A Haplotype Map for Multiple Sclerosis

Summary

Principal Investigator: Stephen L Hauser
Affiliation: University of California
Country: USA
Abstract: DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common and severe disorder of the central nervous system characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal and oligodendrocyte pathology, and progressive neurological dysfunction. MS pathogenesis includes a complex genetic component. In spite of intensive long-standing efforts, the knowledge of MS genetics remains incomplete. Our overall objective is to characterize the repertoire of genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of rapid progress in defining the landscape of genetic organization and cataloging variation across the human genome. This proposal builds on the availability of second generation, high-quality genome-wide association results and comprehensive phenotypic data in a large MS cohort. We propose four main research goals: In Specific Aim 1 high-coverage genome-wide genetic data from a total of approximately 17,000 subjects affected with MS will be pooled and analyzed using a multi-stage and multi- analytical approach to map unambiguous association signals from sequence (SNPs) and copy number (CNVs) polymorphisms and identify novel disease candidate genes, leading to robust and testable hypotheses as to which are the specific common allelic variants conferring susceptibility. Using the meta-analysis-derived genotypes, together with open databases and novel algorithms, we will develop a composite global map of the effects of epistatic interactions and biochemical networks of genomic variation underlying MS pathogenesis. Specific Aim 2 takes advantage of the wealth of phenotypic data available for the different datasets to assess disease course variables and correlations to genotype. Important clinical metrics such as age and site of disease onset, disability at entry of study and progression, and changes in lesion distribution and burden will be incorporated into the analysis of genetic data. This aim directly addresses the question of clinical heterogeneity in MS and the correlation between different phenotypes and genotypes. In Specific Aim 3 we intend to generate high-coverage sequence information for the regulatory regions, exons and flanking regions of genes with unequivocal evidence of association for the discovery of rare variants associated with MS. To efficiently resequence DNA in a large dataset (3,000 patients / 3,000 controls), we will create 120 pools of 50 DNA samples each. Approximately 1,000 low-frequency variants will be genotyped in a validation cohort consisting of 10,000 MS subjects and 10,000 control subjects. As technologies advance and costs retreat, whole exome re-sequencing will be pursued in the second half of the funding cycle. Finally, in Specific Aim 4 we will integrated all the generated data and build an array, the "MS Fine-Mapping Gene-chip," consisting of a comprehensive compendium of common and rare variants covering and flanking confirmed associations with susceptibility and disease expression. All relevant variants will be tested in an independent dataset (10,000 cases / 10,000 controls) for association individually and by combining multiple alleles within a single gene and across multiple genes to assess of causative cumulative effects. From this dataset, we expect to generate a minimal set of DNA variants that individually or in combination can aid in prediction of disease risk and/or progression. The availability of a large and well-characterized cohort as described here, coupled with the aid of high-powered laboratory technologies, provides an outstanding opportunity to identify and characterize MS-related genes. This information may translate into clinically useful genetic biomarkers and reveal novel targets for therapy. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Multiple sclerosis (MS) is a common cause of severe neurological disability resulting from the interruption of myelinated tracts in the central nervous system. MS is second only to trauma as a cause of neurologic disability in young adults, affecting approximately 2 million people worldwide and more than 400,000 individuals in the US. Remarkably, the incidence of MS seems to have increased considerably over the last century, and this increase may have occurred primarily in women. The socioeconomic consequences of this long-lasting disease are staggering as 75- 85% of patients are eventually unemployed and at high risk for social isolation. Conservative estimates indicate that this chronic illness results in healthcare costs exceeding $200 billion annually in the United States alone. Thus, MS is the second most costly neurological disorder after Alzheimer's disease. Despite important advances in therapeutics, none of the currently available disease-modifying drugs convincingly alter the long-term prognosis of the disease. Clinical manifestations are extremely diverse, but very little is known about the underlying cause of this variability. It can vary from a benign illness to a rapidly evolving and incapacitating disease. Onset may be abrupt or insidious, and early symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Most patients ultimately experience progressive disability and twenty-five years after onset approximately 80% of affected individuals will require assistance with ambulation. Thus over the long-term, MS is most often a severe disease requiring profound lifestyle adjustments to the affected and their families. We aim to identify the genes and the gene-specific variants that code for products involved in MS susceptibility. We anticipate that there may be several genes involved in MS risk. These genes may work independently or together, and affect susceptibility in concert with environmental factors. Particular combinations of inherited genetic variants may also determine when symptoms develop, or how the disease progresses. Their identification will help to define the basic etiology of MS, improve risk assessment, and influence therapeutics.
Funding Period: ----------------2004 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis
    An Goris
    Laboratory for Neuroimmunology, Experimental Neurology, KU Leuven, Leuven, Belgium
    Hum Mol Genet 23:1916-22. 2014
  2. pmc Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
    Ashley H Beecham
    1 John P Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA 2
    Nat Genet 45:1353-60. 2013
  3. pmc Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity
    Ulf Schulze-Topphoff
    Department of Neurology, University of California, San Francisco, CA 94143, USA
    J Exp Med 210:1301-9. 2013
  4. pmc Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles
    Inger Lise Mero
    Department of Neurology, Oslo University Hospital, Ulleval, and Department of Medical Genetics, University of Oslo, Oslo, Norway
    PLoS ONE 8:e58352. 2013
  5. pmc B cell exchange across the blood-brain barrier in multiple sclerosis
    H Christian von Büdingen
    Department of Neurology, UCSF, San Francisco, California 94158, USA
    J Clin Invest 122:4533-43. 2012
  6. pmc Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects
    Nikolaos A Patsopoulos
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women s Hospital, Boston, Massachusetts, United States of America Division of Genetics, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America Harvard Medical School, Boston, Massachusetts, United States of America Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS Genet 9:e1003926. 2013
  7. pmc Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis
    Dorothea Buck
    Department of Neurology, Technische Universitat Munchen, Munich, Germany
    Ann Neurol 73:86-94. 2013
  8. ncbi Risk alleles for multiple sclerosis identified by a genomewide study
    David A Hafler
    Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, and Harvard Medical School, Boston, USA
    N Engl J Med 357:851-62. 2007
  9. ncbi APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers
    R M Burwick
    Division of Epidemiology, University of California, School of Public Health, Berkeley, CA 94720, USA
    Neurology 66:1373-83. 2006
  10. ncbi Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis
    S Schmidt
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    Genes Immun 7:384-92. 2006

