Search

Your search keyword '"Inger Lise Mero"' showing total 26 results
Start Over Author "Inger Lise Mero"
26 results on '"Inger Lise Mero"'

1. A mild skeletal phenotype with overlapping features of Miller syndrome and functional characterisation of two new variants of human dihydroorotate dehydrogenase

Author

Inger-Lise Mero, Juan Manuel Orozco Rodriguez, Kathrine Bjørgo, Renee Alexandra Hankin, Ewa Krupinska, Mari Ann Kulseth, Marvin Anthony Rossow, and Wolfgang Knecht

Subjects
Inborn errors of metabolism, Enzymology, Purine and pyrimidine metabolism, Biophysics, Protein production, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth enzymatic reaction of the pyrimidine biosynthesis pathway. Miller syndrome, also known as postaxial acrofacial dysostosis, is caused by biallelic pathogenic variants in DHODH. We present a patient with a relatively mild skeletal phenotype carrying a novel variant of unknown significance in DHODH: c.829G > A, p.(D277N), in combination with a known variant, c.403C > T, p.(R135C). We functionally characterized the DHODH variant D277N in comparison to a very recently reported, but functionally uncharacterized variant P43L, that was found in a patient with more pronounced Miller syndrome features. Because both cases share the same DHODH variant R135C, we aimed to study the effect on enzyme activity of the two variants D277N and P43L to determine pathogenicity and possibly a genotype-phenotype relationship on the R135C background. We found a significant reduction in enzyme activity for both variants. The variant P43L showed a more pronounced loss of function in all assays compatible with other pathogenic variants reported in Miller, whereas the D277N variant showed milder changes that could reflect the mild phenotypic features in our patient. Yet due to a lack of a known threshold of residual enzyme activity to determine pathogenicity, this needs to be confirmed in further studies.

Published
2024
Full Text
View/download PDF

2. Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Author

Nicole Revencu, Astrid Eijkelenboom, Claire Bracquemart, Pia Alhopuro, Judith Armstrong, Eulalia Baselga, Claudia Cesario, Maria Lisa Dentici, Melanie Eyries, Sofia Frisk, Helena Gásdal Karstensen, Nagore Gene-Olaciregui, Sirpa Kivirikko, Cinzia Lavarino, Inger-Lise Mero, Rodolphe Michiels, Elisa Pisaneschi, Bitten Schönewolf-Greulich, Ilse Wieland, Martin Zenker, and Miikka Vikkula

Subjects
ERN, Gene curation, ISSVA, Mosaic, Precision medicine, Postzygotic, Medicine
Abstract

Abstract Background Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. Results Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene–disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene–phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. Conclusions This work provides a detailed evidence-based view of the gene–disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene–phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).

Published
2024
Full Text
View/download PDF

3. Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis.

Author

Marthe T Maehlen, Sella A Provan, Diederik P C de Rooy, Annette H M van der Helm-van Mil, Annemarie Krabben, Tore Saxne, Elisabet Lindqvist, Anne Grete Semb, Till Uhlig, Désirée van der Heijde, Inger Lise Mero, Inge C Olsen, Tore K Kvien, and Benedicte A Lie

Subjects
Medicine, Science
Abstract

OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers. METHOD: A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs). RESULTS: In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2 < ε3/ε3 < ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative. CONCLUSION: APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.

Published
2013
Full Text
View/download PDF

4. Correction to: Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Author

Nicole Revencu, Astrid Eijkelenboom, Claire Bracquemart, Pia Alhopuro, Judith Armstrong, Eulalia Baselga, Claudia Cesario, Maria Lisa Dentici, Melanie Eyries, Sofia Frisk, Helena Gásdal Karstensen, Nagore Gene‑Olaciregui, Sirpa Kivirikko, Cinzia Lavarino, Inger‑Lise Mero, Rodolphe Michiels, Elisa Pisaneschi, Bitten Schönewolf‑Greulich, Ilse Wieland, Martin Zenker, and Miikka Vikkula

Subjects
Medicine
Published
2024
Full Text
View/download PDF

5. Whole-exome sequencing in moyamoya patients of Northern-European origin identifies gene variants involved in Nitric Oxide metabolism: A pilot study

