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2. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Arranz, Maria J, Bakker, Steven, Bender, Stephan, Bramon, Elvira, Collier, David A, Crespo-Facorro, Benedicto, Hall, Jeremy, Iyegbe, Conrad, Jablensky, Assen V, Kahn, René S, Kalaydjieva, Luba, Lawrie, Stephen, Lewis, Cathryn M, Lin, Kuang, Linszen, Don H, Mata, Ignacio, McIntosh, Andrew M, Murray, Robin M, Ophoff, Roel A, Van Os, Jim, Powell, John, Rujescu, Dan, Walshe, Muriel, Weisbrod, Matthias, Wiersma, Durk, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, 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 CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Giannoulatou, Eleni, Hellenthal, Garrett, Pearson, Richard, Pirinen, Matti, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Edkins, Sarah, Gillman, Matthew, Gray, Emma, Gwilliam, Rhian, Hammond, Naomi, Hunt, Sarah E, Jayakumar, Alagurevathi, Liddle, Jennifer, McCann, Owen T, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew, Weston, Paul, Whittaker, Pamela, Widaa, Sara, and McCarthy, Mark I

Subjects
Autoimmune Disease, Schizophrenia, Mental Health, Lupus, Genetics, Brain Disorders, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Alleles, Complement C3, Complement C4, Female, Genetic Predisposition to Disease, HLA Antigens, Haplotypes, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Male, Middle Aged, Sex Characteristics, Sjogren's Syndrome, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

3. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donnelly, Peter, Bates, Lesley, 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 CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, 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, Whittaker, Pamela, Ripke, Stephan, Neale, Benjamin M, Walters, James TR, Farh, Kai‐How, Holmans, Peter A, Lee, Phil, Bulik‐Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, and Chan, Ronald YL

Subjects
Biological Sciences, Genetics, Clinical Research, Schizophrenia, Brain Disorders, Human Genome, Prevention, Serious Mental Illness, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Chromosome Mapping, DNA Copy Number Variations, Databases, Genetic, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Sequence Analysis, DNA, Exome Sequencing, GWAS, IBD mapping, rare variants, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinical Sciences, Neurosciences, Clinical sciences
Abstract

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019

4. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Nikolaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Dardiotis, Efthimios, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
International Multiple Sclerosis Genetics Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

5. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Niklaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Efthimios, Dardiotis, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
Human Genome, Autoimmune Disease, Multiple Sclerosis, Genetics, Biotechnology, Brain Disorders, Neurodegenerative, Clinical Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Systems Biology, International Multiple Sclerosis Genetics Consortium
Abstract

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Published
2019

6. Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort

Author

Hampshire, Adam, Chatfield, Doris A., MPhil, Anne Manktelow, Jolly, Amy, Trender, William, Hellyer, Peter J., Giovane, Martina Del, Newcombe, Virginia F.J., Outtrim, Joanne G., Warne, Ben, Bhatti, Junaid, Pointon, Linda, Elmer, Anne, Sithole, Nyarie, Bradley, John, Kingston, Nathalie, Sawcer, Stephen J., Bullmore, Edward T., Rowe, James B., and Menon, David K.

Published
2022
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7. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Author

Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi-Hsiang, Liu, Ching-Ti, Medina-Gómez, Carolina, Voortman, Trudy, van der Velde, Nathalie, Melhus, Håkan, Robinson-Cohen, Cassianne, Cousminer, Diana L, Nethander, Maria, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia MT, Biggs, Mary L, Psaty, Bruce M, Rotter, Jerome I, Zemel, Babette S, Mitchell, Jonathan A, Taylor, Bruce, Lorentzon, Mattias, Karlsson, Magnus, Jaddoe, Vincent VW, Tiemeier, Henning, Campos-Obando, Natalia, Franco, Oscar H, Utterlinden, Andre G, Broer, Linda, van Schoor, Natasja M, Ham, Annelies C, Ikram, M Arfan, Karasik, David, de Mutsert, Renée, Rosendaal, Frits R, Heijer, Martin den, Wang, Thomas J, Lind, Lars, Orwoll, Eric S, Mook-Kanamori, Dennis O, Michaëlsson, Karl, Kestenbaum, Bryan, Ohlsson, Claes, Mellström, Dan, de Groot, Lisette CPGM, Grant, Struan FA, Kiel, Douglas P, Zillikens, M Carola, Rivadeneira, Fernando, Sawcer, Stephen, Timpson, Nicholas J, and Richards, J Brent

