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2. Deep neural networks learn general and clinically relevant representations of the ageing brain

Author

Leonardsen, E.H., Peng, H., Kaufmann, T., Agartz, I., Andreassen, O.A., Celius, E.G., Espeseth, T., Harbo, H.F., Høgestøl, E.A., Lange, Ann-Marie de, Marquand, A.F., Vidal-Piñeiro, D., Roe, J.M., Selbæk, G., Sørensen, Ø., Smith, S.M., Westlye, L.T., Wolfers, T., Wang, Y., Leonardsen, E.H., Peng, H., Kaufmann, T., Agartz, I., Andreassen, O.A., Celius, E.G., Espeseth, T., Harbo, H.F., Høgestøl, E.A., Lange, Ann-Marie de, Marquand, A.F., Vidal-Piñeiro, D., Roe, J.M., Selbæk, G., Sørensen, Ø., Smith, S.M., Westlye, L.T., Wolfers, T., and Wang, Y.

Abstract

Contains fulltext : 251344.pdf (Publisher’s version ) (Open Access), The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data - the brain age delta - has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

Published
2022

3. Brain disconnectome mapping and serum neurofilament light levels in multiple sclerosis

Author

Rise, H.H., Brune, S., Chien, C., Berge, T., Bos, S.D., Andorrà, M., Valdeolivas, I.P., Beyer, M.K., Sowa, P., Scheel, M., Brandt, A.U., Asseyer, S., Blennow, K., Pedersen, M.L., Zetterberg, H., Thiebaut de Schotten, M., Cellerino, M., Uccelli, A., Paul, F., Villoslada, P., Harbo, H.F., Westlye, L.T., and Høgestøl, E.A.

Subjects
Function and Dysfunction of the Nervous System
Abstract

The pathophysiological mechanisms for classical plaque characteristics and their predictive value for clinical course and outcome in multiple sclerosis is unclear. Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative brain network aberrations and levels of serum neurofilament light chain (sNfL) as a neuroaxonal injury biomarker. Multiple sclerosis patients (n = 328, mean age 42.9 years, 71 % female) were prospectively enrolled at four European multiple sclerosis centres, and reassessed after two years (n = 280). Post-processing of 3 Tesla (3T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient′s white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient and centre as a random factor, sNfL, age, sex, timepoint for visit, diagnosis, and treatment as fixed factors were run. Robust LMM revealed significant associations between higher levels of GD and increased sNfL (t = 2.30, β = 0.03, p = 0.02), age (t = 5.01, β = 0.32, p < 5.5 x 10-7), and diagnosis progressive multiple sclerosis (PMS); t = 1.97, β = 1.06, p = 0.05), but not for sex (t = 0.78, p = 0.43), treatments (effective; t = 0.85, p = 0.39, highly-effective; t = 0.86, p = 0.39) or sNfL change between base line and two-year follow up (t = -1.65, p = 0.10). Voxel-wise analyses revealed distributed associations in cerebellar and brainstem regions. In our prospective multi-site multiple sclerosis cohort, rLMMs demonstrated that the extent of global brain disconnectivity is sensitive to a systemic biomarker of axonal damage, sNfL, in patients with multiple sclerosis. These findings provide a neuropathological correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and clinical relevance in patients with brain disorders.