Author

Markus K.H. Wiedmann, Ingunn V. Steinsvåg, Tovy Dinh, Magnus D. Vigeland, Pål G. Larsson, Hanne Hjorthaug, Ying Sheng, Inger-Lise Mero, and Kaja K. Selmer

Subjects
Moyamoya, Stroke, Nitric oxide, Gene, RNF213, Whole exome sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular steno-occlusive disease of largely unknown etiology. Variants in the RNF213 gene are strongly associated with MMD in East-Asia. In MMD patients of Northern-European origin, no predominant susceptibility variants have been identified so far. Research question: Are there specific candidate genes associated with MMD of Northern-European origin, including the known RNF213 gene? Can we establish a hypothesis for MMD phenotype and associated genetic variants identified for further research? Material and methods: Adult patients of Northern-European origin, treated surgically for MMD at Oslo University Hospital between October 2018 to January 2019 were asked to participate. WES was performed, with subsequent bioinformatic analysis and variant filtering. The selected candidate genes were either previously reported in MMD or known to be involved in angiogenesis. The variant filtering was based on variant type, location, population frequency, and predicted impact on protein function. Results: Analysis of WES data revealed nine variants of interest in eight genes. Five of those encode proteins involved in nitric oxide (NO) metabolism: NOS3, NR4A3, ITGAV, GRB7 and AGXT2. In the AGXT2 gene, a de novo variant was detected, not previously described in MMD. None harboured the p.R4810K missense variant in the RNF213 gene known to be associated with MMD in East-Asian patients. Discussion and conclusion: Our findings suggest a role for NO regulation pathways in Northern-European MMD and introduce AGXT2 as a new susceptibility gene. This pilot study warrants replication in larger patient cohorts and further functional investigations.

Published
2023
Full Text
View/download PDF

6. Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria

Author

Athina, Ververi, Sara, Zagaglia, Lara, Menzies, Julia, Baptista, Richard, Caswell, Stephanie, Baulac, Sian, Ellard, Sally, Lynch, Genomics England Research, Consortium, Thomas S, Jacques, Maninder Singh, Chawla, Martin, Heier, Mari Ann, Kulseth, Inger-Lise, Mero, Anne Katrine, Våtevik, Ichraf, Kraoua, Hanene Ben, Rhouma, Thouraya Ben, Younes, Zouhour, Miladi, Ilhem Ben Youssef, Turki, Wendy D, Jones, Emma, Clement, Christin, Eltze, Kshitij, Mankad, Ashirwad, Merve, Jennifer, Parker, Bethan, Hoskins, Ronit, Pressler, Sniya, Sudhakar, Catherine, DeVile, Tessa, Homfray, Marios, Kaliakatsos, Prab Prabhakar, Ponnudas, Robert, Robinson, Sara Margrete Bøen, Keim, Imen, Habibi, Alexandre, Reymond, Sanjay M, Sisodiya, and Jane A, Hurst

Subjects
Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Published
2022

7. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies

Author

Nathan L. Absalom, Vivian W. Y. Liao, Katrine M. H. Johannesen, Elena Gardella, Julia Jacobs, Gaetan Lesca, Zeynep Gokce-Samar, Alexis Arzimanoglou, Shimriet Zeidler, Pasquale Striano, Pierre Meyer, Ira Benkel-Herrenbrueck, Inger-Lise Mero, Jutta Rummel, Mary Chebib, Rikke S. Møller, Philip K. Ahring, Clinical Genetics, The University of Sydney, Western Sydney University, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), University of Calgary, University of Freiburg [Freiburg], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Università degli studi di Genova = University of Genoa (UniGe), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Oslo University Hospital [Oslo], and MORNET, Dominique

Subjects
Multidisciplinary, Epilepsy, [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, Receptors, GABA-A, General Biochemistry, Genetics and Molecular Biology, Epilepsy/genetics, [SDV] Life Sciences [q-bio], Phenotype, Loss of Function Mutation, Seizures, Gain of Function Mutation, Receptors, GABA-A/genetics, Humans
Abstract

Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

Published
2022
Full Text
View/download PDF

8. Whole-exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways

Author

Elin Tønne, Bernt Johan Due‐Tønnessen, Magnus Dehli Vigeland, Silja Svanstrøm Amundsen, Teodora Ribarska, Pamela Marika Åsten, Ying Sheng, Eirik Helseth, Gregor Duncan Gilfillan, Inger‐Lise Mero, and Ketil Riddervold Heimdal

Subjects
Craniosynostoses, Osteogenesis, Exome Sequencing, Genetics, Humans, Cranial Sutures, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, Signal Transduction
Abstract

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%-30% of the cases. In a recent population-based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole-exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (NFIA, EXTL3, POLR2A, and FOXP2) associated with rare conditions. In two of these (POLR2A and FOXP2), CS has not previously been reported. We further detected a rare predicted damaging variant in SH3BP4, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole-exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.

