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1. Homozygosity Haplotype and Whole-Exome Sequencing Analysis to Identify Potentially Functional Rare Variants Involved in Multiple Sclerosis among Sardinian Families

Author

Teresa Fazia, Daria Marzanati, Anna Laura Carotenuto, Ashley Beecham, Athena Hadjixenofontos, Jacob L. McCauley, Valeria Saddi, Marialuisa Piras, Luisa Bernardinelli, and Davide Gentilini

Subjects
multiplex families, Sardinian population, WES data, rare variants, low-frequency variants, Homozygosity Haplotype analysis, Biology (General), QH301-705.5
Abstract

Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T > G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A > C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A > C), on exon 9 of TTBK1; (iv) a non-synonymous variant (42976917 A > C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3′UTR of MYO16.

Published
2021
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3. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Author

Beecham, Ashley, Patsopoulos, Nikolaos, Xifara, Dionysia, Davis, Mary, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene, Galimberti, Daniela, Gieger, Christian, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah, Jagodic, Maja, Jelčić, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, and Langford, Cordelia

Subjects
Chromosome Mapping, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, White People
Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

4. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Author

International Multiple Sclerosis Genetics Consortium (IMSGC), Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC), Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas MC, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce AC, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, and Harrower, Timothy

Subjects
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, International IBD Genetics Consortium, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Chromosome Mapping, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Genetic Loci, White People, Neurosciences, Prevention, Autoimmune Disease, Genetics, Brain Disorders, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

5. Homozygosity Haplotype and Whole-Exome Sequencing Analysis to Identify Potentially Functional Rare Variants Involved in Multiple Sclerosis among Sardinian Families

Author

Ashley Beecham, Daria Marzanati, Athena Hadjixenofontos, Anna Laura Carotenuto, Luisa Bernardinelli, Valeria Saddi, Jacob L. McCauley, Teresa Fazia, Davide Gentilini, and Marialuisa Piras

Subjects
Male, Microbiology (medical), QH301-705.5, Region form Common Ancestor (RCA), Biology, multiple sclerosis, Polymorphism, Single Nucleotide, Microbiology, Exon, multiplex families, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Multiplex, Sardinian population, Biology (General), Molecular Biology, Genotyping, Alleles, Exome sequencing, Genetics, Multiple sclerosis, Homozygote, Haplotype, Genetic Variation, rare variants, General Medicine, Heritability, medicine.disease, Pedigree, Haplotypes, Italy, RNA splicing, WES data, Female, Homozygosity Haplotype analysis, low-frequency variants, Genome-Wide Association Study
Abstract

Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T &gt, G) in the splicing region on exon 27 of CUL9, (ii) a variant (50245517 A &gt, C) in the splicing region on exon 16 of ATP9A, (iii) a non-synonymous variant (43223539 A &gt, C), on exon 9 of TTBK1, (iv) a non-synonymous variant (42976917 A &gt, C) on exon 9 of PPP2R5D, and v) a variant (109859349-109859354) in 3′UTR of MYO16.

Published
2021
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6. Homozygosity Haplotype and Whole-Exome Sequencing Analysis to Identify Potentially Functional Rare Variants Involved in Multiple Sclerosis among Sardinian Families

Author

Fazia, Teresa, primary, Marzanati, Daria, additional, Carotenuto, Anna Laura, additional, Beecham, Ashley, additional, Hadjixenofontos, Athena, additional, McCauley, Jacob L., additional, Saddi, Valeria, additional, Piras, Marialuisa, additional, Bernardinelli, Luisa, additional, and Gentilini, Davide, additional

Published
2021
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7. Evaluating Mitochondrial DNA Variation in Autism Spectrum Disorders

Author

Hadjixenofontos, Athena, Schmidt, Michael A., Whitehead, Patrice L., Konidari, Ioanna, Hedges, Dale J., Wright, Harry H., Abramson, Ruth K., Menon, Ramkumar, Williams, Scott M., Cuccaro, Michael L., Haines, Jonathan L., Gilbert, John R., Pericak-Vance, Margaret A., Martin, Eden R., and McCauley, Jacob L.

