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2. Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for 12 immune-mediated diseases

Author

Kundu, Kousik, primary, Tardaguila, Manuel, additional, Mann, Alice L., additional, Watt, Stephen, additional, Ponstingl, Hannes, additional, Vasquez, Louella, additional, Von Schiller, Dominique, additional, Morrell, Nicholas W., additional, Stegle, Oliver, additional, Pastinen, Tomi, additional, Sawcer, Stephen J., additional, Anderson, Carl A., additional, Walter, Klaudia, additional, and Soranzo, Nicole, additional

Published
2022
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4. Author Correction: Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Author

Orrù, Valeria, primary, Steri, Maristella, additional, Sidore, Carlo, additional, Marongiu, Michele, additional, Serra, Valentina, additional, Olla, Stefania, additional, Sole, Gabriella, additional, Lai, Sandra, additional, Dei, Mariano, additional, Mulas, Antonella, additional, Virdis, Francesca, additional, Piras, Maria Grazia, additional, Lobina, Monia, additional, Marongiu, Mara, additional, Pitzalis, Maristella, additional, Deidda, Francesca, additional, Loizedda, Annalisa, additional, Onano, Stefano, additional, Zoledziewska, Magdalena, additional, Sawcer, Stephen, additional, Devoto, Marcella, additional, Gorospe, Myriam, additional, Abecasis, Gonçalo R., additional, Floris, Matteo, additional, Pala, Mauro, additional, Schlessinger, David, additional, Fiorillo, Edoardo, additional, and Cucca, Francesco, additional

Published
2020
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5. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Author

Orrù, Valeria, primary, Steri, Maristella, additional, Sidore, Carlo, additional, Marongiu, Michele, additional, Serra, Valentina, additional, Olla, Stefania, additional, Sole, Gabriella, additional, Lai, Sandra, additional, Dei, Mariano, additional, Mulas, Antonella, additional, Virdis, Francesca, additional, Piras, Maria Grazia, additional, Lobina, Monia, additional, Marongiu, Mara, additional, Pitzalis, Maristella, additional, Deidda, Francesca, additional, Loizedda, Annalisa, additional, Onano, Stefano, additional, Zoledziewska, Magdalena, additional, Sawcer, Stephen, additional, Devoto, Marcella, additional, Gorospe, Myriam, additional, Abecasis, Gonçalo R., additional, Floris, Matteo, additional, Pala, Mauro, additional, Schlessinger, David, additional, Fiorillo, Edoardo, additional, and Cucca, Francesco, additional

Published
2020
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8. No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease in nine ADHD candidate SNPs

Author

Geissler, Julia M, Romanos, Marcel, Sheerin, Una-Marie, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Saad, Mohamad, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, Simón-Sánchez, Javier, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Hardy, John, Heutink, Peter, Brice, Alexis, Schulte, Claudia, Gasser, Thomas, Singleton, Andrew B, Wood, Nicholas W, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W, Gerlach, Manfred, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, J Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, members, International Parkinson Disease Genomics Consortium, Evans, Jonathan R, Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Gústafsson, Ómar, Harris, Clare, Nalls, Mike, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Plagnol, Vincent, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Hernandez, Dena G, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Sharma, Manu, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Human genetics, Neurology, Amsterdam Neuroscience - Neurodegeneration, Geissler, Julia M [0000-0003-1878-9647], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Parkinson's disease, Single-nucleotide polymorphism, Genome-wide association study, genetics [Attention Deficit Disorder with Hyperactivity], Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, genetics [Parkinson Disease], medicine, Attention deficit hyperactivity disorder, ADHD, GWAS, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genetic Association Studies, Genetic association, Dopamine transporter, Genetics, TPH2, biology, Parkinson Disease, General Medicine, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Norepinephrine transporter, Attention Deficit Disorder with Hyperactivity, biology.protein, genetics [Polymorphism, Single Nucleotide], Parkinson’s disease, Psychology, 030217 neurology & neurosurgery, CDH13, SNPs
Abstract

Item does not contain fulltext Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.