Published
2022

9. Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies

Author

Dusit Adstamongkonkul, Inger Lise Mero, Morten Buch Engelund, Elena Gardella, Deepali N. Shinde, Felix Boschann, Ingrid Cristian, Irma van de Beek, Johanna C. Acosta Guio, Corinna Stoltenburg, Diana Moskal-Jasińska, Anna C.E. Hurst, Alina T. Midro, Linda Zuurbier, Kristine Lossius, Kevin E. Glinton, Ariel Brautbar, Cyril Mignot, Lindsay B. Henderson, Paul Vos, Carole Brewer, Oliver Puk, Alan Donaldson, Eugeniusz Tarasów, David B. Beck, Julian A. Martinez, Arie van Haeringen, Pawel Stankiewicz, Yline Capri, Amélie Piton, Yaping Yang, Louise Amlie-Wolf, Kevin M. Bowling, Devon Haynes, Saskia Koene, Alberto Gómez, Boris Keren, Margherita Furlan, Karen W. Gripp, Pernille Mathiesen Tørring, Ignacio Briceño, Oskar Schnappauf, Aditi Shah Parikh, Rikke S. Møller, Phillis Lakeman, Beata Stasiewicz-Jarocka, Allan Bayat, Rebecca Signer, and Human Genetics

Subjects
Adult, Male, 0301 basic medicine, Microcephaly, Adolescent, Developmental Disabilities, Haploinsufficiency, Postnatal microcephaly, 030105 genetics & heredity, Bioinformatics, chromatin remodeling, Young Adult, 03 medical and health sciences, Epilepsy, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Abnormalities, Multiple, Language Development Disorders, microcephaly, Child, Genetics (clinical), business.industry, Facies, Infant, Original Articles, Middle Aged, Chromatin Assembly and Disassembly, medicine.disease, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, PHD finger, Child, Preschool, Speech delay, epilepsy, Female, Original Article, Chromosome Deletion, medicine.symptom, business, Transcription Factors
Abstract

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF.

Published
2021
Full Text
View/download PDF

10. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.

Author

Inger-Lise Mero, Marte W Gustavsen, Hanne S Sæther, Siri T Flåm, Pål Berg-Hansen, Helle B Søndergaard, Poul Erik H Jensen, Tone Berge, Anja Bjølgerud, Aslaug Muggerud, Jan H Aarseth, International Multiple Sclerosis Genetics Consortium, Kjell-Morten Myhr, Elisabeth G Celius, Finn Sellebjerg, Jan Hillert, Lars Alfredsson, Tomas Olsson, Annette Bang Oturai, Ingrid Kockum, Benedicte A Lie, Bettina Kulle Andreassen, and Hanne F Harbo

Subjects
Medicine, Science
Abstract

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Published
2013
Full Text
View/download PDF

11. Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general

Author

Lars Alfredsson, Finn Sellebjerg, Marte K. Viken, Marte Wendel Gustavsen, Inger-Lise Mero, Ingrid Kockum, Hanne F. Harbo, Kjell-Morten Myhr, Elisabeth Gulowsen Celius, Jan Harald Aarseth, Tone Berge, Benedicte A. Lie, Tomas Olsson, Annette Bang Oturai, Jan Hillert, Helle Bach Søndergaard, and Pål Berg-Hansen

Subjects
Adult, Male, Hla class ii, Oligoclonal band, Immunology, chemical and pharmacologic phenomena, Human leukocyte antigen, Biology, Ligands, Pathogenesis, Multiple Sclerosis, Relapsing-Remitting, otorhinolaryngologic diseases, medicine, Humans, Immunology and Allergy, Registries, Allele, Receptor, Genetics, Multiple sclerosis, Histocompatibility Antigens Class I, Oligoclonal Bands, Histocompatibility Antigens Class II, hemic and immune systems, medicine.disease, Phenotype, Killer Cells, Natural, Haplotypes, Neurology, Receptors, KIR2DL3, Receptors, KIR2DL2, Receptors, KIR2DL1, Female, Neurology (clinical), HLA-DRB1 Chains
Abstract

Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.