Scientific Experts

  • Philip L De Jager
  • Benjamin A Goldstein
  • Pierre Antoine Gourraud
  • Laura Bergamaschi
  • Lisa M Maier
  • E M Mowry
  • William S Bush
  • Stephen Sawcer
  • Sergio E Baranzini
  • Rebecca L Zuvich
  • Bruce C Cree
  • Jorge R Oksenberg
  • Stephen L Hauser
  • Alastair Compston
  • Maria Ban
  • An Goris
  • Lisa F Barcellos
  • Adrian J Ivinson
  • Jacob L McCauley
  • Margaret A Pericak-Vance
  • David A Hafler
  • Jonathan L Haines
  • Benedicte Dubois
  • John D Rioux
  • Nikolaos A Patsopoulos
  • S L Hauser
  • J R Oksenberg
  • Dorothea Buck
  • Inger Lise Mero
  • Tomas Olsson
  • Simon G Gregory
  • Hanne F Harbo
  • Elisabeth G Celius
  • Paul I W de Bakker
  • Stacy J Caillier
  • L F Barcellos
  • A Compston
  • M A Pericak-Vance
  • Amie Walton
  • S Schmidt
  • Wim Robberecht
  • Verena Grummel
  • Achim Berthele
  • Finn Sellebjerg
  • Jan Hillert
  • Bernhard Hemmer
  • Benedicte A Lie
  • Lars Alfredsson
  • Kjell Morten Myhr
  • Ingrid Kockum
  • Angela Jochim
  • Ashley H Beecham
  • Juliane Winkelmann
  • Christian Gieger
  • Catherine Schaefer
  • Ulf Schulze-Topphoff
  • H Christian von Büdingen
  • Amie Baker
  • Panos Deloukas
  • Peter Donnelly
  • Neil P Robertson
  • Sarah E Hunt
  • Anne Spurkland
  • David Hafler
  • Clive Hawkins
  • Farren B S Briggs
  • M Ban
  • Paola G Bronson
  • D T Okuda
  • Mark J Daly
  • Tai Wai Yeo
  • Eric S Lander
  • J L Haines
  • R M Burwick
  • Bryan J Traynor
  • Frank Diekstra
  • Adriano Chio
  • Leonard H van den Berg
  • Robert H Brown
  • Aleksey Shatunov
  • Jan H Veldink
  • Christopher E Shaw
  • Judith Melki
  • Orla Hardiman
  • John E Landers
  • Gabriele Mora
  • Michael van Es
  • Peter M Andersen
  • Nigel Leigh
  • Jessica van Setten