Published
2021

4. The genetic architecture of human brainstem structures and their involvement in common brain disorders

Author

Elvsåshagen, T., Bahrami, S., Meer, D. van der, Agartz, I., Alnæs, D., Barch, D.M., Baur-Streubel, R., Bertolino, A., Beyer, M.K., Blasi, G., Borgwardt, S., Boye, B., Buitelaar, J.K., Bøen, E., Celius, E.G., Cervenka, S., Conzelmann, A., Coynel, D., Carlo, P. di, Djurovic, S., Eisenacher, S., Espeseth, T., Fatouros-Bergman, H., Flyckt, L., Franke, B., Frei, O., Gelao, B., Harbo, H.F., Hartman, Catharina A., Håberg, A., Heslenfeld, D., Hoekstra, P.J., Høgestøl, E.A., Jonassen, R., Jönsson, E.G., Kirsch, P., Kłoszewska, I., Lagerberg, T.V., Landrø, N.I., Hellard, S. Le, Lesch, K.P., Maglanoc, L.A., Malt, U.F., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Moberget, T., Nordvik, J.E., Nyberg, L., Connell, K.S.O., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pauli, P., Pergola, G., Persson, K., Quervain, D. de, Reif, A., Rokicki, J., Rooij, D. van, Shadrin, A.A., Schmidt, A., Schwarz, E., Selbæk, G., Soininen, H., Sowa, P., Steen, V.M., Tsolaki, M., Vellas, B., Wang, L, Westman, E., Ziegler, G.C., Zink, M., Andreassen, O.A., Westlye, L.T., Kaufmann, T., Elvsåshagen, T., Bahrami, S., Meer, D. van der, Agartz, I., Alnæs, D., Barch, D.M., Baur-Streubel, R., Bertolino, A., Beyer, M.K., Blasi, G., Borgwardt, S., Boye, B., Buitelaar, J.K., Bøen, E., Celius, E.G., Cervenka, S., Conzelmann, A., Coynel, D., Carlo, P. di, Djurovic, S., Eisenacher, S., Espeseth, T., Fatouros-Bergman, H., Flyckt, L., Franke, B., Frei, O., Gelao, B., Harbo, H.F., Hartman, Catharina A., Håberg, A., Heslenfeld, D., Hoekstra, P.J., Høgestøl, E.A., Jonassen, R., Jönsson, E.G., Kirsch, P., Kłoszewska, I., Lagerberg, T.V., Landrø, N.I., Hellard, S. Le, Lesch, K.P., Maglanoc, L.A., Malt, U.F., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Moberget, T., Nordvik, J.E., Nyberg, L., Connell, K.S.O., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pauli, P., Pergola, G., Persson, K., Quervain, D. de, Reif, A., Rokicki, J., Rooij, D. van, Shadrin, A.A., Schmidt, A., Schwarz, E., Selbæk, G., Soininen, H., Sowa, P., Steen, V.M., Tsolaki, M., Vellas, B., Wang, L, Westman, E., Ziegler, G.C., Zink, M., Andreassen, O.A., Westlye, L.T., and Kaufmann, T.

Abstract

Contains fulltext : 225402.pdf (publisher's version ) (Open Access), Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

Published
2020

5. Common brain disorders are associated with heritable patterns of apparent aging of the brain

Author

Kaufmann, T., Meer, D. van der, Doan, N.T., Schwarz, E., Lund, M.J., Agartz, I., Alnaes, D., Barch, D.M., Baur-Streubel, R., Bertolino, A., Bettella, F., Beyer, M.K., Boen, E., Borgwardt, S., Brandt, C.L., Buitelaar, J.K., Celius, E.G., Cervenka, S., Conzelmann, A., Cordova-Palomera, A., Dale, A.M., de Quervain, D.J.F., Carlo, P. di, Djurovic, S., Dorum, E.S., Eisenacher, S., Elvsashagen, T., Espeseth, T., Fatouros-Bergman, H., Flyckt, L., Franke, B., Frei, O., Haatveit, B., Haberg, A.K., Harbo, H.F., Hartman, C.A, Heslenfeld, D., Hoekstra, P.J., Hogestol, E.A., Jernigan, T.L., Jonassen, R., Jonsson, E.G., Kirsch, P., Kloszewska, I., Kolskar, K.K., Landro, N.I., Hellard, S. Le, Lesch, K.P., Lovestone, S., Lundervold, A., Lundervold, A.J., Maglanoc, L.A., Malt, U.F., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Moberget, T., Norbom, L.B., Nordvik, J.E., Nyberg, L., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pauli, P., Pergola, G., Persson, K., Richard, G., Rokicki, J., Sanders, A.M., Selbaek, G., Shadrin, A.A., Smeland, O.B., Soininen, H., Sowa, P., Steen, V.M., Tsolaki, M., Ulrichsen, K.M., Vellas, B., Wang, L, Westman, E., Ziegler, G.C., Zink, M., Andreassen, O.A., Westlye, L.T., Kaufmann, T., Meer, D. van der, Doan, N.T., Schwarz, E., Lund, M.J., Agartz, I., Alnaes, D., Barch, D.M., Baur-Streubel, R., Bertolino, A., Bettella, F., Beyer, M.K., Boen, E., Borgwardt, S., Brandt, C.L., Buitelaar, J.K., Celius, E.G., Cervenka, S., Conzelmann, A., Cordova-Palomera, A., Dale, A.M., de Quervain, D.J.F., Carlo, P. di, Djurovic, S., Dorum, E.S., Eisenacher, S., Elvsashagen, T., Espeseth, T., Fatouros-Bergman, H., Flyckt, L., Franke, B., Frei, O., Haatveit, B., Haberg, A.K., Harbo, H.F., Hartman, C.A, Heslenfeld, D., Hoekstra, P.J., Hogestol, E.A., Jernigan, T.L., Jonassen, R., Jonsson, E.G., Kirsch, P., Kloszewska, I., Kolskar, K.K., Landro, N.I., Hellard, S. Le, Lesch, K.P., Lovestone, S., Lundervold, A., Lundervold, A.J., Maglanoc, L.A., Malt, U.F., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Moberget, T., Norbom, L.B., Nordvik, J.E., Nyberg, L., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pauli, P., Pergola, G., Persson, K., Richard, G., Rokicki, J., Sanders, A.M., Selbaek, G., Shadrin, A.A., Smeland, O.B., Soininen, H., Sowa, P., Steen, V.M., Tsolaki, M., Ulrichsen, K.M., Vellas, B., Wang, L, Westman, E., Ziegler, G.C., Zink, M., Andreassen, O.A., and Westlye, L.T.