Published
2014
Full Text
View/download PDF

12. Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

Author

Steffan D. Bos, Hanne F. Harbo, Noriko Isobe, Inger Lise Mero, Stephen L. Hauser, Jorge R. Oksenberg, Marte Wendel Gustavsen, Pål Berg-Hansen, Pierre-Antoine Gourraud, Stacy J. Caillier, and Elisabeth Gulowsen Celius

Subjects
Adult, Male, Multiple Sclerosis, Genotype, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Article, Risk Factors, Genetic variation, medicine, Humans, Genetic Testing, Age of Onset, Genetic testing, Genetic association, medicine.diagnostic_test, Multiple sclerosis, Oligoclonal Bands, Genetic Variation, Middle Aged, medicine.disease, Neurology, Immunoglobulin G, Immunology, Female, Neurology (clinical), Age of onset, Biomarkers
Abstract

Background: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. Objective: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. Methods: Norwegian MS patients ( n = 639) and healthy controls ( n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients ( n = 1997) and controls ( n = 708). Results: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts ( P << 10−22). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. Conclusion: The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

Published
2013
Full Text
View/download PDF

13. 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
Full Text
View/download PDF

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

Author

Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences

Subjects
Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
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
2016
Full Text
View/download PDF

15. From genes to characteristics of multiple sclerosis

Author

Inger-Lise Mero and Hanne F. Harbo

Subjects
Central Nervous System, Multiple Sclerosis, Multiple sclerosis, Treatment options, Genome-wide association study, General Medicine, Human leukocyte antigen, Disease, Biology, medicine.disease, Bioinformatics, Biobank, Treatment Outcome, Neurology, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Neurology (clinical), Genetic risk, Gene, Biological Specimen Banks, Demyelinating Diseases
Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating heterogeneous disease of the central nervous system, probably caused by an interaction of common genetic and environmental factors. Much progress has been made through the last few years in genetic studies of MS, and a growing list of genetic risk factors is now available. Biobanking and large collaborations have been prerequisites for this research, and detailed genetic and molecular characterizations are underway, with hopes for to translating new knowledge about MS pathogenesis and characteristics of the disease to personalized, better treatment options for each patient with MS.

Published
2012
Full Text
View/download PDF

16. Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655

Author

Jeppe Romme Christensen, Magdalena Lindén, Finn Sellebjerg, Tomas Olsson, Annette Bang Oturai, Ingrid Kockum, Kjell-Morten Myhr, Elisabeth Gulowsen Celius, Inger-Lise Mero, Hanne F. Harbo, Per Soelberg Sørensen, Lars Börnsen, Helle Bach Søndergaard, and Jan Hillert

Subjects
Male, Multiple Sclerosis, Short Report, Genome-wide association study, Scandinavian and Nordic Countries, Biology, KLRB1 Gene, Polymorphism, Single Nucleotide, Pathogenesis, Gene Frequency, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetics (clinical), Autoimmune disease, Regulation of gene expression, Multiple sclerosis, Case-control study, medicine.disease, KLRB1, Gene Expression Regulation, Case-Control Studies, Immunology, Female, Genome-Wide Association Study, NK Cell Lectin-Like Receptor Subfamily B
Abstract

Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00–1.13)) in a large Scandinavian case–control study of 5367 MS patients and 4485 controls. The expression of KLRB1 in blood from MS patients was higher compared with healthy controls (P

Published
2011
Full Text
View/download PDF

17. Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus

Author

Elisabeth Gulowsen Celius, Benedicte A. Lie, Åslaug R. Lorentzen, Stine Granum, Dag E. Undlien, Anne Spurkland, C. Smestad, Marte K. Viken, Hanne Skarpodde Sæther, Alastair Compston, Hanne F. Harbo, Jan Harald Aarseth, Saeedi H, Stephen Sawcer, Beate Skinningsrud, Kjell-Morten Myhr, Maria Ban, and Inger-Lise Mero

Subjects
Adult, Male, Linkage disequilibrium, Multiple Sclerosis, Genotype, Monosaccharide Transport Proteins, Immunology, Single-nucleotide polymorphism, Genome-wide association study, Thymus Gland, CLEC16A, Biology, Polymorphism, Single Nucleotide, Young Adult, Gene Frequency, Genetics, Humans, Protein Isoforms, SNP, Genetic Predisposition to Disease, Lectins, C-Type, Allele frequency, Alleles, Genetics (clinical), Gene Expression Profiling, Odds ratio, Middle Aged, Gene Expression Regulation, Female, Genome-Wide Association Study
Abstract

Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P=5.3 x 10⁻⁸, odds ratio 1.18, 95% confidence interval=1.11-1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P=0.004), but not in blood, possibly implying a thymus- or cell-specific splice regulation.