Subjects
Biological Sciences, Health Sciences, Genetics, Prevention, Multiple Sclerosis, Nutrition, Autoimmune Disease, Neurodegenerative, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Cholestanetriol 26-Monooxygenase, Cytochrome P450 Family 2, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Vitamin D Deficiency, GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Published
2017

9. Class II HLA interactions modulate genetic risk for multiple sclerosis.

Author

Moutsianas, Loukas, Jostins, Luke, Beecham, Ashley, Dilthey, Alexander, Xifara, Dionysia, Ban, Maria, Shah, Tejas, Patsopoulos, Nikolaos, Alfredsson, Lars, Anderson, Carl, Attfield, Katherine, Barrett, Jeffrey, Binder, Thomas, Booth, David, Buck, Dorothea, Celius, Elisabeth, Cotsapas, Chris, DAlfonso, Sandra, Dendrou, Calliope, Donnelly, Peter, Dubois, Bénédicte, Fontaine, Bertrand, Fugger, Lars, Goris, An, Graetz, Christiane, Hemmer, Bernhard, Hillert, Jan, Kockum, Ingrid, Leslie, Stephen, Lill, Christina, Martinelli-Boneschi, Filippo, Olsson, Tomas, Oturai, Annette, Saarela, Janna, Søndergaard, Helle, Spurkland, Anne, Taylor, Bruce, Winkelmann, Juliane, Zipp, Frauke, Haines, Jonathan, Pericak-Vance, Margaret, Spencer, Chris, Stewart, Graeme, Hafler, David, Ivinson, Adrian, Harbo, Hanne, De Jager, Philip, Compston, Alastair, McCauley, Jacob, Sawcer, Stephen, McVean, Gil, Hauser, Stephen, Oksenberg, Jorge, Baranzini, Sergio, and Gourraud, Pierre-Antoine

Subjects
Alleles, Epistasis, Genetic, Genetic Predisposition to Disease, Histocompatibility Antigens Class II, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide
Abstract

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

Published
2015

10. An ImmunoChip study of multiple sclerosis risk in African Americans.

Author

Isobe, Noriko, Madireddy, Lohith, Khankhanian, Pouya, Matsushita, Takuya, Caillier, Stacy J, Moré, Jayaji M, Gourraud, Pierre-Antoine, McCauley, Jacob L, Beecham, Ashley H, International Multiple Sclerosis Genetics Consortium, Piccio, Laura, Herbert, Joseph, Khan, Omar, Cohen, Jeffrey, Stone, Lael, Santaniello, Adam, Cree, Bruce AC, Onengut-Gumuscu, Suna, Rich, Stephen S, Hauser, Stephen L, Sawcer, Stephen, and Oksenberg, Jorge R

Subjects
International Multiple Sclerosis Genetics Consortium, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Case-Control Studies, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Genome-Wide Association Study, Black or African American, African Americans, ImmunoChip, linkage disequilibrium, multiple sclerosis, Human Genome, Neurodegenerative, Brain Disorders, Neurosciences, Genetics, Autoimmune Disease, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.

Published
2015

11. No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis

Author

Goris, An, van Setten, Jessica, Diekstra, Frank, Ripke, Stephan, Patsopoulos, Nikolaos A, Sawcer, Stephen J, van Es, Michael, Andersen, Peter M, Melki, Judith, Meininger, Vincent, Hardiman, Orla, Landers, John E, Brown, Robert H, Shatunov, Aleksey, Leigh, Nigel, Al-Chalabi, Ammar, Shaw, Christopher E, Traynor, Bryan J, Chiò, Adriano, Restagno, Gabriella, Mora, Gabriele, Ophoff, Roel A, Oksenberg, Jorge R, Van Damme, Philip, Compston, Alastair, Robberecht, Wim, Dubois, Bénédicte, van den Berg, Leonard H, De Jager, Philip L, Veldink, Jan H, and de Bakker, Paul IW

Subjects
Human Genome, ALS, Multiple Sclerosis, Rare Diseases, Autoimmune Disease, Neurosciences, Genetics, Neurodegenerative, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Comorbidity, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, International Multiple Sclerosis Genetics Consortium, Australia and New Zealand MS Genetics Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

Published
2014

12. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.