Abstract

Contains fulltext : 208604.pdf (publisher's version ) (Closed access), Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

Published
2019

6. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (Nature Communications, (2019), 10, 1, (2236), 10.1038/s41467-019-09773-y)

Author

Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), Baranzini, S.E. (Sergio), Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), and Baranzini, S.E. (Sergio)

Abstract

The original version of this Article contained an error in the spelling of the author Nikolaos A. Patsopoulos, which was incorrectly given as Niklaos A. Patsopoulos, and author Efthimios Dardiotis, which was incorrectly given as Dardiotis Efthimios. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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8. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Author

Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., Harbo, H.F., Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., and Harbo, H.F.

Abstract

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender

Published
2015

9. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke and dementias

Author

Burgunder, J.-M., Finsterer, J., Szolnoki, Z., Fontaine, B., Baets, Jonathan, Van Broeckhoven, Christine, Donato, S., De Jonghe, Peter, Lynch, T., Mariotti, C., Schöls, L., Spinazzola, A., Tabrizi, S.J., Tallaksen, C., Zeviani, M., Harbo, H.F., and Gasser, T.

Subjects
Human medicine
Abstract

Objectives: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. Results: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimers disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. Conclusion: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.

Published
2010

10. EFNS guidelines on the molecular diagnosis of mitochondrial disorders

Author

Finsterer, J., Harbo, H.F., Baets, Jonathan, Van Broeckhoven, Christine, Di Donato, S., Fontaine, B., De Jonghe, Peter, Lossos, A., Lynch, T., Mariotti, C., Schöls, L., Spinazzola, A., Szolnoki, Z., Tabrizi, S.J., Tallaksen, C.M.E., Zeviani, M., Burgunder, J.-M., and Gasser, T.

Subjects
Encephalomyopathies, Hereditary disease, Metabolic myopathies, Mitochondrial myopathy, Molecular genetics, Humans, Mitochondrial Diseases, Molecular Biology, Human medicine
Abstract

Objectives: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. Background: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. Search strategy: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. Results: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. Recommendations: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

Published
2009

11. EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias

Author

Harbo, H.F., Finsterer, J., Baets, Jonathan, Van Broeckhoven, Christine, di Donato, S., De Jonghe, Peter, Lossos, A., Lynch, T., Mariotti, C., Schoels, L., Spinazzola, A., Szolnoki, Z., Tabrizi, S.J., Tallaksen, C., Zeviani, M., Burgunder, J.-M., and Gasser, T.

Subjects
Human medicine
Abstract

Background and purpose: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. Methods: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. Results and conclusion: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Published
2009

12. 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

13. Molecular diagnosis of neurogenetic disorders : motoneuron, peripheral nerve and muscle disorders

Author

Burgunder, J-M., Schöls, L., Baets, J., Andersen, Peter M., Gasser, T., Szolnoki, Z., Fontaine, B., Van Broeckhoven, C., Di Donato, S., De Jonghe, P., Lynch, T., Mariotti, C., Spinazzola, A., Tabrizi, S.J., Tallaksen, C., Zeviani, M., Harbo, H.F., Finsterer, J., Burgunder, J-M., Schöls, L., Baets, J., Andersen, Peter M., Gasser, T., Szolnoki, Z., Fontaine, B., Van Broeckhoven, C., Di Donato, S., De Jonghe, P., Lynch, T., Mariotti, C., Spinazzola, A., Tabrizi, S.J., Tallaksen, C., Zeviani, M., Harbo, H.F., and Finsterer, J.

Abstract

Objectives: The EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about the planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. Results: The best level of evidence for genetic testing recommendation (Level B) can be found for the disorders with specific presentations, including familial ALS, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders a precise description of the phenotype, including the use of immunological methods in the case of myopathies, is considered good clinical practice to guide molecular genetic testing. Conclusion: These guidelines are provisional and the availability of molecular-genetic epidemiological data in the future about the neurogenetic disorders under discussion in the present paper will allow improved recommendation with an increased level of evidence.