Published
2010
Full Text
View/download PDF

18. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Author

Christian Gieger, Federica Esposito, B. Bryneda, Per Soelberg Sørensen, Laura Bergamaschi, Elisabeth Gulowsen Celius, Ingrid Kockum, An Goris, Alastair Compston, Sandra D'Alfonso, Rodney J. Scott, P. I. W. de Bakker, Clive Hawkins, Barbara Elaine Stranger, Åslaug R. Lorentzen, Paola Cavalla, Annette Bang Oturai, Anne Spurkland, Janna Saarela, Helle Bach Søndergaard, Jeannette Lechner-Scott, Jacob L. McCauley, Adrian J. Ivinson, Filippo Martinelli Boneschi, Lars Alfredsson, Tomas Olsson, Carmen Infante-Duarte, Jonathan L. Haines, Sabine Cepok, Aarno Palotie, Lisa F. Barcellos, Stephen L. Hauser, Robert Heard, Manuel Comabella, Frauke Zipp, Leena Peltonen, Bénédicte Dubois, Rita Dobosi, Mauri Reunanen, John D. Rioux, Jorge R. Oksenberg, Juliane Winkelmann, Virpi M. Leppä, Maurizio Leone, Keijo Koivisto, P. L. De Jager, Margaret A. Pericak-Vance, Jan Hillert, Roberto Bergamaschi, Cristin Aubin, David A. Hafler, Inger-Lise Mero, Bruce A.C. Cree, Neil Robertson, Stephen Sawcer, Finn Sellebjerg, William S. Bush, Isabelle Cournu-Rebeix, Hanne F. Harbo, B. Hemmer, Luisa Bernardinelli, Gary W. Beecham, Mathew B Cox, David R. Booth, Graeme J. Stewart, Nikolaos A. Patsopoulos, Mark J. Daly, G. Comi, and Bertrand Fontaine

Subjects
Multiple Sclerosis, Immunology, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Interleukin-12 Subunit p35, Cell Line, 03 medical and health sciences, 0302 clinical medicine, IL12A, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genetics (clinical), Cell Proliferation, 030304 developmental biology, 0303 health sciences, Tumor Suppressor Proteins, Multiple sclerosis, Cell cycle, medicine.disease, 3. Good health, Celiac Disease, Case-Control Studies, Expression quantitative trait loci, Leukocytes, Mononuclear, RGS Proteins, 030217 neurology & neurosurgery
Abstract

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value = 3.55 × 10–9), IL12A (P = 3.08 × 10–8) and MPHOSPH9/CDK2AP1 (P = 3.96 × 10–8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P = 1.18 × 10–5) and in peripheral blood mononuclear cells from subjects with MS (P = 0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

Published
2010
Full Text
View/download PDF

19. Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

Author

Teppo Varilo, Chris H. Polman, Maria-Liisa Sumelahti, Stacey Gabriel, Anna-Maija Kristiina Sulonen, Arpo Aromaa, David A. Hafler, Pentti J. Tienari, Inger-Lise Mero, Eveliina Jakkula, Stephen L. Hauser, Aarno Palotie, Daniel B. Mirel, Mauri Reunanen, Leena Peltonen, Ludwig Kappos, Shaun Purcell, Annette Bang Oturai, Anu Kemppinen, Helle Bach Søndergaard, Irina Elovaara, Hanne F. Harbo, Philip L. De Jager, Tuula Pirttilä, Keijo Koivisto, Virpi Leppa, Janna Saarela, Mark J. Daly, Suvi P. Kallio, Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Subjects
STAT3 Transcription Factor, Linkage disequilibrium, Multiple Sclerosis, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Report, Genotype, Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Allele, Base Pairing, Alleles, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Haplotype, Reproducibility of Results, Odds ratio, Genetics, Population, Haplotypes, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Published
2010
Full Text
View/download PDF

20. Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis

Author

Anne Spurkland, Benedicte A. Lie, Hanne F. Harbo, Marita Olsson, Ji-Yao Sun, David Senitzer, C. Smestad, Inger-Lise Mero, Bente Woldseth, Tom H. Karlsen, Elisabeth Gulowsen Celius, Åslaug R. Lorentzen, and Erik Thorsby

Subjects
Adult, Male, Multiple Sclerosis, Adolescent, Human leukocyte antigen, Biology, KIR2DL4, Young Adult, Receptors, KIR, KIR2DL1, medicine, Humans, Child, Receptor, Genetic Carrier Screening, Multiple sclerosis, HLA-DR Antigens, Middle Aged, medicine.disease, Neurology, KIR3DL2, HLA-B Antigens, Immunology, Female, Neurology (clinical), KIR3DL1, HLA-DRB1 Chains, Protein Binding, KIR2DS4
Abstract

Objective Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. A human leukocyte antigen (HLA) class II association is well established (DRB1*1501-DQB1*0602), but more recently HLA class II–independent associations with HLA class I variants have also been reported. The HLA class I (HLA-A, -B, -C) molecules serve as ligands for both T-cell receptors and killer immunoglobulin-like receptors (KIRs). We investigated the HLA class I alleles defined by their KIR binding motifs and the KIR genes to evaluate whether these genes could influence MS susceptibility or severity, alone or in combination. Methods We typed Norwegian MS patients (n = 631) and controls (n = 555) for HLA-A, -B, -C and -DRB1 alleles as well as the presence or absence of genes encoding inhibitory (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, KIR3DL2, KIR3DL3) and activating (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DL4, KIR2DS4, KIR2DS5, KIR3DS1) KIRs. Results The frequency of the HLA-Bw4 specificity, which is the ligand for the inhibitory KIR3DL1, was significantly reduced in MS patients as compared with controls (41.4% vs 55.1%, puncorrected (uc) = 4.6 × 10−6). Also after stratifying for known HLA class II associations, the HLA-Bw4 association was seen (puc = 0.002). No significant differences in gene carrier frequencies of inhibitory and activating KIRs were observed. However, our data indicate that MS patients who carry the activating KIR2DS2 and the inhibitory KIR2DL2 genes have more severe disease than patients not carrying these genes. Interpretation Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA-Bw4, was found to protect against MS in an HLA-DRB1 independent manner. Ann Neurol 2009;65:658–666

Published
2009
Full Text
View/download PDF

21. No evidence of association between mutant alleles of theCYP27B1gene and multiple sclerosis

Author

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

Subjects
Genetics, Mutation, Multiple sclerosis, Mutant, 25-Hydroxyvitamin D3 1-alpha-hydroxylase, Rickets, Biology, medicine.disease, medicine.disease_cause, Neurology, medicine, Neurology (clinical), Allele, Allele frequency, Gene
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
Full Text
View/download PDF

22. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis

Author

Hanne F. Harbo, Helle Bach Søndergaard, Frank Dudbridge, Åslaug R. Lorentzen, Jenny Link, C. Smestad, Thomas Masterman, Irina Elovaara, Annette Bang Oturai, Jan Hillert, Inger-Lise Mero, Ingrid Kockum, Elisabeth Gulowsen Celius, Jan Harald Aarseth, Benedicte A. Lie, Janna Saarela, Finn Sellebjerg, Anu Kemppinen, Tomas Olsson, Anne Spurkland, Maria Ban, and Kjell-Morten Myhr

Subjects
Multiple Sclerosis, Genotype, Short Report, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Polymorphism (computer science), Genetics, Humans, Genetic Predisposition to Disease, Rare functional variant, Allele frequency, Genetics (clinical), 030304 developmental biology, TYK2 Kinase, 0303 health sciences, Odds ratio, Minor allele frequency, Case-Control Studies, Immunology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.

