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Nikolaos A Patsopoulos,
Federica Esposito,
Joachim Reischl,
Stephan Lehr,
David Bauer,
Jürgen Heubach,
Rupert Sandbrink,
Christoph Pohl,
Gilles Edan,
Ludwig Kappos, [......],
Jonathan Haines,
Stephen L Hauser,
Jacob McCauley,
Adrian Ivinson,
Jorge R Oksenberg,
Margaret Pericak-Vance,
Stephen J Sawcer,
Philip L De Jager,
David A Hafler,
Paul I W de Bakker
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ABSTRACT: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.
We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease.
We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1).
We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
Annals of Neurology 12/2011; 70(6):897-912. · 11.09 Impact Factor
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Current Neurology and Neuroscience Reports 08/2011; 11(6):526-8. · 3.45 Impact Factor
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Stephen Sawcer,
Garrett Hellenthal,
Matti Pirinen,
Chris C A Spencer,
Nikolaos A Patsopoulos,
Loukas Moutsianas,
Alexander Dilthey,
Zhan Su,
Colin Freeman,
Sarah E Hunt, [......],
Jan Hillert,
Adrian J Ivinson,
Philip L De Jager,
Leena Peltonen,
Graeme J Stewart,
David A Hafler,
Stephen L Hauser,
Gil McVean,
Peter Donnelly,
Alastair Compston
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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.
Nature 08/2011; 476(7359):214-9. · 36.28 Impact Factor
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ABSTRACT: To determine the frequency of hypothalamic lesions in patients with multiple sclerosis (MS) using conventional MRI (cMRI) protocols.
Brain cMRI (1.5 Tesla) scans of 105 Caucasian patients with classical MS (50 with stable and 55 with more active disease) and 12 patients with longitudinal extensive myelopathy (LEM) were reviewed retrospectively. NMO-IgG antibody was assayed in patients with hypothalamic lesions.
Hypothalamic lesions were found in 13.3% of MS patients and in none of the LEM patients. A higher frequency of hypothalamic lesions was found in patients with active MS (18.2%) than in the stable group (8.0%), but this did not reach statistical significance (p=0.13). Patients with hypothalamic lesions also had more lesions in other cerebral structures. None of the LEM patients had hypothalamic lesions. No patients with hypothalamic lesions were positive for NMO-IgG.
Hypothalamic lesions in MS are more frequent than previously reported and are not associated with NMO-IgG antibody.
Journal of neurology, neurosurgery, and psychiatry 07/2011; 82(7):819-22. · 4.87 Impact Factor
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ABSTRACT: The association of human leukocyte antigen (HLA) genes and multiple sclerosis (MS) has been extensively investigated in Caucasians, but less so in Oriental races such as Chinese.
To review studies on association of HLA class II alleles with MS in the Chinese population.
An extensive search for published studies up to June 2010 was performed in the electronic databases. The meta-analysis facilities in the NCSS statistical package were utilized to analyze the findings in these studies. The odds ratios (ORs) of HLA-DR allele distributions in MS were analyzed against controls.
Eleven case-control studies were identified: nine genotyping and two serotyping studies. Six genotyping studies were suitable for HLA-DRB1 allele meta-analysis, which showed that HLA-DRB1*15 was associated with risk of MS in the combined group (308 cases and 407 controls; OR 1.39) while the HLA-DRB1*09 and HLA-DRB1*0901 alleles were protective. When the equivalent serotypes in these six studies were combined with the results from the two serotyping studies (431 cases and 652 controls) for a meta-analysis of HLA-DR serotypes, HLA-DR2 was a risk factor (OR 1.63) and HLA-DR9 was strongly protective in the combined group (OR 0.64).
Although limited data are available, our meta-analysis suggests that HLA-DR2/DRB1*15 are also associated with risk of MS in the Chinese population but less strongly so than in Western MS populations, whereas HLA-DR9 alleles appear to confer resistance in this population.
Multiple Sclerosis 12/2010; 17(4):382-8. · 4.26 Impact Factor
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ABSTRACT: There have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles.
To investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype.
Two hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping. The numbers, locations, shape and segmental extent of cord lesions were analysed and were correlated with carriage of individual HLA-DRB1 alleles and diplotypes.