Published
2013
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8. Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci

Author

Ashley Beecham, Anna Ticca, Roberta Pastorino, Teresa Fazia, Carlo Berzuini, Luisa Bernardinelli, Mark Abney, Pier Paolo Bitti, Luisa Foco, Davide Gentilini, Lide Han, Hui Guo, Charalampos Papachristou, Jacob L. McCauley, and Athena Hadjixenofontos

Subjects
0301 basic medicine, Genetics, Linkage (software), Multiple Sclerosis, biology, Genetic Linkage, Multiple sclerosis, Single-nucleotide polymorphism, medicine.disease, Major histocompatibility complex, Polymorphism, Single Nucleotide, 03 medical and health sciences, 030104 developmental biology, Italy, Neurology, Genetic linkage, medicine, biology.protein, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Neurology (clinical), Alleles, Founder effect
Abstract

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability. Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence. Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p-value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions. Results: We identified 486 MS-associated ( p –4) and 18,426 MS-linked ( p Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS.

Published
2017

10. Contents Vol. 44, 2015

Author

Chantal M. E. Tallaksen, Byung-Woo Yoon, Erik H. Niks, Valery L. Feigin, Alexander F. Lipka, Maziar Moradi-Lakeh, Kelly Jones, Cathrine Brunborg, Angelina H. Maniaol, Kathryn M. McPherson, Ashley Beecham, John F. Kurtzke, Moon-Ku Han, Clara P. Manrique, Alice Theadom, Mohammad Ali Sahraian, Braden Te Ao, Leticia Tornes, Seung-Mi Lee, Jong-Moo Park, Tomas Kalincik, Sylvia R. Delgado, Margaret A. Pericak-Vance, Suzanne Barker-Collo, J.J.G. Verschuuren, Anthony Dowell, Pouria Heydarpour, Druckerei Stückle, Wan-Chun Huang, Luuk Dekker, Solomon Chih-Cheng Chen, Byung Joo Park, Shabnam Abtahi, Anne T. Heldal, Jacob L. McCauley, Martin Tobias, Shayan Khoshkish, Athena Hadjixenofontos, Trine Haug Popperud, Chin-Li Lu, Paul Brown, Melissa R. Ortega, Nicola J. Starkey, Marion I. Boldingh, Nam Kyong Choi, Kottil Rammohan, and Shanthi Ameratunga

Subjects
Traditional medicine, Epidemiology, business.industry, Medicine, Neurology (clinical), business
Published
2015

11. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.

Subjects
Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2016

12. Economic Analysis of the Internalization the Externalities in Environmental Goods

Author

Odysseas Kopsidas and Andreas Hadjixenofontos

Subjects
Contingent valuation, media_common.quotation_subject, Public good, Environmental economics, Experimental economics, Unit (housing), Microeconomics, Cultural heritage, Economics, Economic analysis, Business, Sensitivity (control systems), Decision-making, Internalization, Externality, media_common
Abstract

The environment is characterized as a public good. Public goods are goods that provide benefits for society as a whole or part of it, usually regardless of whether the individual people are willing to pay to have these benefits. This proposed project is not viable in profitable terms to private enterprise, so it applied a modified version of the CVM (Contingent Valuation Method) to realize this project. The purpose of the paper is to present a modified model of an internalizing external costs caused by the operation of a manufacturing unit in conjunction with the new reality created. Using the CBA (Cost-Benefit Analysis), all critical parameters problem attributed to a single base assessment, which facilitates decision making process. The basis of evaluation is to compare benefits and costs. It is used the CVM in case study and the results show that there is less sensitivity for restoration of the cultural heritage monuments in comparison with the sensitivity for restoration of the natural and urban environment in general.

Published
2017

14. Evaluating Mitochondrial DNA Variation in Autism Spectrum Disorders

Author

Michael A. Schmidt, Patrice L. Whitehead, Dale J. Hedges, Jonathan L. Haines, Scott M. Williams, Harry H. Wright, Michael L. Cuccaro, Ruth K. Abramson, Athena Hadjixenofontos, Ramkumar Menon, John R. Gilbert, Ioanna Konidari, Eden R. Martin, Jacob L. McCauley, and Margaret A. Pericak-Vance

Subjects
Proband, Genetics, Mitochondrial DNA, Haplotype, Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease, behavioral disciplines and activities, mental disorders, Genetic variation, medicine, Autism, Genetics (clinical), Genetic association
Abstract

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.

Published
2012

15. Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci

Author

Fazia, Teresa, primary, Pastorino, Roberta, additional, Foco, Luisa, additional, Han, Lide, additional, Abney, Mark, additional, Beecham, Ashley, additional, Hadjixenofontos, Athena, additional, Guo, Hui, additional, Gentilini, Davide, additional, Papachristou, Charalampos, additional, Bitti, Pier Paolo, additional, Ticca, Anna, additional, Berzuini, Carlo, additional, McCauley, Jacob L, additional, and Bernardinelli, Luisa, additional

Published
2017
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16. Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci.