Author

Patsopoulos, Nikolaos, Barcellos, Lisa, Hintzen, Rogier, Schaefer, Catherine, van Duijn, Cornelia, Noble, Janelle, Raj, Towfique, Gourraud, Pierre-Antoine, Stranger, Barbara, Olsson, Tomas, Taylor, Bruce, Sawcer, Stephen, Hafler, David, Carrington, Mary, De Jager, Philip, de Bakker, Paul, and Oksenberg, Jorge

Subjects
Alleles, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DP beta-Chains, HLA-DRB1 Chains, Haplotypes, Histocompatibility Antigens Class I, Humans, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Major Histocompatibility Complex, Membrane Proteins, Multiple Sclerosis, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Type I
Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Published
2013

13. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author

Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden P, 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 CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard D, 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, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew J, Weston, Paul, Widaa, Sara, Whittaker, Pamela, and McCarthy, Mark I

Subjects
Mental health, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Schizophrenia, Sweden, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Published
2013

14. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis.

Author

Ban, Maria, Caillier, Stacy, Mero, Inger-Lise, Myhr, Kjell-Morten, Celius, Elisabeth, Aarseth, Jan, Torkildsen, Øivind, Harbo, Hanne, Sawcer, Stephen, Compston, Alastair, Hauser, Stephen, and Oksenberg, Jorge

Subjects
25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Female, Gene Frequency, Genetic Association Studies, Humans, Male, Multiple Sclerosis, Mutation, Norway, United Kingdom
Abstract

An association has previously been reported between susceptibility to multiple sclerosis and the rare mutant alleles of the CYP27B1 gene responsible for autosomal recessive vitamin D-dependent rickets type 1 (VDDR1). In an attempt to replicate this finding, we screened 495 multiplex families and 2,092 single affected families, together with 4,594 cases and 3,583 controls (a total of 17,073 individuals) but were unable to find any evidence supporting this putative association. Our data do not indicate that mutations responsible for VDDR1 influence the risk of developing multiple sclerosis.

Published
2013

15. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Author

International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris CA, 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, Martinelli Boneschi, Filippo, 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 AC, Cross, Anne H, Cusi, Daniele, Daly, Mark J, Davis, Emma, de Bakker, Paul IW, Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Bénédicte, and Ellinghaus, David

Subjects
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, T-Lymphocytes, Helper-Inducer, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, HLA-A Antigens, HLA-DR Antigens, Sample Size, Cell Differentiation, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Europe, Genome-Wide Association Study, HLA-DRB1 Chains, Genetics, Neurosciences, Neurodegenerative, Clinical Research, Brain Disorders, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Neurological, Inflammatory and immune system, General Science & Technology
Abstract

Multiple sclerosis 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. 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, 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. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. 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 9,772 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 HLA-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 overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

16. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris CA, 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, Celine, 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, Francoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B, Cozen, Wendy, Cree, Bruce AC, Cross, Anne H, Cusi, Daniele, Daly, Mark J, Davis, Emma, de Bakker, Paul IW, Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Benedicte, Ellinghaus, David, Elovaara, Irina, and Esposito, Federica

Subjects
Neurosciences, Prevention, Multiple Sclerosis, Biotechnology, Autoimmune Disease, Genetics, Brain Disorders, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Inflammatory and immune system, Alleles, Cell Differentiation, Europe, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, HLA-A Antigens, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Sample Size, T-Lymphocytes, Helper-Inducer, International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, General Science & Technology
Abstract

Multiple sclerosis 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. 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, 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. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. 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 9,772 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 HLA-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 overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

17. A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.

Author

Cree, Bruce AC, Rioux, John D, McCauley, Jacob L, Gourraud, Pierre-Antoine FD, Goyette, Philippe, McElroy, Joseph, De Jager, Philip, Santaniello, Adam, Vyse, Timothy J, Gregersen, Peter K, Mirel, Daniel, Hafler, David A, Haines, Jonathan L, Pericak-Vance, Margaret A, Compston, Alastair, Sawcer, Stephen J, Oksenberg, Jorge R, Hauser, Stephen L, IMAGEN, and IMSGC

Subjects
IMAGEN, IMSGC, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Histocompatibility Antigens Class I, HLA-DR Antigens, Logistic Models, Case-Control Studies, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, HLA-DRB1 Chains, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundIn Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.Methodology/principal findingsA case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.ConclusionsA MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

Published
2010

18. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production.

