Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants - PubMed (original) (raw)

Randomized Controlled Trial

. 2007 Nov;39(11):1329-37.

doi: 10.1038/ng.2007.17. Epub 2007 Oct 21.

Australo-Anglo-American Spondylitis Consortium (TASC); Paul R Burton, David G Clayton, Lon R Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P Kwiatkowski, Mark I McCarthy, Willem H Ouwehand, Nilesh J Samani, John A Todd, Peter Donnelly, Jeffrey C Barrett, Dan Davison, Doug Easton, David M Evans, Hin-Tak Leung, Jonathan L Marchini, Andrew P Morris, Chris C A Spencer, Martin D Tobin, Antony P Attwood, James P Boorman, Barbara Cant, Ursula Everson, Judith M Hussey, Jennifer D Jolley, Alexandra S Knight, Kerstin Koch, Elizabeth Meech, Sarah Nutland, Christopher V Prowse, Helen E Stevens, Niall C Taylor, Graham R Walters, Neil M Walker, Nicholas A Watkins, Thilo Winzer, Richard W Jones, Wendy L McArdle, Susan M Ring, David P Strachan, Marcus Pembrey, Gerome Breen, David St Clair, Sian Caesar, Katharine Gordon-Smith, Lisa Jones, Christine Fraser, Elaine K Green, Detelina Grozeva, Marian L Hamshere, Peter A Holmans, Ian R Jones, George Kirov, Valentina Moskivina, Ivan Nikolov, Michael C O'Donovan, Michael J Owen, David A Collier, Amanda Elkin, Anne Farmer, Richard Williamson, Peter McGuffin, Allan H Young, I Nicol Ferrier, Stephen G Ball, Anthony J Balmforth, Jennifer H Barrett, Timothy D Bishop, Mark M Iles, Azhar Maqbool, Nadira Yuldasheva, Alistair S Hall, Peter S Braund, Richard J Dixon, Massimo Mangino, Suzanne Stevens, John R Thompson, Francesca Bredin, Mark Tremelling, Miles Parkes, Hazel Drummond, Charles W Lees, Elaine R Nimmo, Jack Satsangi, Sheila A Fisher, Alastair Forbes, Cathryn M Lewis, Clive M Onnie, Natalie J Prescott, Jeremy Sanderson, Christopher G Matthew, Jamie Barbour, M Khalid Mohiuddin, Catherine E Todhunter, John C Mansfield, Tariq Ahmad, Fraser R Cummings, Derek P Jewell, John Webster, Morris J Brown, Mark G Lathrop, John Connell, Anna Dominiczak, Carolina A Braga Marcano, Beverley Burke, Richard Dobson, Johannie Gungadoo, Kate L Lee, Patricia B Munroe, Stephen J Newhouse, Abiodun Onipinla, Chris Wallace, Mingzhan Xue, Mark Caulfield, Martin Farrall, Anne Barton; Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee; Ian N Bruce, Hannah Donovan, Steve Eyre, Paul D Gilbert, Samantha L Hilder, Anne M Hinks, Sally L John, Catherine Potter, Alan J Silman, Deborah P M Symmons, Wendy Thomson, Jane Worthington, David B Dunger, Barry Widmer, Timothy M Frayling, Rachel M Freathy, Hana Lango, John R B Perry, Beverley M Shields, Michael N Weedon, Andrew T Hattersley, Graham A Hitman, Mark Walker, Kate S Elliott, Christopher J Groves, Cecilia M Lindgren, Nigel W Rayner, Nicolas J Timpson, Eleftheria Zeggini, Melanie Newport, Giorgio Sirugo, Emily Lyons, Fredrik Vannberg, Adrian V S Hill, Linda A Bradbury, Claire Farrar, Jennifer J Pointon, Paul Wordsworth, Matthew A Brown, Jayne A Franklyn, Joanne M Heward, Matthew J Simmonds, Stephen C L Gough, Sheila Seal; Breast Cancer Susceptibility Collaboration (UK); Michael R Stratton, Nazneen Rahman, Maria Ban, An Goris, Stephen J Sawcer, Alastair Compston, David Conway, Muminatou Jallow, Melanie Newport, Giorgio Sirugo, Kirk A Rockett, Suzannah J Bumpstead, Amy Chaney, Kate Downes, Mohammed J R Ghori, Rhian Gwilliam, Sarah E Hunt, Michael Inouye, Andrew Keniry, Emma King, Ralph McGinnis, Simon Potter, Rathi Ravindrarajah, Pamela Whittaker, Claire Widden, David Withers, Niall J Cardin, Dan Davison, Teresa Ferreira, Joanne Pereira-Gale, Ingeleif B Hallgrimsdo'ttir, Bryan N Howie, Zhan Su, Yik Ying Teo, Damjan Vukcevic, David Bentley, Matthew A Brown, Alastair Compston, Martin Farrall, Alistair S Hall, Andrew T Hattersley, Adrian V S Hill, Miles Parkes, Marcus Pembrey, Michael R Stratton, Sarah L Mitchell, Paul R Newby, Oliver J Brand, Jackie Carr-Smith, Simon H S Pearce, R McGinnis, A Keniry, P Deloukas, John D Reveille, Xiaodong Zhou, Anne-Marie Sims, Alison Dowling, Jacqueline Taylor, Tracy Doan, John C Davis, Laurie Savage, Michael M Ward, Thomas L Learch, Michael H Weisman, Mathew Brown

Affiliations

Randomized Controlled Trial

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Wellcome Trust Case Control Consortium et al. Nat Genet. 2007 Nov.

Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

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Figures

Figure 1

Figure 1

Minus log10 p values for the Armitage test of trend for MHC association with Ankylosing Spondylitis (top panel), Auto-Immune Thyroid Disease (middle panel), and Multiple Sclerosis (bottom panel). Note in particular how evidence for association extends along very long regions of the MHC, reflecting statistical power to detect association even when linkage disequilibrium amongst SNPs is relatively low and/or the possibility of multiple disease-predisposing loci.

Figure 2

Figure 2

Minus log10 p values for the Armitage test of trend for genome-wide association scans of ankylosing spondylitis, auto-immune thyroid disease, breast cancer and multiple sclerosis. The spacing between SNPs on the plot is uniform and does not reflect distances between the SNPs. The vertical dashed lines reflect chromosomal boundaries. The horizontal dashed lines display the cutoff of p = 10-6. Note that SNPs within the MHC are not included in this diagram.

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