Author

Fazia, Teresa, Pastorino, Roberta, Foco, Luisa, Han, Lide, Abney, Mark, Beecham, Ashley, Hadjixenofontos, Athena, Guo, Hui, Gentilini, Davide, Papachristou, Charalampos, Bitti, Pier Paolo, Ticca, Anna, Berzuini, Carlo, McCauley, Jacob L., and Bernardinelli, Luisa

Subjects
SINGLE nucleotide polymorphisms, MULTIPLE sclerosis, GENETICS of multiple sclerosis, DEMYELINATION, MAJOR histocompatibility complex
Abstract

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability. Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence. Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p-value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions. Results: We identified 486 MS-associated (p < 1 × 10–4) and 18,426 MS-linked (p < 0.05) SNPs. A total of 111 loci were both linked and associated with MS, 18 of them pointing to 14 non-major histocompatibility complex (MHC) genes, and 93 of them located in the MHC region. Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS. [ABSTRACT FROM AUTHOR]

Published
2018
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17. Enrichment for Northern European-derived multiple sclerosis risk alleles in Sardinia

Author

Roberta Pastorino, A Hadjixenofontos, L Bernardinelli, Pier Paolo Bitti, Pierre-Antoine Gourraud, Luisa Foco, V Bakthavachalam, Anna Ticca, and Jacob L. McCauley

Subjects
Adult, Male, Risk, Multiple Sclerosis, Adolescent, Biology, Major histocompatibility complex, Young Adult, medicine, Humans, In patient, Genetic Predisposition to Disease, Genetic risk, Age of Onset, Child, Alleles, Genetics, Multiple sclerosis, Middle Aged, medicine.disease, United States, Europe, Neurology, Italy, Risk allele, biology.protein, Female, Neurology (clinical)
Abstract

Background: The list of genomic loci associated with multiple sclerosis (MS) susceptibility outside the major histocompatibility complex (MHC) in patients of Northern European (NE) ancestry has increased to 103. Despite the extraordinarily high MS prevalence in the isolated Sardinian population, the contribution of genetic risk factors to MS in Sardinia is largely not understood. Objective: The objective of this paper is to examine the relevance of non-MHC MS susceptibility variants in Sardinia. Methods: We examined a log-additive MS-specific genetic burden score (MSGB) using 110 NE-derived risk alleles in a dataset of 75 Sardinian cases, 346 Sardinian controls and 177 cases and 1967 controls from the United States (US). Results: Sardinian cases demonstrate a heavier non-MHC MSGB load than Sardinian controls and US cases ( p = 2E-06, p = 1E-06, respectively). Furthermore, Sardinian controls carry a heavier burden than US controls ( p = 2E-14). Our results confirm the limited ability of the 110-SNP MSGB to predict disease status in Sardinia (AUROC = 0.629). Conclusions: Risk alleles discovered in samples of NE ancestry are relevant to MS in Sardinia. Our results suggest a general enrichment of MS susceptibility alleles in Sardinians, encouraging the pursuit of further studies of MS in this population.

Published
2014

18. Clinical Expression of Multiple Sclerosis in Hispanic Whites of Primarily Caribbean Ancestry

Author

Ashley Beecham, Sylvia R. Delgado, Athena Hadjixenofontos, Leticia Tornes, Jacob L. McCauley, Clara P. Manrique, Melissa R. Ortega, Margaret A. Pericak-Vance, and Kottil Rammohan

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Pathology, Multiple Sclerosis, Epidemiology, business.industry, Multiple sclerosis, Age Factors, Hispanic or Latino, medicine.disease, White People, Phenotype, Expression (architecture), Caribbean Region, Disease Presentation, Internal medicine, medicine, Humans, Hispanic population, Female, Neurology (clinical), business
Abstract