Author

Maier, Lisa M, Lowe, Christopher E, Cooper, Jason, Downes, Kate, Anderson, David E, Severson, Christopher, Clark, Pamela M, Healy, Brian, Walker, Neil, Aubin, Cristin, Oksenberg, Jorge R, Hauser, Stephen L, Compston, Alistair, Sawcer, Stephen, International Multiple Sclerosis Genetics Consortium, De Jager, Philip L, Wicker, Linda S, Todd, John A, and Hafler, David A

Subjects
International Multiple Sclerosis Genetics Consortium, Humans, Multiple Sclerosis, Diabetes Mellitus, Type 1, Disease Susceptibility, Genetic Predisposition to Disease, Case-Control Studies, Genotype, Genetic Heterogeneity, Alleles, Solubility, Adult, Interleukin-2 Receptor alpha Subunit, Diabetes Mellitus, Type 1, Genetics, Developmental Biology
Abstract

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

Published
2009

20. A second major histocompatibility complex susceptibility locus for multiple sclerosis

Author

Yeo, Tai Wai, De Jager, Philip L, Gregory, Simon G, Barcellos, Lisa F, Walton, Amie, Goris, An, Fenoglio, Chiara, Ban, Maria, Taylor, Craig J, Goodman, Reyna S, Walsh, Emily, Wolfish, Cara S, Horton, Roger, Traherne, James, Beck, Stephan, Trowsdale, John, Caillier, Stacy J, Ivinson, Adrian J, Green, Todd, Pobywajlo, Susan, Lander, Eric S, Pericak-Vance, Margaret A, Haines, Jonathan L, Daly, Mark J, Oksenberg, Jorge R, Hauser, Stephen L, Compston, Alastair, Hafler, David A, Rioux, John D, and Sawcer, Stephen

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Human Genome, Brain Disorders, Genetics, Autoimmune Disease, Multiple Sclerosis, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Female, Genetic Predisposition to Disease, HLA-D Antigens, Humans, Major Histocompatibility Complex, Male, Microsatellite Repeats, Middle Aged, Polymorphism, Single Nucleotide, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveVariation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.MethodsUsing a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.ResultsScreening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).InterpretationVariation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

Published
2007

21. ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

Author

Jacobs, Benjamin M, primary, Schalk, Luisa, additional, Dunne, Angie, additional, Scalfari, Antonio, additional, Nandoskar, Ashwini, additional, Gran, Bruno, additional, Mein, Charles A, additional, Sellers, Charlotte, additional, Spilker, Cord, additional, Rog, David, additional, Visentin, Elisa, additional, Bezzina, Elizabeth Lindsey, additional, Uzochukwu, Emeka, additional, Tallantyre, Emma, additional, Wozniak, Eva, additional, Sacre, Eve, additional, Hassan-Smith, Ghaniah, additional, Ford, Helen L, additional, Harris, Jade, additional, Bradley, Joan, additional, Breedon, Joshua, additional, Brooke, Judith, additional, Kreft, Karim L, additional, Tuite Dalton, Katherine, additional, George, Katila, additional, Papachatzaki, Maria, additional, O'Malley, Martin, additional, Peter, Michelle, additional, Mattoscio, Miriam, additional, Rhule, Neisha, additional, Evangelou, Nikos, additional, Vinod, Nimisha, additional, Quinn, Outi, additional, Shamji, Ramya, additional, Kaimal, Rashmi, additional, Boulton, Rebecca, additional, Tanveer, Riffat, additional, Middleton, Rod, additional, Murray, Roxanne, additional, Bellfield, Ruth, additional, Hoque, Sadid, additional, Patel, Shakeelah, additional, Raj, Sonia, additional, Gumus, Stephanie, additional, Mitchell, Stephanie, additional, Sawcer, Stephen, additional, Arun, Tarunya, additional, Pogreban, Tatiana, additional, Brown, Terri-Louise, additional, Begum, Thamanna, additional, Antoine, Veronica, additional, Rashid, Waqar, additional, Noyce, Alastair J, additional, Silber, Eli, additional, Morris, Huw, additional, Giovannoni, Gavin, additional, and Dobson, Ruth, additional

Published
2023
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25. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease

Author

Robak, Laurie A, Jansen, Iris E, van Rooij, Jeroen, Uitterlinden, André G, Kraaij, Robert, Jankovic, Joseph, Heutink, Peter, Shulman, Joshua M, Nalls, Mike A, Plagnol, Vincent, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-, Yoav, Berendse, Henk W, 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, Majounie, Elisa, Charlesworth, Gavin, Lungu, Codrin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Mark Cooper, J, 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, Evans, Jonathan R, Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Raphael Gibbs, J, Goate, Alison, Gray, Emma, Guerreiro, Rita, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Wurster, Isabel, Mätzler, Walter, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, Lungu, Codrin, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Escott-Price, Valentina, Mudanohwo, Ese, O’Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Shulman, Joshua, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Bettella, Francesco, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Wood, Nicholas W, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, and Singleton, Andrew B

Published
2017
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26. A polygenic resilience score moderates the genetic risk for schizophrenia

