PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Integrative genomics identifies LMO1 as a neuroblastoma oncogene 
Nature  2010;469(7329):216-220.
Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths1,2. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10−16, odds ratio of risk allele = 1.34 (95% confidence interval 1.25–1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.
doi:10.1038/nature09609
PMCID: PMC3320515  PMID: 21124317
2.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 
Sawcer, Stephen | Hellenthal, Garrett | Pirinen, Matti | Spencer, Chris C.A. | Patsopoulos, Nikolaos A. | Moutsianas, Loukas | Dilthey, Alexander | Su, Zhan | Freeman, Colin | Hunt, Sarah E. | Edkins, Sarah | Gray, Emma | Booth, David R. | Potter, Simon C. | Goris, An | Band, Gavin | Oturai, Annette Bang | Strange, Amy | Saarela, Janna | Bellenguez, Céline | Fontaine, Bertrand | Gillman, Matthew | Hemmer, Bernhard | Gwilliam, Rhian | Zipp, Frauke | Jayakumar, Alagurevathi | Martin, Roland | Leslie, Stephen | Hawkins, Stanley | Giannoulatou, Eleni | D’alfonso, Sandra | Blackburn, Hannah | Boneschi, Filippo Martinelli | Liddle, Jennifer | Harbo, Hanne F. | Perez, Marc L. | Spurkland, Anne | Waller, Matthew J | Mycko, Marcin P. | Ricketts, Michelle | Comabella, Manuel | Hammond, Naomi | Kockum, Ingrid | McCann, Owen T. | Ban, Maria | Whittaker, Pamela | Kemppinen, Anu | Weston, Paul | Hawkins, Clive | Widaa, Sara | Zajicek, John | Dronov, Serge | Robertson, Neil | Bumpstead, Suzannah J. | Barcellos, Lisa F. | Ravindrarajah, Rathi | Abraham, Roby | Alfredsson, Lars | Ardlie, Kristin | Aubin, Cristin | Baker, Amie | Baker, Katharine | Baranzini, Sergio E. | Bergamaschi, Laura | Bergamaschi, Roberto | Bernstein, Allan | Berthele, Achim | Boggild, Mike | Bradfield, Jonathan P. | Brassat, David | Broadley, Simon A. | Buck, Dorothea | Butzkueven, Helmut | Capra, Ruggero | Carroll, William M. | Cavalla, Paola | Celius, Elisabeth G. | Cepok, Sabine | Chiavacci, Rosetta | Clerget-Darpoux, Françoise | Clysters, Katleen | Comi, Giancarlo | Cossburn, Mark | Cournu-Rebeix, Isabelle | Cox, Mathew B. | Cozen, Wendy | Cree, Bruce A.C. | Cross, Anne H. | Cusi, Daniele | Daly, Mark J. | Davis, Emma | de Bakker, Paul I.W. | Debouverie, Marc | D’hooghe, Marie Beatrice | Dixon, Katherine | Dobosi, Rita | Dubois, Bénédicte | Ellinghaus, David | Elovaara, Irina | Esposito, Federica | Fontenille, Claire | Foote, Simon | Franke, Andre | Galimberti, Daniela | Ghezzi, Angelo | Glessner, Joseph | Gomez, Refujia | Gout, Olivier | Graham, Colin | Grant, Struan F.A. | Guerini, Franca Rosa | Hakonarson, Hakon | Hall, Per | Hamsten, Anders | Hartung, Hans-Peter | Heard, Rob N. | Heath, Simon | Hobart, Jeremy | Hoshi, Muna | Infante-Duarte, Carmen | Ingram, Gillian | Ingram, Wendy | Islam, Talat | Jagodic, Maja | Kabesch, Michael | Kermode, Allan G. | Kilpatrick, Trevor J. | Kim, Cecilia | Klopp, Norman | Koivisto, Keijo | Larsson, Malin | Lathrop, Mark | Lechner-Scott, Jeannette S. | Leone, Maurizio A. | Leppä, Virpi | Liljedahl, Ulrika | Bomfim, Izaura Lima | Lincoln, Robin R. | Link, Jenny | Liu, Jianjun | Lorentzen, Åslaug R. | Lupoli, Sara | Macciardi, Fabio | Mack, Thomas | Marriott, Mark | Martinelli, Vittorio | Mason, Deborah | McCauley, Jacob L. | Mentch, Frank | Mero, Inger-Lise | Mihalova, Tania | Montalban, Xavier | Mottershead, John | Myhr, Kjell-Morten | Naldi, Paola | Ollier, William | Page, Alison | Palotie, Aarno | Pelletier, Jean | Piccio, Laura | Pickersgill, Trevor | Piehl, Fredrik | Pobywajlo, Susan | Quach, Hong L. | Ramsay, Patricia P. | Reunanen, Mauri | Reynolds, Richard | Rioux, John D. | Rodegher, Mariaemma | Roesner, Sabine | Rubio, Justin P. | Rückert, Ina-Maria | Salvetti, Marco | Salvi, Erika | Santaniello, Adam | Schaefer, Catherine A. | Schreiber, Stefan | Schulze, Christian | Scott, Rodney J. | Sellebjerg, Finn | Selmaj, Krzysztof W. | Sexton, David | Shen, Ling | Simms-Acuna, Brigid | Skidmore, Sheila | Sleiman, Patrick M.A. | Smestad, Cathrine | Sørensen, Per Soelberg | Søndergaard, Helle Bach | Stankovich, Jim | Strange, Richard C. | Sulonen, Anna-Maija | Sundqvist, Emilie | Syvänen, Ann-Christine | Taddeo, Francesca | Taylor, Bruce | Blackwell, Jenefer M. | Tienari, Pentti | Bramon, Elvira | Tourbah, Ayman | Brown, Matthew A. | Tronczynska, Ewa | Casas, Juan P. | Tubridy, Niall | Corvin, Aiden | Vickery, Jane | Jankowski, Janusz | Villoslada, Pablo | Markus, Hugh S. | Wang, Kai | Mathew, Christopher G. | Wason, James | Palmer, Colin N.A. | Wichmann, H-Erich | Plomin, Robert | Willoughby, Ernest | Rautanen, Anna | Winkelmann, Juliane | Wittig, Michael | Trembath, Richard C. | Yaouanq, Jacqueline | Viswanathan, Ananth C. | Zhang, Haitao | Wood, Nicholas W. | Zuvich, Rebecca | Deloukas, Panos | Langford, Cordelia | Duncanson, Audrey | Oksenberg, Jorge R. | Pericak-Vance, Margaret A. | Haines, Jonathan L. | Olsson, Tomas | Hillert, Jan | Ivinson, Adrian J. | De Jager, Philip L. | Peltonen, Leena | Stewart, Graeme J. | Hafler, David A. | Hauser, Stephen L. | McVean, Gil | Donnelly, Peter | Compston, Alastair
Nature  2011;476(7359):214-219.
Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
doi:10.1038/nature10251
PMCID: PMC3182531  PMID: 21833088
multiple sclerosis; GWAS; genetics
3.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
doi:10.1038/nature07999
PMCID: PMC2943511  PMID: 19404256
4.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
doi:10.1038/nature07953
PMCID: PMC2925224  PMID: 19404257
5.  Copy number variation at 1q21.1 associated with neuroblastoma 
Nature  2009;459(7249):987-991.
Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in cancer, we performed a genome-wide association study (GWAS) of CNVs in the childhood cancer neuroblastoma, a disease where SNP variations are known to influence susceptibility1,2. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. We identified a common CNV at 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets (Pcombined = 2.97 × 10−17; OR = 2.49, 95% CI: 2.02 to 3.05). This CNV was validated by quantitative PCR, fluorescent in situ hybridization, and analysis of matched tumor specimens, and was shown to be heritable in an independent set of 713 cancer-free trios. We identified a novel transcript within the CNV which showed high sequence similarity to several “Neuroblastoma breakpoint family” (NBPF) genes3,4 and represents a new member of this gene family (NBPFX). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a novel NBPF gene in early tumorigenesis of this childhood cancer.
doi:10.1038/nature08035
PMCID: PMC2755253  PMID: 19536264

Results 1-5 (5)