Dataset Information

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

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.

SUBMITTER: Wellcome Trust Case Control Consortium

PROVIDER: S-EPMC2680141 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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

Burton Paul R PR Clayton David G DG Cardon Lon R LR Craddock Nick N Deloukas Panos P Duncanson Audrey A Kwiatkowski Dominic P DP McCarthy Mark I MI Ouwehand Willem H WH Samani Nilesh J NJ Todd John A JA Donnelly Peter P Barrett Jeffrey C JC Davison Dan D Easton Doug D Evans David M DM Evans David M DM Leung Hin-Tak HT Marchini Jonathan L JL Morris Andrew P AP Spencer Chris C A CC Tobin Martin D MD Attwood Antony P AP Boorman James P JP Cant Barbara B Everson Ursula U Hussey Judith M JM Jolley Jennifer D JD Knight Alexandra S AS Koch Kerstin K Meech Elizabeth E Nutland Sarah S Prowse Christopher V CV Stevens Helen E HE Taylor Niall C NC Walters Graham R GR Walker Neil M NM Watkins Nicholas A NA Winzer Thilo T Jones Richard W RW McArdle Wendy L WL Ring Susan M SM Strachan David P DP Pembrey Marcus M Breen Gerome G St Clair David D Caesar Sian S Gordon-Smith Katharine K Jones Lisa L Fraser Christine C Green Elaine K EK Grozeva Detelina D Hamshere Marian L ML Holmans Peter A PA Jones Ian R IR Kirov George G Moskivina Valentina V Nikolov Ivan I O'Donovan Michael C MC Owen Michael J MJ Collier David A DA Elkin Amanda A Farmer Anne A Williamson Richard R McGuffin Peter P Young Allan H AH Ferrier I Nicol IN Ball Stephen G SG Balmforth Anthony J AJ Barrett Jennifer H JH Bishop Timothy D TD Iles Mark M MM Maqbool Azhar A Yuldasheva Nadira N Hall Alistair S AS Braund Peter S PS Dixon Richard J RJ Mangino Massimo M Stevens Suzanne S Thompson John R JR Bredin Francesca F Tremelling Mark M Parkes Miles M Drummond Hazel H Lees Charles W CW Nimmo Elaine R ER Satsangi Jack J Fisher Sheila A SA Forbes Alastair A Lewis Cathryn M CM Onnie Clive M CM Prescott Natalie J NJ Sanderson Jeremy J Matthew Christopher G CG Barbour Jamie J Mohiuddin M Khalid MK Todhunter Catherine E CE Mansfield John C JC Ahmad Tariq T Cummings Fraser R FR Jewell Derek P DP Webster John J Brown Morris J MJ Lathrop Mark G MG Connell John J Dominiczak Anna A Marcano Carolina A Braga CA Burke Beverley B Dobson Richard R Gungadoo Johannie J Lee Kate L KL Munroe Patricia B PB Newhouse Stephen J SJ Onipinla Abiodun A Wallace Chris C Xue Mingzhan M Caulfield Mark M Farrall Martin M Barton Anne A Bruce Ian N IN Donovan Hannah H Eyre Steve S Gilbert Paul D PD Hilder Samantha L SL Hinks Anne M AM John Sally L SL Potter Catherine C Silman Alan J AJ Symmons Deborah P M DP Thomson Wendy W Worthington Jane J Dunger David B DB Widmer Barry B Frayling Timothy M TM Freathy Rachel M RM Lango Hana H Perry John R B JR Shields Beverley M BM Weedon Michael N MN Hattersley Andrew T AT Hitman Graham A GA Walker Mark M Elliott Kate S KS Groves Christopher J CJ Lindgren Cecilia M CM Rayner Nigel W NW Timpson Nicolas J NJ Zeggini Eleftheria E Newport Melanie M Sirugo Giorgio G Lyons Emily E Vannberg Fredrik F Hill Adrian V S AV Bradbury Linda A LA Farrar Claire C Pointon Jennifer J JJ Wordsworth Paul P Brown Matthew A MA Franklyn Jayne A JA Heward Joanne M JM Simmonds Matthew J MJ Gough Stephen C L SC Seal Sheila S Stratton Michael R MR Rahman Nazneen N Ban Maria M Goris An A Sawcer Stephen J SJ Compston Alastair A Conway David D Jallow Muminatou M Newport Melanie M Sirugo Giorgio G Rockett Kirk A KA Bumpstead Suzannah J SJ Chaney Amy A Downes Kate K Ghori Mohammed J R MJ Gwilliam Rhian R Hunt Sarah E SE Inouye Michael M Keniry Andrew A King Emma E McGinnis Ralph R Potter Simon S Ravindrarajah Rathi R Whittaker Pamela P Widden Claire C Withers David D Cardin Niall J NJ Davison Dan D Ferreira Teresa T Pereira-Gale Joanne J Hallgrimsdo'ttir Ingeleif B IB Howie Bryan N BN Su Zhan Z Teo Yik Ying YY Vukcevic Damjan D Bentley David D Brown Matthew A MA Compston Alastair A Farrall Martin M Hall Alistair S AS Hattersley Andrew T AT Hill Adrian V S AV Parkes Miles M Pembrey Marcus M Stratton Michael R MR Mitchell Sarah L SL Newby Paul R PR Brand Oliver J OJ Carr-Smith Jackie J Pearce Simon H S SH McGinnis R R Keniry A A Deloukas P P Reveille John D JD Zhou Xiaodong X Sims Anne-Marie AM Dowling Alison A Taylor Jacqueline J Doan Tracy T Davis John C JC Savage Laurie L Ward Michael M MM Learch Thomas L TL Weisman Michael H MH Brown Mathew M

Nature genetics 20071021 11

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 spon ...[more]

PMID: 17952073

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Project description:Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the dataset. Immunohistochemistry for subgroup-specific ‘signature’ genes was used to determine subgroup affiliation for 294 non-overlapping medulloblastomas on two independent tissue microarrays (TMAs). Multiple unsupervised analyses of transcriptional profiles identified four distinct, non-overlapping molecular variants: WNT, SHH, Group C, and Group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) could reliably and uniquely classify formalin fixed medulloblastomas in ~98% of cases. Group C patients (NPR3 +ve tumors) exhibited a significantly diminished progression free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma sub-classification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. A total of 103 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.

Dataset Information

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

Publications

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

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