Focal cord lesions were present in 82.9% of cases, with numbers being maximal in the cervical cord and increasing with disease duration. Focal lesions were usually round or oval in shape but in 35% of cases subpial wedge-shaped lesions were present. Diffuse cord involvement was present in 10% of cases and correlated with carriage of HLA-DRB1*1501 and with higher disability. Carriage of the minor allele HLA-DRB1*0701 was significantly associated with numbers of wedge-shaped lesions and lesions in the cervical cord, while HLA-DRB1*1104 and DRB1*0103 were significantly associated respectively with higher and lower numbers of thoracic cord lesions. HLA-DRB1*1501 and the HLA-DRB1*11 sub-alleles DRB1*1101 and DRB1*1104 were significantly associated with the segmental length of cord lesions.
Our study is the first to investigate the frequency of subpial wedge-shaped lesions in the cord in vivo and has provided preliminary evidence that HLA-DRB1 alleles may play a role in determining the severity and extent of spinal cord involvement in MS.
Journal of the neurological sciences 09/2010; 300(1-2):114-9. · 2.32 Impact Factor
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ABSTRACT: We aimed to characterize the clinical profile and human leukocyte antigen (HLA)-DRB1 genotype of patients with late onset multiple sclerosis (LOMS) in Western Australia. The clinical features, laboratory studies and HLA-DRB1 alleles were analysed in patients with multiple sclerosis (MS) with onset over 50years of age and compared with 100 patients with early onset MS (EOMS). Of a cohort of 829 patients with MS, 73 (8.8%) presented at over 50years of age, including 14 (1.7%) over 60years. Patients with LOMS had a lower female to male ratio, more frequent initial motor dysfunction, less frequent sensory symptoms and optic neuritis, a more frequent primary-progressive course and shorter time to reach Extended Disability Status Scale (EDSS) scores of 3.0 and 6.0. More LOMS patients were initially misdiagnosed compared to patients with EOMS. HLA-DRB1 *1501 was strongly associated with both LOMS and EOMS compared to the Control subjects, while HLA-DRB1 *0801 was over-represented in patients with LOMS. We concluded that patients with LOMS have a different clinical profile when compared to those with EOMS. Carriers of HLA-DRB1 *0801 may be more prone to develop MS at a later age.
Journal of Clinical Neuroscience 08/2010; 17(8):1009-13. · 1.25 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a heterogeneous disease with variable clinical features and magnetic resonance imaging (MRI) findings. We report four MS cases with unusual wedge-shaped lesions in the paramedian ventral medulla oblongata demonstrated on MRI. The clinical features and MRI characteristics of the medullary lesions suggest an impairment of venous drainage. We propose that the formation of these wedge-shaped lesions may be related to the pattern of venous drainage in the ventral medulla and raised venous pressure due to chronic cerebrospinal venous insufficiency which has recently been described in MS.
Journal of the neurological sciences 03/2010; 290(1-2):190-3. · 2.32 Impact Factor
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ABSTRACT: Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method.
To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping.
Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study.
In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS.
Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles.
Multiple Sclerosis 03/2010; 16(5):526-32. · 4.26 Impact Factor
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ABSTRACT: Previous autoantibody (AAb) studies in multiple sclerosis MS have produced conflicting results. The objective of this study was to determine AAb frequency and association with the HLA-DRB1 genotype. Antinuclear antibody, antithyroid peroxidase and anti-aquaporin-4 assays and HLA-DRB1 genotyping were performed in 198 MS patients and 188 controls. There were no significant differences in AAb frequency or titres between MS and control subjects. AQP4-IgG was not found in any MS patients. There was no correlation between AAbs and HLA-DRB1 alleles. In conclusion, this study failed to confirm previous reports of increased AAbs in MS or to show an association between HLA-DRB1 genotype and the presence of AAbs.
Multiple Sclerosis 02/2010; 16(3):351-4. · 4.26 Impact Factor
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Journal of Clinical Neuroscience - J CLIN NEUROSCI. 01/2010; 17(12):1628-1628.
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ABSTRACT: The contribution of genetic factors to the age at onset in multiple sclerosis is poorly understood. Our objective was to investigate the disease modifying effects of HLA-DRB1 alleles and allele interactions on age at onset of multiple sclerosis. High-resolution four-digit HLA-DRB1 genotyping was performed in a cohort of 461 multiple sclerosis patients from the Perth Demyelinating Diseases Database. Carriage of the HLA-DRB1*1501 risk allele was not significantly associated with age at onset but HLA-DRB1*0801 was associated with a later onset of the disease. The HLA-DRB1*0401 allele was associated with a reduced age at onset when combined with DRB1*1501 but may delay age at onset when combined with DRB1*0801. These findings indicate that epistatic interactions at the HLA-DRB1 locus have significant modifying effects on age at onset of multiple sclerosis and demonstrate the value of high-resolution genotyping in detecting such associations.