Published
2018
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9. Exploring rare and low-frequency variants in the Saguenay–Lac-Saint-Jean population identified genes associated with asthma and allergy traits

Author

Morin, Andréanne, primary, Madore, Anne-Marie, additional, Kwan, Tony, additional, Ban, Maria, additional, Partanen, Jukka, additional, Rönnblom, Lars, additional, Syvänen, Ann-Christine, additional, Sawcer, Stephen, additional, Stunnenberg, Hendrik, additional, Lathrop, Mark, additional, Pastinen, Tomi, additional, and Laprise, Catherine, additional

Published
2018
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10. Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Author

Power, Robert A, Nagoshi, Craig, DeFries, John C, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Adult, Male, Intelligence, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Consanguinity, 03 medical and health sciences, Cognition, 0302 clinical medicine, Genetics, Humans, Child, education, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Genome, Human, Homozygote, Assortative mating, Minor allele frequency, Case-Control Studies, Female, Inbreeding, 030217 neurology & neurosurgery
Abstract

The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin-cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P=0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P=0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

Published
2013

11. Population- and individual-specific regulatory variation in Sardinia

Author

Pala, Mauro, primary, Zappala, Zachary, additional, Marongiu, Mara, additional, Li, Xin, additional, Davis, Joe R, additional, Cusano, Roberto, additional, Crobu, Francesca, additional, Kukurba, Kimberly R, additional, Gloudemans, Michael J, additional, Reinier, Frederic, additional, Berutti, Riccardo, additional, Piras, Maria G, additional, Mulas, Antonella, additional, Zoledziewska, Magdalena, additional, Marongiu, Michele, additional, Sorokin, Elena P, additional, Hess, Gaelen T, additional, Smith, Kevin S, additional, Busonero, Fabio, additional, Maschio, Andrea, additional, Steri, Maristella, additional, Sidore, Carlo, additional, Sanna, Serena, additional, Fiorillo, Edoardo, additional, Bassik, Michael C, additional, Sawcer, Stephen J, additional, Battle, Alexis, additional, Novembre, John, additional, Jones, Chris, additional, Angius, Andrea, additional, Abecasis, Gonçalo R, additional, Schlessinger, David, additional, Cucca, Francesco, additional, and Montgomery, Stephen B, additional

Published
2017
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12. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

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

Subjects
Genetic Markers, Bipolar Disorder, Population, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, Disease, Biology, Population stratification, Article, Arthritis, Rheumatoid, Crohn Disease, Gene Frequency, Diabetes Mellitus, Chromosomes, Human, Humans, Genetic Predisposition to Disease, education, Allele frequency, Genetics, education.field_of_study, Multidisciplinary, Geography, Genome, Human, CDKN2BAS, United Kingdom, Human genetics, C431 Medical Genetics, Genetics, Population, Case-Control Studies, Hypertension
Abstract

There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

Published
2007

13. Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells

Author

Morin, Andréanne, primary, Kwan, Tony, additional, Ge, Bing, additional, Letourneau, Louis, additional, Ban, Maria, additional, Tandre, Karolina, additional, Caron, Maxime, additional, Sandling, Johanna K., additional, Carlsson, Jonas, additional, Bourque, Guillaume, additional, Laprise, Catherine, additional, Montpetit, Alexandre, additional, Syvanen, Ann-Christine, additional, Ronnblom, Lars, additional, Sawcer, Stephen J., additional, Lathrop, Mark G., additional, and Pastinen, Tomi, additional

Published
2016
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14. Erratum: Corrigendum: Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls

Author

Fortune, Mary D, primary, Guo, Hui, additional, Burren, Oliver, additional, Schofield, Ellen, additional, Walker, Neil M, additional, Ban, Maria, additional, Sawcer, Stephen J, additional, Bowes, John, additional, Worthington, Jane, additional, Barton, Anne, additional, Eyre, Steve, additional, Todd, John A, additional, and Wallace, Chris, additional

Published
2015
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15. Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls

Author

Fortune, Mary D, primary, Guo, Hui, additional, Burren, Oliver, additional, Schofield, Ellen, additional, Walker, Neil M, additional, Ban, Maria, additional, Sawcer, Stephen J, additional, Bowes, John, additional, Worthington, Jane, additional, Barton, Anne, additional, Eyre, Steve, additional, Todd, John A, additional, and Wallace, Chris, additional

Published
2015
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16. Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci

Author

Lemire, Mathieu, primary, Zaidi, Syed H.E., additional, Ban, Maria, additional, Ge, Bing, additional, Aïssi, Dylan, additional, Germain, Marine, additional, Kassam, Irfahan, additional, Wang, Mike, additional, Zanke, Brent W., additional, Gagnon, France, additional, Morange, Pierre-Emmanuel, additional, Trégouët, David-Alexandre, additional, Wells, Philip S., additional, Sawcer, Stephen, additional, Gallinger, Steven, additional, Pastinen, Tomi, additional, and Hudson, Thomas J., additional

Published
2015
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22. Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project

Author

Horton, Roger, primary, Gibson, Richard, additional, Coggill, Penny, additional, Miretti, Marcos, additional, Allcock, Richard J., additional, Almeida, Jeff, additional, Forbes, Simon, additional, Gilbert, James G. R., additional, Halls, Karen, additional, Harrow, Jennifer L., additional, Hart, Elizabeth, additional, Howe, Kevin, additional, Jackson, David K., additional, Palmer, Sophie, additional, Roberts, Anne N., additional, Sims, Sarah, additional, Stewart, C. Andrew, additional, Traherne, James A., additional, Trevanion, Steve, additional, Wilming, Laurens, additional, Rogers, Jane, additional, de Jong, Pieter J., additional, Elliott, John F., additional, Sawcer, Stephen, additional, Todd, John A., additional, Trowsdale, John, additional, and Beck, Stephan, additional

Published
2008
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30. A genome screen for multiple sclerosis in Sardinian multiplex families

Author

Coraddu, Francesca, primary, Sawcer, Stephen, additional, D'Alfonso, Sandra, additional, Lai, Marina, additional, Hensiek, Anke, additional, Solla, Elisabetta, additional, Broadley, Simon, additional, Mancosu, Cristina, additional, Pugliatti, Maura, additional, Marrosu, Maria Giovanna, additional, and Compston, Alastair, additional

Published
2001
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33. HLA typing in the United Kingdom multiple sclerosis genome screen

Author

Coraddu, Francesca, primary, Sawcer, Stephen, additional, Feakes, Robert, additional, Chataway, Jeremy, additional, Broadley, Simon, additional, Jones, Hywel B., additional, Clayton, David, additional, Gray, Julia, additional, Smith, Sheila, additional, Taylor, Craig, additional, Goodfellow, Peter N., additional, and Compston, A., additional

Published
1998
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36. Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits

Author

Morin, Andréanne, Madore, Anne-Marie, Kwan, Tony, Ban, Maria, Partanen, Jukka, Rönnblom, Lars, Syvänen, Ann-Christine, Sawcer, Stephen, Stunnenberg, Hendrik, Lathrop, Mark, Pastinen, Tomi, and Laprise, Catherine

Subjects
Adult, Aged, 80 and over, Male, Ribosomal Proteins, Adolescent, Quebec, Middle Aged, Polymorphism, Single Nucleotide, Asthma, 3. Good health, Neuropilin-2, DNA-Binding Proteins, Mitochondrial Proteins, Gene Frequency, Child, Preschool, Serpin E2, Humans, Female, Child, Microtubule-Associated Proteins, Aged, Receptors, CXCR6, Transcription Factors
Abstract

The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant- and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3'-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.

37. The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination

Author

Pu, Annie, Mishra, Manoj K, Dong, Yifei, Ghorbanigazar, Samira, Stephenson, Erin L, Rawji, Khalil S, Silva, Claudia, Kitagawa, Hiroshi, Sawcer, Stephen, and Yong, V Wee

Subjects
Inflammation, Male, Mice, Knockout, CSPG, Multiple Sclerosis, Macrophages, Membrane Proteins, N-Acetylglucosaminyltransferases, Oligodendrocyte, Polymorphism, Single Nucleotide, 3. Good health, Mice, Inbred C57BL, Mice, Chondroitin Sulfate Proteoglycans, Animals, Humans, Female, Demyelination, EXTL2, Demyelinating Diseases
Abstract

BACKGROUND: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. METHODS: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 deficient (EXTL2-/-) mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. RESULTS: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genome-wide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2-/- mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2-/- mice had exacerbated axonal damage and myelin disruption relative to wild-type mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow-derived macrophages from EXTL2-/- mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). CONCLUSIONS: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.

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