Objective: The clinical characteristics of multiple sclerosis (MS) are not well defined in Hispanic populations. We hypothesized that disease presentation in Hispanic white (HW) patients will be different from non-Hispanic white (NHW) patients given their ancestral background and reported lower disease prevalence. This study was undertaken to compare HW of primarily Caribbean ancestry to NHW on clinical characteristics of MS. Methods: We assessed 312 HW and 312 NHW patients with definite MS for clinical disease characteristics obtained through consented review of medical records. In order to assess the relationship between age-related phenotypes and ethnicity, linear regression was used. Logistic regression was used to assess the relationship between ethnicity and descriptors of disease presentation and severity as well as presence of neurological symptoms. Results: We observed a significantly younger age at diagnosis (p = 1.38E-02) and age at exam (p = 2.36E-05) in HW. However, age at first symptom did not differ significantly between the two groups. Furthermore, within HW, the mean age at first symptom and age at diagnosis was significantly younger in those born in the United States (p < 1.00E-03 for both). Interestingly, we noted an increase in ambulatory disability in HW patients, primarily among those with relapsing disease (p = 4.18E-03). Conclusions: We found several differences in age-related phenotypes and disease severity between HW of primarily Caribbean origin and NHW patients. To our knowledge, this is the largest study to date that examined the clinical characteristics of MS in Hispanic patients of largely Caribbean origin.

Published
2014

19. Evaluating mitochondrial DNA variation in autism spectrum disorders

Author

Athena, Hadjixenofontos, Michael A, Schmidt, Patrice L, Whitehead, Ioanna, Konidari, Dale J, Hedges, Harry H, Wright, Ruth K, Abramson, Ramkumar, Menon, Scott M, Williams, Michael L, Cuccaro, Jonathan L, Haines, John R, Gilbert, Margaret A, Pericak-Vance, Eden R, Martin, and Jacob L, McCauley

Subjects
Adult, Adolescent, Genetic Variation, behavioral disciplines and activities, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Young Adult, Haplotypes, Child Development Disorders, Pervasive, Child, Preschool, mental disorders, Mutation, Humans, Child, Genome-Wide Association Study
Abstract

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.

Published
2012

22. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility

Author

Damotte, V, Guillot-Noel, L, Patsopoulos, N A, Madireddy, L, El Behi, M, Ban, Maria, Baranzini, Sergio, Barcellos, Lisa, Beecham, Gary, Beecham, Ashley, Bernardinelli, Luisa, Booth, David, Bos, Steffan, Buck, Dorothea, Bush, William, Comabella, Manuel, Compston, Alastair, Cotsapas, Chris, Cournu-Rebeix, Isabelle, Cree, Bruce, D'Alfonso, Sandra, Daly, Mark, Damotte, Vincent, Davis, Mary, de Bakker, Paul, De Jager, Philip L, Dubois, Benedicte, Esposito, Federica, Fontaine, Bertrand, Goris, An, Gourraud, Pierre-Antoine, Green, Todd, Gulowsen Celius, Elisabeth, Hadjixenofontos, Athena, Hafler, David, Haines, Jonathan, Flinstad, Hanne F, Hauser, Stephen, Hawkins, Clive, Hemmer, Bernhard, Hillert, Jan, Hintzen, Rogier, Horáková, Dana, Ivinson, Adrian J, Kemppinen, Anu, Kira, Jun-ichi, Kockum, Ingrid, Lincoln, Robin, Martin, Roland, Martinelli Boneschi, Filippo, McCauley, Jacob L, Mero, Inger-Lise, Oksenberg, Jorge, Olsson, Tomas, Oturai, Annette, Palotie, Aarno, Patsopoulos, Nikolaos, Pericak-Vance, Margaret, Rioux, John, Saarela, Janna, Sawcer, Stephen, Schnetz-Boutaud, Nathalie, Sellebjerg, Finn, Soendergaard, Helle, Soelberg Sorensen, Per, Spurkland, Anne, Stankovich, Jim, Stewart, Graeme, Taylor, Bruce, Ticca, Anna, West, Sandra, Zipp, Frauke, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Rathi, Ricketts, Michelle, Waller, Matthew J, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Deloukas, Panos, Dilthey, Alexander, Leslie, Stephen, Moutsianas, Loukas, Perez, Marc L, McVean, Gil, McCarthy, Mark I, De Jager, P L, Baranzini, S E, Cournu-Rebeix, I, Fontaine, B, Damotte, V, Guillot-Noel, L, Patsopoulos, N A, Madireddy, L, El Behi, M, Ban, Maria, Baranzini, Sergio, Barcellos, Lisa, Beecham, Gary, Beecham, Ashley, Bernardinelli, Luisa, Booth, David, Bos, Steffan, Buck, Dorothea, Bush, William, Comabella, Manuel, Compston, Alastair, Cotsapas, Chris, Cournu-Rebeix, Isabelle, Cree, Bruce, D'Alfonso, Sandra, Daly, Mark, Damotte, Vincent, Davis, Mary, de Bakker, Paul, De Jager, Philip L, Dubois, Benedicte, Esposito, Federica, Fontaine, Bertrand, Goris, An, Gourraud, Pierre-Antoine, Green, Todd, Gulowsen Celius, Elisabeth, Hadjixenofontos, Athena, Hafler, David, Haines, Jonathan, Flinstad, Hanne F, Hauser, Stephen, Hawkins, Clive, Hemmer, Bernhard, Hillert, Jan, Hintzen, Rogier, Horáková, Dana, Ivinson, Adrian J, Kemppinen, Anu, Kira, Jun-ichi, Kockum, Ingrid, Lincoln, Robin, Martin, Roland, Martinelli Boneschi, Filippo, McCauley, Jacob L, Mero, Inger-Lise, Oksenberg, Jorge, Olsson, Tomas, Oturai, Annette, Palotie, Aarno, Patsopoulos, Nikolaos, Pericak-Vance, Margaret, Rioux, John, Saarela, Janna, Sawcer, Stephen, Schnetz-Boutaud, Nathalie, Sellebjerg, Finn, Soendergaard, Helle, Soelberg Sorensen, Per, Spurkland, Anne, Stankovich, Jim, Stewart, Graeme, Taylor, Bruce, Ticca, Anna, West, Sandra, Zipp, Frauke, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Rathi, Ricketts, Michelle, Waller, Matthew J, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Deloukas, Panos, Dilthey, Alexander, Leslie, Stephen, Moutsianas, Loukas, Perez, Marc L, McVean, Gil, McCarthy, Mark I, De Jager, P L, Baranzini, S E, Cournu-Rebeix, I, and Fontaine, B