Multiple Sclerosis 12/2009; 16(1):15-20. · 4.26 Impact Factor
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ABSTRACT: Susceptibility to multiple sclerosis (MS) has been consistently associated with the Human Leukocyte Antigen (HLA)-DRB11501 genotype, however effects on disease severity and clinical outcome have varied in different populations. We present the results of a high-resolution HLA-DRB1 genotyping and genotype-phenotype correlation study in a large West Australian MS cohort. Our findings indicate that in this population, which is of largely Anglo-Celtic and Northern European origin, HLA-DRB11501 is not only a strong determinant of disease risk but may also be associated with disease severity as measured by the Multiple Sclerosis Severity Score (MSSS), with the MSSS increasing by an estimated 0.51 per DRB11501 allele. We also found evidence that the HLA-DRB11201 allele is associated with less severe disease.
Journal of neuroimmunology 12/2009; 219(1-2):109-13. · 2.84 Impact Factor
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ABSTRACT: We describe a patient presenting with the rapid onset of incomplete Wallenberg syndrome (WS) as the initial clinical manifestation of multiple sclerosis (MS). This patient was initially diagnosed with acute ischaemic lateral medullary syndrome, but further assessment led to the diagnosis of definite MS. Our report aims to highlight the importance of awareness of MS as a cause of WS, as well as the potential misdiagnosis of MS as stroke.
Journal of Clinical Neuroscience 10/2009; 16(12):1700-2. · 1.25 Impact Factor
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ABSTRACT: High-resolution HLA-DRB1 genotyping was performed in 97 OCB-positive and 68 OCB-negative cases with demyelinating disease to determine the influence of HLA-DRB1 alleles on the presence of OCB in a West Australian multiple sclerosis (MS) cohort. Carriage of the HLA-DRB1*1501 allele was associated with both OCB-positive and OCB-negative MS compared with controls, but more strongly with the OCB-positive group, and increased the likelihood of having OCB 2.1-fold with evidence of a dominant dose-effect. The HLA-DRB1*0301 allele was negatively correlated with OCB, with all homozygotes OCB-negative, suggesting a possible recessive protective effect of HLA-DRB1*0301. There was no significant correlation between OCB and the DRB1*04 alleles which have been associated with OCB-negative MS in previous Swedish and Japanese studies. Evidence of allelic interactions was found with HLA-DRB1*1501/*1301 heterozygotes having a reduced frequency of OCB and HLA-DRB1*0301/*0401 heterozygotes all being OCB-negative. These findings confirm the strong association between HLA-DRB1*1501 and OCB which has been found in other populations but indicate that the influence of other HLA-DRB1 alleles varies in different populations. Our study is the first to show that HLA-DRB1 allele interactions and dose-effects influence the frequency of OCB.
Journal of the neurological sciences 10/2009; 288(1-2):63-7. · 2.32 Impact Factor
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ABSTRACT: To characterise West Australian cases of longitudinally extensive myelopathy (LEM).
Twenty six patients with LEM were identified from a cohort of 983 patients with demyelinating disease. Clinical and MRI data and AQP4-IgG results were reviewed.
LEM cases were classified as conventional MS (CMS) 13, neuromyelitis optica (NMO) 7, and isolated LEM 6. LEM was the initial presentation in 13/26 cases. In CMS cases lesions were mainly in the lower cervical cord (C4-C7) whereas in NMO and isolated LEM they were more often thoracic and were longer. The severity of disability was highly variable but was greater in the NMO than the CMS group. Only one of 20 patients tested was seropositive for AQP4-IgG.
LEM occurred as part of CMS or NMO or in isolation. Patients with LEM had highly heterogeneous clinical characteristics and a low rate of AQP4-IgG seropositivity.
