31 March 2010

CNVs and common disease

Common copy number variations unlikely to contribute significantly towards common diseases

Genome-wide association results.

Genome-wide association results. Distribution of -log10(P) along the 23 chromosomes. The x-axis shows the chromosomes numbered from 1 to X. CNVs included in these plots were filtered on the basis of a clustering quality score and manual inspection of the most significant associations. The two apparent associations on chromosome 2 for rheumatoid arthritis and type 1 diabetes result from a dispersed duplication in which the variation is actually located within the HLA locus.

A study of the genetics of common diseases including diabetes, heart disease and bipolar disorder has found that commonly occurring copy number variations - duplicated or missing chunks of DNA in our genome - are unlikely to play a major role in such diseases. The research, funded by the Wellcome Trust, is published online today in the journal Nature.

In 2007, the Wellcome Trust Case Control Consortium (WTCCC) published the results of the largest ever study of the genetics of common diseases, revealing for the first time a number of genes which were found to increase the risk of developing certain diseases. Since then, dozens more genes have been found.

Despite the large numbers of genes discovered, scientists are still some way off explaining all of the heritability of the diseases. For example, for type 2 diabetes, there are now around thirty genetic variants known to influence susceptibility to the disease, but these only account for about 10 per cent of the known inherited risk of developing these conditions.

One theory for this so-called 'missing heritability' was that it may have been caused by copy number variations (CNVs). These mainly occur when copies of the genome are passed down from parent to child. Just as mutations in the genome can give rise to different forms of genes, so whole segments of the genome may end up being duplicated or deleted - these are known as CNVs. CNVs have already been found to cause disease in rare cases, however. For example, deletions of part of chromosome 16 have previously been shown to lead to severe obesity from a young age.

Researchers from the WTCCC analysed common CNVs in DNA samples from 3,000 healthy volunteers and compared them to 16,000 patients - 2,000 each with bipolar disorder, breast cancer, coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, type 1 diabetes and type 2 diabetes respectively.

The team identified and confirmed three loci (genetic regions) that contained a commonly occurring CNV and were also associated with common disease. However, all three loci had been identified previously by searching for changes in single letters of the DNA code (known as single nucleotide polymorphisms, or 'SNPs'); by comparison, this technique, used in the original WTCCC study, identified twenty-four genetic loci. None of the three CNV loci is believed to be a 'functional variant' - in other words, it is unlikely that they contribute to disease.

"It seems unlikely that common CNVs play a major role in the genetic basis of common diseases, either through particular CNVs having a strong effect or through a large number of CNVs each contributing a small effect," concludes Dr Matt Hurles from Wellcome Trust Sanger Institute. "This is certainly the case for the diseases that we studied, but is likely to be the case for other common diseases, too."

"There was a strong view that CNVs would be important for common disease, and that they would explain much of the missing heritability," says Professor Peter Donnelly from the University of Oxford, who chairs the WTCCC. "We now believe this is not the case. Our results will be surprising and disappointing for some parts of the community."

" It seems unlikely that common CNVs play a major role in the genetic basis of common diseases, either through particular CNVs having a strong effect or through a large number of CNVs each contributing a small effect. "

Dr Matt Hurles

Professor Donnelly believes that the estimates of heritability may have been overstated, and there is consequently less missing than was previously thought. The remaining genetic contribution to disease will likely comprise rare CNVs and rare SNPs, and epigenetic factors, as well as many more common gene variants and, to a lesser extent, common CNVs.

"Understanding bipolar disorder and other complex diseases is as much about ruling out possible suspects as it is about identifying new ones," says Nick Craddock, Professor of Psychiatry at Cardiff University and a study author. "We now know that we can likely focus our attention away from common CNVs and focus on other common and rare genetic variations, which we hope will provide biological insights that will lead to important advances in human physical and mental health."

Researchers involved in the WTCCC will now try to better understand the collective role of both rarer SNPs and rarer CNVs. A study funded recently by the National Institutes of Health in the US and by the Wellcome Trust, and led by Professor Mark McCarthy from the University of Oxford, will search for a contribution of rarer SNPs towards type 2 diabetes.