Abstract

Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood–brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.

Published
2014

23. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, Ashley H., Patsopoulos, Nikolaos A., Xifara, Dionysia K., Davis, Mary F., Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S., Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F., Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R., Hintzen, Rogier, F Barcellos, Lisa, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Bach Sondergaard, Helle, Baker, Amie, Band, Gavin, Baranzini, Sergio E., Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Celine, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C., Blackburn, Hannah, Bomfim, Izaura L., Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J., Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G., Coman, Irene, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C., Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R., Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T., Donnelly, Peter, Dubois, Benedicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y., Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E., Jagodic, Maja, Jelcic, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H., Leone, Maurizio A., Leppa, Virpi, Liberatore, Giuseppe, Lie, Benedicte A., Lill, Christina M., Linden, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Mannisto, Satu, Manrique, Clara P., Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Sian E., Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P., Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C., Sellebjerg, Finn, Selter, Rebecca C., Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Soelberg Sorensen, Per, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M., Vucic, Steve, Westerlind, Helga, Wiley, James S., Wilkins, Alastair, Wilson, James F., Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L., Pericak-Vance, Margaret A., Ivinson, Adrian J., Stewart, Graeme, Hafler, David, Hauser, Stephen L., Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J., McCauley, Jacob L., Beecham, Ashley H., Patsopoulos, Nikolaos A., Xifara, Dionysia K., Davis, Mary F., Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S., Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F., Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R., Hintzen, Rogier, F Barcellos, Lisa, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Bach Sondergaard, Helle, Baker, Amie, Band, Gavin, Baranzini, Sergio E., Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Celine, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C., Blackburn, Hannah, Bomfim, Izaura L., Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J., Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G., Coman, Irene, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C., Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R., Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T., Donnelly, Peter, Dubois, Benedicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y., Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E., Jagodic, Maja, Jelcic, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H., Leone, Maurizio A., Leppa, Virpi, Liberatore, Giuseppe, Lie, Benedicte A., Lill, Christina M., Linden, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Mannisto, Satu, Manrique, Clara P., Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Sian E., Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P., Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C., Sellebjerg, Finn, Selter, Rebecca C., Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Soelberg Sorensen, Per, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M., Vucic, Steve, Westerlind, Helga, Wiley, James S., Wilkins, Alastair, Wilson, James F., Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L., Pericak-Vance, Margaret A., Ivinson, Adrian J., Stewart, Graeme, Hafler, David, Hauser, Stephen L., Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J., and McCauley, Jacob L.

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P andlt; 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P andlt; 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals., Funding Agencies|US National Institutes of Health||Wellcome Trust||UK MS Society||UK Medical Research Council||US National MS Society||Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre||DeNDRon||Swedish Brain Foundation||Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Heart-Lung Foundation||Foundation for Strategic Research

Published
2013
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24. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., McCauley, J.L., Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., and McCauley, J.L.