Author

Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez

Subjects
Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Published
2021

27. The Role of the CD58 Locus in Multiple Sclerosis

Author

De Jager, Philip L., Baecher-Allan, Clare, Maier, Lisa M., Arthur, Ariel T., Ottoboni, Linda, Barcellos, Lisa, McCauley, Jacob L., Sawcer, Stephen, Goris, An, Saarela, Janna, Yelensky, Roman, Price, Alkes, Leppa, Virpi, Patterson, Nick, de Bakker, Paul I. W., Tran, Dong, Aubin, Cristin, Pobywajlo, Susan, Rossin, Elizabeth, Hu, Xinli, Ashley, Charles W., Choy, Edwin, Rioux, John D., Pericak-Vance, Margaret A., Ivinson, Adrian, Booth, David R., Stewart, Graeme J., Palotie, Aarno, Peltonen, Leena, Dubois, Bénédicte, Haines, Jonathan L., Werner, Howard L., Compston, Alastair, Hauser, Stephen L., Daly, Mark J., Reich, David, Oksenberg, Jorge R., Hafler, David A., and Kieff, Elliott D.

Published
2009
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28. The genetic aspects of multiple sclerosis

Author

Sawcer Stephen

Subjects
Genetics, genome-wide association study, multiple sclerosis, Neurology. Diseases of the nervous system, RC346-429
Abstract

The epidemiology of multiple sclerosis has been extensively investigated and two features have consistently emerged: marked geographical variation in prevalence and substantial familial clustering. At first sight, geographic variation would seem to imply an environmental cause for the disease, while familial clustering would seem to suggest that genetic factors have the predominant etiological effect. However, given that geographic variation in prevalence could result from variation in the frequency of genetic risk alleles and that familial clustering might result from shared environmental exposure rather than shared genetic risk alleles, it is clear that these crude inferences are unreliable. Epidemiologists have been resourceful in their attempts to resolve this apparent conflict between "nurture and nature" and have employed a whole variety of sophisticated methods to try and untangle the etiology of multiple sclerosis. The body of evidence that has emerged from these efforts has formed the foundation for decades of research seeking to identify relevant genes and this is the obvious place to start any consideration of the genetics of multiple sclerosis.

Published
2009

29. Mononeuritis multiplex: an unexpectedly frequent feature of severe COVID-19

Author

Sawcer, Stephen, Menon, David, Newcombe, Virginia, Warburton, Elizabeth, Needham, Edward, Sawcer, Stephen [0000-0001-7685-0974], Menon, David [0000-0002-3228-9692], Newcombe, Virginia [0000-0001-6044-9035], Needham, Edward [0000-0001-7042-7462], and Apollo - University of Cambridge Repository

Subjects
Nerve injury, Intensive Care Units, Muscle Weakness, Mononeuritis multiplex, SARS-CoV-2, Mononeuropathies, COVID-19, Humans, Neuropathy
Abstract

The prolonged mechanical ventilation that is often required by patients with severe COVID-19 is expected to result in significant Intensive Care Unit – Acquired Weakness (ICUAW) in many of the survivors. However, in our post-COVID-19 follow up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to multiple axonal mononeuropathies. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such a mononeuritis multiplex. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to relate simply to “critical illness neuromyopathy”. While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are surprisingly frequent and often disabling in patients recovering from severe COVID-19.

Published
2020
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30. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Author

Goris, An, Pauwels, Ine, Gustavsen, Marte W., van Son, Brechtje, Hilven, Kelly, Bos, Steffan D., Celius, Elisabeth Gulowsen, Berg-Hansen, Pål, Aarseth, Jan, Myhr, Kjell-Morten, D’Alfonso, Sandra, Barizzone, Nadia, Leone, Maurizio A., Boneschi, Filippo Martinelli, Sorosina, Melissa, Liberatore, Giuseppe, Kockum, Ingrid, Olsson, Tomas, Hillert, Jan, Alfredsson, Lars, Bedri, Sahl Khalid, Hemmer, Bernhard, Buck, Dorothea, Berthele, Achim, Knier, Benjamin, Biberacher, Viola, van Pesch, Vincent, Sindic, Christian, Oturai, Annette Bang, Søndergaard, Helle Bach, Sellebjerg, Finn, Jensen, Poul Erik H., Comabella, Manuel, Montalban, Xavier, Pérez-Boza, Jennifer, Malhotra, Sunny, Lechner-Scott, Jeannette, Broadley, Simon, Slee, Mark, Taylor, Bruce, Kermode, Allan G., Gourraud, Pierre-Antoine, Sawcer, Stephen J., Andreassen, Bettina Kullle, Dubois, Bénédicte, and Harbo, Hanne F.