Notes to Editors

Publication details

  • Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

    Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, Giannoulatou E, Holmes C, Marchini JL, Stirrups K, Tobin MD, Wain LV, Yau C, Aerts J, Ahmad T, Andrews TD, Arbury H, Attwood A, Auton A, Ball SG, Balmforth AJ, Barrett JC, Barroso I, Barton A, Bennett AJ, Bhaskar S, Blaszczyk K, Bowes J, Brand OJ, Braund PS, Bredin F, Breen G, Brown MJ, Bruce IN, Bull J, Burren OS, Burton J, Byrnes J, Caesar S, Clee CM, Coffey AJ, Connell JM, Cooper JD, Dominiczak AF, Downes K, Drummond HE, Dudakia D, Dunham A, Ebbs B, Eccles D, Edkins S, Edwards C, Elliot A, Emery P, Evans DM, Evans G, Eyre S, Farmer A, Ferrier IN, Feuk L, Fitzgerald T, Flynn E, Forbes A, Forty L, Franklyn JA, Freathy RM, Gibbs P, Gilbert P, Gokumen O, Gordon-Smith K, Gray E, Green E, Groves CJ, Grozeva D, Gwilliam R, Hall A, Hammond N, Hardy M, Harrison P, Hassanali N, Hebaishi H, Hines S, Hinks A, Hitman GA, Hocking L, Howard E, Howard P, Howson JM, Hughes D, Hunt S, Isaacs JD, Jain M, Jewell DP, Johnson T, Jolley JD, Jones IR, Jones LA, Kirov G, Langford CF, Lango-Allen H, Lathrop GM, Lee J, Lee KL, Lees C, Lewis K, Lindgren CM, Maisuria-Armer M, Maller J, Mansfield J, Martin P, Massey DC, McArdle WL, McGuffin P, McLay KE, Mentzer A, Mimmack ML, Morgan AE, Morris AP, Mowat C, Myers S, Newman W, Nimmo ER, O'Donovan MC, Onipinla A, Onyiah I, Ovington NR, Owen MJ, Palin K, Parnell K, Pernet D, Perry JR, Phillips A, Pinto D, Prescott NJ, Prokopenko I, Quail MA, Rafelt S, Rayner NW, Redon R, Reid DM, Renwick, Ring SM, Robertson N, Russell E, St Clair D, Sambrook JG, Sanderson JD, Schuilenburg H, Scott CE, Scott R, Seal S, Shaw-Hawkins S, Shields BM, Simmonds MJ, Smyth DJ, Somaskantharajah E, Spanova K, Steer S, Stephens J, Stevens HE, Stone MA, Su Z, Symmons DP, Thompson JR, Thomson W, Travers ME, Turnbull C, Valsesia A, Walker M, Walker NM, Wallace C, Warren-Perry M, Watkins NA, Webster J, Weedon MN, Wilson AG, Woodburn M, Wordsworth BP, Young AH, Zeggini E, Carter NP, Frayling TM, Lee C, McVean G, Munroe PB, Palotie A, Sawcer SJ, Scherer SW, Strachan DP, Tyler-Smith C, Brown MA, Burton PR, Caulfield MJ, Compston A, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Mathew CG, Pembrey M, Satsangi J, Stratton MR, Worthington J, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand W, Parkes M, Rahman N, Todd JA, Samani NJ and Donnelly P

    Nature 2010;464;7289;713-20

Funding

This work was supported by the Wellcome Trust.

Participating Centres

  • A full list of participating centres is available at the Nature website.

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.

Websites

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.

Website

Contact the Press Office

Don Powell Media and Public Relations Manager
Wellcome Trust Sanger Institute, Hinxton, Cambs, CB10 1SA, UK

Tel +44 (0)1223 496 928
Mobile +44 (0)7753 775 397
Fax +44 (0)1223 494 919
Email press.office@sanger.ac.uk

* quick link - http://q.sanger.ac.uk/ekjmiisy