Published
2009
Full Text
View/download PDF

23. Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus

Author

Hanne F. Harbo, Anne Spurkland, Dahle Mk, Ingvild Sørum Leikfoss, Tone Berge, Benedicte A. Lie, and Inger-Lise Mero

Subjects
Multiple Sclerosis, Monosaccharide Transport Proteins, Immunology, Down-Regulation, Single-nucleotide polymorphism, Suppressor of Cytokine Signaling Proteins, CLEC16A, Thymus Gland, Biology, Polymorphism, Single Nucleotide, Suppressor of Cytokine Signaling 1 Protein, Genetics, CIITA, Humans, Genetic Predisposition to Disease, Lectins, C-Type, Child, Gene, Genetics (clinical), Genetic association, Case-control study, Membrane Proteins, DNA-Binding Proteins, Real-time polymerase chain reaction, Case-Control Studies, Chromosomal region
Abstract

Genome-wide association studies have revealed that the 16p13 chromosomal region, including CLEC16A, DEXI, CIITA and SOCS1, is associated with susceptibility to autoimmune diseases. As non-coding single-nucleotide polymorphisms (SNPs) may confer susceptibility to disease by affecting expression of nearby genes, we examined whether autoimmune-associated intronic CLEC16A SNPs (rs12708716, rs6498169 and rs7206912) correlate with the expression of CLEC16A itself as well as neighboring genes in whole-blood and thymic samples. Real-time quantitative PCR analyses show that SOCS1 and DEXI expression was lower in thymic samples carrying at least one of the CLEC16A risk alleles compared with non-carriers of the risk allele. Linear regression analysis revealed a significant correlation between the expression level of CLEC16A and that of SOCS1 and DEXI in thymic samples. These data indicate a possible regulatory role for multiple sclerosis-associated non-coding CLEC16A SNPs and a common control mechanism for the expression of CLEC16A, SOCS1 and DEXI.

Published
2012

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

Author

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

Subjects
25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Male, Multiple Sclerosis, Gene Frequency, Norway, Mutation, Humans, Female, Genetic Association Studies, United Kingdom, Article
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
2012

25. Polymorphisms of the BDNF gene show neither association with multiple sclerosis susceptibility nor clinical course

Author

Hanne F. Harbo, Åslaug R. Lorentzen, Leiv Sandvik, Elisabeth Gulowsen Celius, Inger-Lise Mero, Benedicte A. Lie, Jan Harald Aarseth, Nils Inge Landrø, Kjell-Morten Myhr, and C. Smestad

Subjects
Adult, Male, Multiple Sclerosis, Immunology, Single-nucleotide polymorphism, Disease course, Methionine, Disease severity, Neurotrophic factors, medicine, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Age of Onset, Cognitive impairment, Genetic Association Studies, Genetics, Polymorphism, Genetic, business.industry, Norway, Multiple sclerosis, Brain-Derived Neurotrophic Factor, Clinical course, Valine, medicine.disease, Bdnf gene, nervous system, Neurology, Disease Progression, Female, Neurology (clinical), business
Abstract

Brain-derived neurotrophic factor (BDNF) has been proposed a protective role in multiple sclerosis (MS) in several studies. The val 66 met polymorphism alters the function of the BDNF protein, and has along with rs56164415 previously been reported to be associated with MS. We genotyped BDNF SNPs val 66 met and rs56164415 in 2149 Norwegian MS patients and 2747 healthy controls. No association was found for any of the SNPs to disease susceptibility or any clinical or demographic parameters including sex, age at onset, disease course, disease severity and cognitive impairment.

Published
2011

26. Association to the Glypican-5 gene in multiple sclerosis

Author

Andre Franke, Inger-Lise Mero, Eva Ellinghaus, Elisabeth Gulowsen Celius, Tom H. Karlsen, Åslaug R. Lorentzen, Benedicte A. Lie, Hanne F. Harbo, C. Smestad, Espen Melum, Kjell-Morten Myhr, and Jan Harald Aarseth

Subjects
Adult, Male, Linkage disequilibrium, Multiple Sclerosis, Adolescent, Immunology, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Young Adult, Glypicans, Polymorphism (computer science), medicine, Demyelinating disease, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Child, Gene, Aged, Genetics, Chromosomes, Human, Pair 13, Norway, Multiple sclerosis, Middle Aged, medicine.disease, Neurology, Case-Control Studies, Intronic SNP, Female, Neurology (clinical), Genome-Wide Association Study
Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter including chromosome 13q31-32 and the Glypican-5 and Glypican-6 genes. In order to further explore the 13q31-32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (p(corr)=0.006). Thus, this study supports that MS susceptibility at 13q31-32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results