Published
2015
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31. The problems and promises of research into human immunology and autoimmune disease

Author

Roep, Bart O., Buckner, Jane, Sawcer, Stephen, Toes, Rene, and Zipp, Frauke

Subjects
T cells -- Physiological aspects -- Research, Autoantigens -- Physiological aspects -- Research, Autoimmune diseases -- Risk factors -- Diagnosis -- Care and treatment -- Research, Biological sciences, Health
Abstract

Translational research in autoimmunity is hampered by a number of hurdles, including a lack of knowledge regarding initiating and pathologically relevant autoantigens, the low frequency of autoreactive pathogenic B and T cells, difficulty in accessing the affected tissue, differences between self-reactive and pathogen-specific lymphocytes, a lack of etiologically relevant preclinical animal models and the heterogeneity of disease presentation. Given the need for biomarkers and new therapeutics, it is imperative that these hurdles be surmounted., From rodent models to the clinic Preclinical animal models of human autoimmune diseases have been invaluable for the discovery of key immune processes, basic disease mechanisms and candidate immune-targeting strategies [...]

Published
2012

33. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)

Author

Jones, Joanne L., Phuah, Chia-Ling, Cox, Amanda L., Thompson, Sara A., Ban, Maria, Shawcross, Jacqueline, Walton, Amie, Sawcer, Stephen J., Compston, Alastair, and Coles, Alasdair J.

Subjects
Autoimmunity -- Health aspects, Autoimmunity -- Research, Interleukins -- Health aspects, Interleukins -- Research, Multiple sclerosis -- Genetic aspects, Multiple sclerosis -- Drug therapy, Multiple sclerosis -- Research
Abstract

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity., Introduction Autoimmunity arising in the context of lymphopenia is well recognized experimentally but rarely encountered and, hence, difficult to study in humans. We have identified an example of predictable autoimmunity [...]

Published
2009
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34. 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, 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, 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, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Published
2007
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35. A high-density screen for linkage in multiple sclerosis: international multiple sclerosis genetics consortium *

Author

Sawcer, Stephen, Ban, Maria, Maranian, Mel, Yeo, Tai Wai, Compston, Alastair, Kirby, Andrew, Daly, Mark J., De Jager, Philip L., Walsh, Emily, Lander, Eric S., Rioux, John D., Hafler, David A., Ivinson, Adrian, Rimmler, Jacqueline A., Gregory, Simon, Schmidt, Silke, Pericak-Vance, Margaret A., Akesson, Eva, Hillert, Jan, Datta, Pameli, Oturai, Annette, Ryder, Lars P., Harbo, Hanne F., Spurkland, Anne, Myhr, Kjell-Morten, Laaksonen, Mikko, Booth, David, Heard, Robert, Stewart, Graeme, Lincoln, Robin, Barcellos, Lisa F., Hauser, Stephen L., Oksenberg, Jorge R., Kenealy, Shannon J., and Haines, Jonathan L.

Subjects
Multiple sclerosis -- Genetic aspects, Human genetics -- Research, Biological sciences
Published
2005

36. MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis

Author

Lill, Christina M., Schjeide, Brit-Maren M., Graetz, Christiane, Ban, Maria, Alcina, Antonio, Ortiz, Miguel A., Pérez, Jennifer, Damotte, Vincent, Booth, David, Lopez de Lapuente, Aitzkoa, Broer, Linda, Schilling, Marcel, Akkad, Denis A., Aktas, Orhan, Alloza, Iraide, Antigüedad, Alfredo, Arroyo, Rafa, Blaschke, Paul, Buttmann, Mathias, Chan, Andrew, Compston, Alastair, Cournu-Rebeix, Isabelle, Dörner, Thomas, Epplen, Joerg T., Fernández, Óscar, Gerdes, Lisa-Ann, Guillot-Noël, Léna, Hartung, Hans-Peter, Hoffjan, Sabine, Izquierdo, Guillermo, Kemppinen, Anu, Kroner, Antje, Kubisch, Christian, Kümpfel, Tania, Li, Shu-Chen, Lindenberger, Ulman, Lohse, Peter, Lubetzki, Catherine, Luessi, Felix, Malhotra, Sunny, Mescheriakova, Julia, Montalban, Xavier, Papeix, Caroline, Paredes, Lidia F., Rieckmann, Peter, Steinhagen-Thiessen, Elisabeth, Winkelmann, Alexander, Zettl, Uwe K., Hintzen, Rogier, Vandenbroeck, Koen, Stewart, Graeme, Fontaine, Bertrand, Comabella, Manuel, Urcelay, Elena, Matesanz, Fuencisla, Sawcer, Stephen, Bertram, Lars, and Zipp, Frauke

