biggest UK adult twin registry of 11,000 twins used to study the genetic and environmental aetiology of age related complex traits and diseases. The DTR has been one of the major departments of King's College London Division of Genetics and Molecular Medicine since 2006 with a team of over 40 staff.

Erasmus Medical Center

The Erasmus Medical Center is an academic medical centre in which new knowledge is being developed and passed on to future professionals. This knowledge covers a broad field of interests that stretches from illness to health, and from individual to community healthcare. Erasmus Medical Center is the Netherlands' largest academic medical centre. As such it is able to provide special opportunities for education, research, and patient care in this country. Erasmus MC is an innovative centre for high-quality knowledge development, training, and care in the fields of illness and health.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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The Wellcome Trust

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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