29 September 2010

Is explaining variation in height a tall order?

Number of genetic variants associated with height shoots up to 180

Cumulative number of susceptibility loci expected to be discovered. The projection includes those loci that have already been identified and others as yet undetected, by the expected percentage of variation explained and sample size required. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance, were replicated, and had at least 1% power.

Cumulative number of susceptibility loci expected to be discovered. The projection includes those loci that have already been identified and others as yet undetected, by the expected percentage of variation explained and sample size required. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance, were replicated, and had at least 1% power.

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Hundreds of common genetic variants across the human genome influence adult height, according to a study of over 180,000 individuals published today 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, yet today's study, which includes funding from the Wellcome Trust, still only accounts for around ten per cent of our inherited variation in height, highlighting the challenging nature of unravelling the genetics of height.

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 GIANT Consortium* - analysed data from the DNA samples of over 180,000 individuals looking for genetic variants known as 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 known as single nucleotide polymorphisms - 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.

"Finding these SNPs, these genetic signposts for human height, is a colossal challenge answerable only by large-scale collaboration and resource and data sharing," says Dr Nicole Soranzo, from the Wellcome Trust Sanger Institute and an author on the paper. "And, of course, the genetic pathways behind complex traits like human height do not stand in isolation. It is by comparing genetic markers for height with markers for other human traits that we can begin to understand the fabric of human disease on a much larger scale.

"Genome-wide association studies are empowering us to do just that."

Researchers from the GIANT Consortium, including teams from the UK, USA, Iceland and the Netherlands, identified SNPs associated with height in adults in 180 regions of the genome (known as 'loci'); over a hundred of these regions were identified for the first time.

" It is by comparing genetic markers for height with markers for other human traits that we can begin to understand the fabric of human disease on a much larger scale. "

Dr Nicole Soranzo

"Height clearly has a lot to do with genetics - shorter parents tend to have shorter children, and taller parents tend to have taller children," says Dr Joel Hirschhorn of Children's Hospital Boston, the Broad Institute and Harvard Medical School. "This paper is the biggest step forward to date in understanding which of the genetic variants that differ between people account for our differences in height."

The researchers found that the loci were not distributed randomly across the genome but that they clustered within genomic loci and in biological pathways: 21 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. "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, and that 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, University of Exeter. "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."

*Genome-wide Investigation of ANthropometric Traits Consortium

Notes to Editors

Publication details

  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.

    Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segrè AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Mägi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, König IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Müller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpeläinen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Paré G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietiläinen KH, Pouta A, Ridderstråle M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kähönen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimäki T, Melander O, Mosley TH, Musk AW, Nieminen MS, O'Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tönjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Grönberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Völzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O'Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM and Hirschhorn JN

    Nature 2010;467;7317;832-8

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A full list of funding agencies is available at the Nature website.

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