Published
2013
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40. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Mitrovič, Mitja, primary, Patsopoulos, Nikolaos A., additional, Beecham, Ashley H., additional, Dankowski, Theresa, additional, Goris, An, additional, Dubois, Bénédicte, additional, D’hooghe, Marie B., additional, Lemmens, Robin, additional, Van Damme, Philip, additional, Søndergaard, Helle Bach, additional, Sellebjerg, Finn, additional, Sorensen, Per Soelberg, additional, Ullum, Henrik, additional, Thørner, Lise W., additional, Werge, Thomas, additional, Saarela, Janna, additional, Cournu-Rebeix, Isabelle, additional, Damotte, Vincent, additional, Fontaine, Bertrand, additional, Guillot-Noel, Lena, additional, Lathrop, Mark, additional, Vukusik, Sandra, additional, Gourraud, Pierre-Antoine, additional, Andlauer, Till F.M., additional, Pongratz, Viola, additional, Buck, Dorothea, additional, Gasperi, Christiane, additional, Bayas, Antonios, additional, Heesen, Christoph, additional, Kümpfel, Tania, additional, Linker, Ralf, additional, Paul, Friedemann, additional, Stangel, Martin, additional, Tackenberg, Björn, additional, Bergh, Florian Then, additional, Warnke, Clemens, additional, Wiendl, Heinz, additional, Wildemann, Brigitte, additional, Zettl, Uwe, additional, Ziemann, Ulf, additional, Tumani, Hayrettin, additional, Gold, Ralf, additional, Grummel, Verena, additional, Hemmer, Bernhard, additional, Knier, Benjamin, additional, Lill, Christina M., additional, Luessi, Felix, additional, Dardiotis, Efthimios, additional, Agliardi, Cristina, additional, Barizzone, Nadia, additional, Mascia, Elisabetta, additional, Bernardinelli, Luisa, additional, Comi, Giancarlo, additional, Cusi, Daniele, additional, Esposito, Federica, additional, Ferrè, Laura, additional, Comi, Cristoforo, additional, Galimberti, Daniela, additional, Leone, Maurizio A., additional, Sorosina, Melissa, additional, Mescheriakova, Julia, additional, Hintzen, Rogier, additional, van Duijn, Cornelia, additional, Teunissen, Charlotte E., additional, Bos, Steffan D., additional, Myhr, Kjell-Morten, additional, Celius, Elisabeth G., additional, Lie, Benedicte A., additional, Spurkland, Anne, additional, Comabella, Manuel, additional, Montalban, Xavier, additional, Alfredsson, Lars, additional, Stridh, Pernilla, additional, Hillert, Jan, additional, Jagodic, Maja, additional, Piehl, Fredrik, additional, Jelčić, Ilijas, additional, Martin, Roland, additional, Sospedra, Mireia, additional, Ban, Maria, additional, Hawkins, Clive, additional, Hysi, Pirro, additional, Kalra, Seema, additional, Karpe, Fredrik, additional, Khadake, Jyoti, additional, Lachance, Genevieve, additional, Neville, Matthew, additional, Santaniello, Adam, additional, Caillier, Stacy J., additional, Calabresi, Peter A., additional, Cree, Bruce A.C., additional, Cross, Anne, additional, Davis, Mary F., additional, Haines, Jonathan L., additional, de Bakker, Paul I.W., additional, Delgado, Silvia, additional, Dembele, Marieme, additional, Edwards, Keith, additional, Fitzgerald, Kathryn C., additional, Hakonarson, Hakon, additional, Konidari, Ioanna, additional, Lathi, Ellen, additional, Manrique, Clara P., additional, Pericak-Vance, Margaret A., additional, Piccio, Laura, additional, Schaefer, Cathy, additional, McCabe, Cristin, additional, Weiner, Howard, additional, Goldstein, Jacqueline, additional, Olsson, Tomas, additional, Hadjigeorgiou, Georgios, additional, Taylor, Bruce, additional, Tajouri, Lotti, additional, Charlesworth, Jac, additional, Booth, David R., additional, Harbo, Hanne F., additional, Ivinson, Adrian J., additional, Hauser, Stephen L., additional, Compston, Alastair, additional, Stewart, Graeme, additional, Zipp, Frauke, additional, Barcellos, Lisa F., additional, Baranzini, Sergio E., additional, Martinelli-Boneschi, Filippo, additional, D’Alfonso, Sandra, additional, Ziegler, Andreas, additional, Oturai, Annette, additional, McCauley, Jacob L., additional, Sawcer, Stephen J., additional, Oksenberg, Jorge R., additional, De Jager, Philip L., additional, Kockum, Ingrid, additional, Hafler, David A., additional, and Cotsapas, Chris, additional