Published
2012
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14. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., Compston, A., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., and Compston, A.

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 disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 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 susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

15. MYO9B polymorphisms in multiple sclerosis

Author

Kemppinen, A., Suvela, M., Tienari, P.J., Elovaara, I., Koivisto, K., Pirttila, T., Reunanen, M., Rautakorpi, I., Hillert, J., Lundmark, F., Oturai, A., Ryder, L., Harbo, H.F., Celius, E.G., Palotie, A., Daly, M., Peltonen, L., Saarela, J., Kemppinen, A., Suvela, M., Tienari, P.J., Elovaara, I., Koivisto, K., Pirttila, T., Reunanen, M., Rautakorpi, I., Hillert, J., Lundmark, F., Oturai, A., Ryder, L., Harbo, H.F., Celius, E.G., Palotie, A., Daly, M., Peltonen, L., and Saarela, J.

Abstract

Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS Udgivelsesdato: 2009/6

Published
2009

16. The SH2D2A gene and susceptibility to multiple sclerosis

Author

Lorentzen, A.R., Smestad, C., Lie, B.A., Oturai, Annette Bang, Akesson, E., Saarela, J., Myhr, K.M., Vartdal, F., Celius, E.G., Sørensen, Per Soelberg, Hillert, J., Spurkland, A., Harbo, H.F., Lorentzen, A.R., Smestad, C., Lie, B.A., Oturai, Annette Bang, Akesson, E., Saarela, J., Myhr, K.M., Vartdal, F., Celius, E.G., Sørensen, Per Soelberg, Hillert, J., Spurkland, A., and Harbo, H.F.

Abstract

We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid position 52 in TSAd. The GA(16)-rs926103()A haplotype was associated with MS in Norwegians (OR 1.4, P=0.04). A similar trend was observed among Danes. In the independent Norwegian, Danish and Swedish sample sets the GA(16) allele showed a combined OR of 1.13, P=0.05. Thus, the present study shows that the SH2D2A gene may contribute to susceptibility to MS Udgivelsesdato: 2008/7/15

Published
2008

17. A follow-up study of Nordic multiple sclerosis candidate gene regions

Author

Datta, P., primary, Harbo, H.F., additional, Ryder, L.P., additional, Akesson, E., additional, Benedikz, J., additional, Celius, E.G., additional, Andersen, O., additional, Myhr, K.-M., additional, Sandberg-Wollheim, M., additional, Hillert, J., additional, Svejgaard, A., additional, Sorensen, P.S., additional, Spurkland, A., additional, and Oturai, A., additional

Published
2007
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18. Genes in the HLA class I region may contribute to the HLA class II‐associated genetic susceptibility to multiple sclerosis

Author

Harbo, H.F., primary, Lie, B.A., additional, Sawcer, S., additional, Celius, E.G., additional, Dai, K.‐Z., additional, Oturai, A., additional, Hillert, J., additional, Lorentzen, Å.R., additional, Laaksonen, M., additional, Myhr, K.‐M., additional, Ryder, L.P., additional, Fredrikson, S., additional, Nyland, H., additional, Sørensen, P.S., additional, Sandberg‐Wollheim, M., additional, Andersen, O., additional, Svejgaard, A., additional, Edland, A., additional, Mellgren, S.I., additional, Compston, A., additional, Vartdal, F., additional, and Spurkland, A., additional

Published
2004
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19. A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis.

Author

Akesson, E., Oturai, A., Berg, J., Fredrikson, S., Andersen, O., Harbo, H.F., Laaksonen, M., Myhr, K.M., Nyland, H.I., Ryder, L.P., Sandberg-Wollheim, N., Sorensen, P.S., Spurkland, A., Svejgaard, A., Holmans, P., Compston, A., Hillert, J., and Sawcer, S.

Subjects
GENETICS of multiple sclerosis, MEDICAL genetics
Abstract

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified—1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p1213, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis. [ABSTRACT FROM AUTHOR]

Published
2002
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20. Analysis of an interferon-γ gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients.

Author

Dai, Y., Masterman, T., Huang, W.X., Sandberg-Wollheim, M., Laaksonen, M., Harbo, H.F., Oturai, A., Ryder, L.P., Soelberg-Sørensen, P., Svejgaard, A., and Hillert, J.

Subjects
CYTOKINES, MULTIPLE sclerosis, MESSENGER RNA
Abstract

The proinflammatory cytokine interferon (IFN)-γ has been shown to influence the course of multiple sclerosis (MS). The IFN-γ (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-γ mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octile. Comparison of IFN-γ mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-γ mRNA expression in vivo. [ABSTRACT FROM AUTHOR]

Published
2001
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