Journal of neurology, neurosurgery, and psychiatry 09/2009; 81(2):209-12. · 4.87 Impact Factor
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Melanie Bahlo,
David R Booth,
Simon A Broadley,
Matthew A Brown,
Simon J Foote,
Lyn R Griffiths,
Trevour J. Kilpatrick,
Jeanette Lechner-Scott,
Pablo Moscato,
Victoria M Perreau, [......],
William M Carroll,
Caron Chapman, Allan G Kermode,
Mark Marriott,
Deborah Mason,
Robert N Heard,
Michael P. Pender,
Mark Slee,
Niall Tubridy,
Ernest Willoughby
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ABSTRACT: To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
Nature Genetics 08/2009; · 35.53 Impact Factor
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ABSTRACT: To determine the diagnoses in a population of patients with presumed optic neuritis (ON) in China and compare the spectrum of etiologies with those in western countries, we studied a group of 204 patients referred to a teaching hospital with a presumptive diagnosis of ON. We conducted detailed medical and family history, thorough ophthalmologic and neurological examinations, and laboratory tests including neuroimaging. Patients were diagnosed using international diagnostic criteria. One hundred and thirteen patients (55.4%) met ON criteria, among whom 83 patients (73.5%) were diagnosed with idiopathic demyelinating optic neuritis (IDON). Brain MRI white matter lesions were found in 11 of 78 (14.1%) clinically "isolated" IDON patients. Tuberculosis meningitis was found in 2 patients and syphilis in 1 patient. The cause of ON in 26 patients (23.0%) remained uncertain, but it was still likely to be IDON accompanied by secondary axonal degeneration. Leber's hereditary optic neuropathy (LHON) was found in 38 patients (18.6%), confirmed by mitochondrial DNA point mutation screening. Seventeen patients (8.3%) had ischemic optic neuropathy. A spectrum of other entities mimicked ON. Therefore, idiopathic demyelinating ON was the most common type of optic neuropathy in our group. Despite minor differences regarding the causes and prognosis, the etiology of ON in our population is similar to that reported in Western countries.
Journal of Clinical Neuroscience 01/2009; 15(12):1346-9. · 1.25 Impact Factor
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ABSTRACT: The diversity of multiple sclerosis (MS) and the nosology of the conventional form of MS (CMS), optic-spinal MS (OSMS) and neuromyelitis optica (NMO) have been subject to controversy.
The purpose of this study was to investigate whether the current Asian optic-spinal multiple sclerosis (OSMS) criteria could also apply in Western countries, and whether or not cerebrospinal fluid (CSF) and imaging features in the Western Australian patient population of demyelinating disease was similar to that found in Asia.
This study retrospectively reviewed 915 individual case notes with central nervous system demyelinating disease seen by two neurologists in Western Australia (WA). 842 cases had sufficient data to be included in the analysis. The patient population was predominantly Caucasian, representing approximately two-thirds of MS cases in WA. The mean duration of follow-up for the whole studied cohort was 12.5 years, with 136 patients (16.2%) being followed-up for more than 20 years.
The study confirmed the relatively low frequency of OSMS as a proportion of total demyelinating disease occurring in western countries, with 31 OSMS (3.7%) cases in contrast to 703 CMS cases (83.5%). It is likely, however, that our retrospective classification significantly underestimated the proportion of OSMS cases when compared with prospectively classified Asian cohorts. There were 11 OSMS cases that could also be classified as NMO according to published diagnostic criteria. The remainder of the spectrum comprised clinically isolated syndromes such as 50 acute myelitis (AM, 5.9%), 42 optic neuritis (ON, 5%) and 16 "atypical" cases such as tumefactive MS and acute disseminated encephalomyelitis (1.9%). The clinical characteristics of OSMS in our study were compatible with so-called Asian MS in many respects: oligoclonal bands (OCBs) were less frequent in OSMS (29.4%) than in CMS (66.4%, p = 0.003); visual evoked potentials and spinal MRI abnormalities were more prevalent in OSMS (85% and 92.6%) than in CMS (71.4% and 85%); as were long spinal cord lesions in OSMS (22.2%) versus CMS (3.4%, p,0.001). Brain abnormalities were seen in 48.4% of OSMS patients and 96.2% of CMS patients (p = 0.001). OCBs were identified in 7% of acute myelitis, 14.3% of optic neuritis and 73.4% of primary progressive MS patients.
This cross-sectional study presents the full spectrum of demyelinating disease in WA, which has a stable population representing 10% of the total Australian population and suggests that the current classifications of MS, OSMS or NMO, ON and AM share many clinical and laboratory features, such as female predominance, age at onset, duration of disease and CSF investigations (including OCBs and MRI). Moreover, characteristics of the WA population were similar to those reported in Asian patients.
Journal of neurology, neurosurgery, and psychiatry 03/2008; 79(9):1022-6. · 4.87 Impact Factor
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Journal of Clinical Neuroscience 01/2007; 13(10):1037-8. · 1.25 Impact Factor