Published
2020
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42. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, Paul B., Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Published
2010
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45. Obesity and Multiple Sclerosis: A Mendelian Randomization Study

Author

Mokry, Lauren E., Ross, Stephanie, Timpson, Nicholas J., Sawcer, Stephen, Davey Smith, George, and Richards, J. Brent

Subjects
Obesity -- Complications and side effects, Body mass index -- Analysis, Multiple sclerosis -- Risk factors, Biological sciences
Abstract

Background Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS. Methods and Findings Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10.sup.-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m.sup.2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10.sup.-5, I.sup.2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely. Conclusion Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity., Author(s): Lauren E. Mokry 1,2, Stephanie Ross 2, Nicholas J. Timpson 3, Stephen Sawcer 4, George Davey Smith 3, J. Brent Richards 1,2,5,6,7,* Introduction Multiple sclerosis (MS) is a debilitating [...]

Published
2016
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46. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis (vol 101, pg 227, 2017)

Author

Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi-Hsiang, Liu, Ching-Ti, Medina-Gomez, Carolina, Voortman, Trudy, van der Velde, Nathalie, Melhus, Hakan, Robinson-Cohen, Cassianne, Cousminer, Diana L., Nethander, Maria, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia M. T., Biggs, Mary L., Psaty, Bruce M., Rotter, Jerome I., Zemel, Babette S., Mitchell, Jonathan A., Taylor, Bruce, Lorentzon, Mattias, Karlsson, Magnus, Jaddoe, Vincent V. W., Tiemeier, Henning, Campos-Obando, Natalia, Franco, Oscar H., Utterlinden, Andre G., Broer, Linda, van Schoor, Natasja M., Ham, Annelies C., Ikram, M. Arfan, Karasik, David, de Mutsert, Renee, Rosendaal, Frits R., den Heijer, Martin, Wang, Thomas J., Lind, Lars, Orwoll, Eric S., Mook-Kanamori, Dennis O., Michaelsson, Karl, Kestenbaum, Bryan, Ohlsson, Claes, Mellstrom, Dan, de Groot, Lisette C. P. G. M., Grant, Struan F. A., Kiel, Douglas P., Zillikens, M. Carola, Rivadeneira, Fernando, Sawcer, Stephen, Timpson, Nicholas J., Richards, J. Brent, General practice, APH - Aging & Later Life, Epidemiology and Data Science, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, and APH - Personalized Medicine

Published
2018

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

Author

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

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.

Published
2019
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48. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Onderzoek, Brain, Hersenen-Medisch 1, Harold, Denise, Connolly, Siobhan, Riley, Brien P., Kendler, Kenneth S., McCarthy, Shane E., McCombie, William R., Richards, Alex, Owen, Michael J., O'Donovan, Michael C., Walters, James, Donnelly, Peter, Bates, Lesley, 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 N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Celine, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Cahn, Wiepke, Van Os, Jim, Onderzoek, Brain, Hersenen-Medisch 1, Harold, Denise, Connolly, Siobhan, Riley, Brien P., Kendler, Kenneth S., McCarthy, Shane E., McCombie, William R., Richards, Alex, Owen, Michael J., O'Donovan, Michael C., Walters, James, Donnelly, Peter, Bates, Lesley, 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 N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Celine, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Cahn, Wiepke, and Van Os, Jim

Published
2019

50. Suggestive Evidence for Association of Human Chromosome 18q12-q21 and Its Orthologue on Rat and Mouse Chromosome 18 With Several Autoimmune Diseases

Author

Merriman, Tony R., Cordell, Heather J., Eaves, Iain A., Danoy, Patrick A., Coraddu, Francesca, Barber, Rachael, Cucca, Francesco, Broadley, Simon, Sawcer, Stephen, Compston, Alastair, Wordsworth, Paul, Shatford, Jane, Laval, Steve, Jirholt, Johan, Holmdahl, Rikard, Theofilopoulos, Argyrios N., Kono, Dwight H., Tuomilehto, Jaakko, Tuomilehto-Wolf, Eva, Buzzetti, Raffaella, Marrosu, Maria Giovanna, Undlien, Dag E., Rønningen, Kjersti S., Ionesco-Tirgoviste, C., Shield, Julian P., Pociot, Fleming, Nerup, Jorn, Jacob, Chaim O., Polychronakos, Constantin, Bain, Steve C., and Todd, John A.

Published
2001

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