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83 New genes for height found

83 new gene variants that strongly influence human height have been discovered in a study led by Queen Mary University of London, Montreal Heart Institute, The Broad Institute and the University of Exeter, UK. The gene STC2 may yield new strategies to treat growth failures affecting 3-5% of all children.

The study was carried out using data from the United Kingdom Biobank - one of the world's largest health studies. It includes extensive information on demographic and lifestyle factors, as well as the genetic make-up of the 500,000 men and women enrolled in the study. Participants are being followed long term to allow scientists to study a wide range of diseases, including dementia, arthritis, cancer, heart attacks and stroke.

"In our study, we use adult height as a simple observable physical trait to understand how information in our DNA can explain how we are all different. The idea is that if we can understand genetics of human height, we can apply this to develop genetic tools to predict other traits, or the risk of developing common diseases."

Guillaume Lettre PhD, Professor, Department of Medicine, Faculty of Medicine, Université de Montréal, and Montreal Heart Institute, Montreal, Quebec, Canada.

The research, published in Nature, is the largest genetic study of adult height to date, with the international team of researchers analysing DNA from over 700,000 participants across the globe to determine why people have different heights.

Adult height is mostly determined by the information encoded in our DNA — children from tall parents tend to be taller, and those from short parents are shorter. But growth from a small baby into an adult, and the role of genetics, is one of the most poorly understood areas of human biology.

Hundreds of DNA changes that influence height have already been identified, but these common DNA changes often influence height by less than 1 mm.

In this study, scientists find new DNA changes that lead to differences in height of up to 2 cm - over 10 times the average effect of previous gene variants.

Senior co-lead author Panos Deloukas PhD, Professor, Queen Mary University of London (QMUL), UK: "The new genetic variants we found are rare in the population. But, their large effects on human height have revealed important new insights into human skeletal growth. The identified genes will help in predicting a person's risk for developing certain growth disorders. There is also the hope we may one day be able to develop a precision medicine approach for dealing with growth disorders."

Dr Andrew R Wood, co-lead analyst in the study at the University of Exeter adds: "Our latest discovery means we can now explain over a quarter of the heritable factors involved in influencing a person's height. How the body grows from a 40-50 cm baby into a perfectly proportioned adult three to four times that size — and, how it occurs that some of us end up being over half a metre taller than others, is a fascinating but poorly understood aspect of biology."

Many of the new DNA changes are located in genes implicated in growth or bone biology, but many also highlight new biological processes that influence height in humans.

The researchers looked in more detail at two of the changes found in a gene called STC2. Only 1 person in 1,000 carries one of these genetic variants, but those who do are 1-2 cm taller.

Researchers at Aarhus University, Denmark, suggest these variants modify height by interfering with availability of growth factors in the blood. STC2 may therefore yield new therapeutic strategies to treat growth failures affecting 3-5% of all children.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1–2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Notes on this paper:
* Study participants included those from the UK, Canada, USA, The Netherlands, Denmark, Germany, Switzerland, Iceland, France, Greece, Italy, Australia, Sweden, Finland, Norway, Austria, South Africa, China, Taiwan, Saudi Arabia, Singapore and Pakistan.

* UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health and Scottish Government and has also received funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK.

* Research paper: 'Rare and low-frequency coding variants alter human adult height'. Marouli et al. Nature. Doi 10.1038/nature21039. Research paper will appear here: http://dx.doi.org/10.1038/nature21039

About Queen Mary University of London
Queen Mary University of London (QMUL) is one of the UK's leading universities, and one of the largest institutions in the University of London, with 21,187 students from more than 155 countries. A member of the Russell Group, QMUL works across the humanities and social sciences, medicine and dentistry, and science and engineering, with inspirational teaching directly informed by our research. In the most recent national assessment of the quality of research, we were placed ninth in the UK (REF 2014). As well as our main site at Mile End - which is home to one of the largest self-contained residential campuses in London - QMUL has campuses at Whitechapel, Charterhouse Square, and West Smithfield dedicated to the study of medicine, and a base for legal studies at Lincoln's Inn Fields. QMUL has a rich history in London with roots in Europe's first public hospital, St Barts; England's first medical school, The London; one of the first colleges to provide higher education to women, Westfield College; and the Victorian philanthropic project, the People's Palace at Mile End. QMUL has an annual turnover of £350m, a research income worth £125m (2014/15), and generates employment and output worth £700m to the UK economy each year.
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Feb 10, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Scientists have found new DNA changes that lead to differences in height of up to 2 cm,
over 10 times the average of previous gene variants. It is hoped this data will one day
be useful in developing precision approaches to dealing with growth disorders.
Image Credit: Science News (L) Yao Ming at 2.29 m (7 ft 6 in) — (R) Danny DeVito 1.47 m (4 ft10 in)



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