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

25. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, McCauley, JL, Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, and McCauley, JL

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

26. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jel?i?, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J, McCauley, Jacob L, (IMSGC), International Multiple Sclerosis Genetics Consortium, Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jel?i?, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J, McCauley, Jacob L, and (IMSGC), International Multiple Sclerosis Genetics Consortium

Published
2013

28. Whole-Exome Sequencing in Multiplex Families Identifies Novel Rare Variants in Multiple Sclerosis (P05.137)

Author

Haines, Jonathan, primary, Beecham, Ashley, additional, McCauley, Jacob, additional, Hadjixenofontos, Athena, additional, Whitehead, Patrice, additional, Konidari, Ioanna, additional, Aviram, Anat, additional, Pasco, Yuslin, additional, Hauser, Stephen, additional, Oksenberg, Jorge, additional, Hedges, Dale, additional, Vance, Jeffery, additional, and Pericak-Vance, Margaret, additional

Published
2013
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29. Evaluating Mitochondrial DNA Variation in Autism Spectrum Disorders

Author

Hadjixenofontos, Athena, primary, Schmidt, Michael A., additional, Whitehead, Patrice L., additional, Konidari, Ioanna, additional, Hedges, Dale J., additional, Wright, Harry H., additional, Abramson, Ruth K., additional, Menon, Ramkumar, additional, Williams, Scott M., additional, Cuccaro, Michael L., additional, Haines, Jonathan L., additional, Gilbert, John R., additional, Pericak-Vance, Margaret A., additional, Martin, Eden R., additional, and McCauley, Jacob L., additional

Published
2012
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30. Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci.

Author

Fazia T, Pastorino R, Foco L, Han L, Abney M, Beecham A, Hadjixenofontos A, Guo H, Gentilini D, Papachristou C, Bitti PP, Ticca A, Berzuini C, McCauley JL, and Bernardinelli L

Subjects
Alleles, Humans, Italy, Polymorphism, Single Nucleotide genetics, Genetic Linkage genetics, Genetic Predisposition to Disease genetics, Multiple Sclerosis genetics
Abstract

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability., Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence., Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p -value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions., Results: We identified 486 MS-associated ( p  < 1 × 10 -4 ) and 18,426 MS-linked ( p  < 0.05) SNPs. A total of 111 loci were both linked and associated with MS, 18 of them pointing to 14 non-major histocompatibility complex (MHC) genes, and 93 of them located in the MHC region., Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS.

Published
2018
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31. Enrichment for Northern European-derived multiple sclerosis risk alleles in Sardinia.

Author

Hadjixenofontos A, Gourraud PA, Bakthavachalam V, Foco L, Ticca A, Bitti P, Pastorino R, Bernardinelli L, and McCauley JL

Subjects
Adolescent, Adult, Age of Onset, Alleles, Child, Europe epidemiology, Female, Humans, Italy epidemiology, Male, Middle Aged, Risk, United States epidemiology, Young Adult, Genetic Predisposition to Disease, Multiple Sclerosis epidemiology, Multiple Sclerosis genetics
Abstract

Background: The list of genomic loci associated with multiple sclerosis (MS) susceptibility outside the major histocompatibility complex (MHC) in patients of Northern European (NE) ancestry has increased to 103. Despite the extraordinarily high MS prevalence in the isolated Sardinian population, the contribution of genetic risk factors to MS in Sardinia is largely not understood., Objective: The objective of this paper is to examine the relevance of non-MHC MS susceptibility variants in Sardinia., Methods: We examined a log-additive MS-specific genetic burden score (MSGB) using 110 NE-derived risk alleles in a dataset of 75 Sardinian cases, 346 Sardinian controls and 177 cases and 1967 controls from the United States (US)., Results: Sardinian cases demonstrate a heavier non-MHC MSGB load than Sardinian controls and US cases (p = 2E-06, p = 1E-06, respectively). Furthermore, Sardinian controls carry a heavier burden than US controls (p = 2E-14). Our results confirm the limited ability of the 110-SNP MSGB to predict disease status in Sardinia (AUROC = 0.629)., Conclusions: Risk alleles discovered in samples of NE ancestry are relevant to MS in Sardinia. Our results suggest a general enrichment of MS susceptibility alleles in Sardinians, encouraging the pursuit of further studies of MS in this population., (© The Author(s), 2015.)

Published
2015
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