Detail Information

Publications44

  1. pmc No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis
    An Goris
    Laboratory for Neuroimmunology, Experimental Neurology, KU Leuven, Leuven, Belgium
    Hum Mol Genet 23:1916-22. 2014
    ..Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS. ..
  2. pmc Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
    Ashley H Beecham
    1 John P Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA 2
    Nat Genet 45:1353-60. 2013
    ..This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals...
  3. pmc Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity
    Ulf Schulze-Topphoff
    Department of Neurology, University of California, San Francisco, CA 94143, USA
    J Exp Med 210:1301-9. 2013
    ..Collectively, our results reveal a critical role for Tob1 in adaptive T cell immune responses that drive development of EAE, thus providing support for the development of Tob1 as a biomarker for demyelinating disease activity...
  4. pmc Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles
    Inger Lise Mero
    Department of Neurology, Oslo University Hospital, Ulleval, and Department of Medical Genetics, University of Oslo, Oslo, Norway
    PLoS ONE 8:e58352. 2013
    ..This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied...
  5. pmc B cell exchange across the blood-brain barrier in multiple sclerosis
    H Christian von Büdingen
    Department of Neurology, UCSF, San Francisco, California 94158, USA
    J Clin Invest 122:4533-43. 2012
    ..These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states...
  6. pmc Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects
    Nikolaos A Patsopoulos
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women s Hospital, Boston, Massachusetts, United States of America Division of Genetics, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America Harvard Medical School, Boston, Massachusetts, United States of America Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS Genet 9:e1003926. 2013
    ..This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles. ..
  7. pmc Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis
    Dorothea Buck
    Department of Neurology, Technische Universitat Munchen, Munich, Germany
    Ann Neurol 73:86-94. 2013
    ..The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS...
  8. ncbi Risk alleles for multiple sclerosis identified by a genomewide study
    David A Hafler
    Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, and Harvard Medical School, Boston, USA
    N Engl J Med 357:851-62. 2007
    ..Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis...
  9. ncbi APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers
    R M Burwick
    Division of Epidemiology, University of California, School of Public Health, Berkeley, CA 94720, USA
    Neurology 66:1373-83. 2006
    ..The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism...
  10. ncbi Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis
    S Schmidt
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    Genes Immun 7:384-92. 2006
    ....
  11. pmc A second major histocompatibility complex susceptibility locus for multiple sclerosis
    Tai Wai Yeo
    Department of Clinical Neurosciences, University of Cambridge, Addenbrooke s Hospital, Cambridge, United Kingdom
    Ann Neurol 61:228-36. 2007
    ..The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed...
  12. ncbi Polymorphisms in the neuromyelitis optica auto-antigen AQP4 and susceptibility to multiple sclerosis
    Maria Ban
    J Neurol 254:398-9. 2007
  13. ncbi Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis
    Simon G Gregory
    Center for Human Genetics, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nat Genet 39:1083-91. 2007
    ..The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer...
  14. pmc Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility
    Maria Ban
    Department of Clinical Neurosciences, University of Cambridge, Addenbrooke s Hospital, Cambridge, United Kingdom
    PLoS ONE 3:e2891. 2008
    ..These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis...
  15. pmc Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals
    Farren B S Briggs
    Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, CA 94720 7356, USA
    Hum Mol Genet 19:4286-95. 2010
    ..74-0.90, P = 9.7 × 10(-5)). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted...
  16. pmc A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01
    Bruce A C Cree
    Department of Neurology, University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 5:e11296. 2010
    ..Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial...
  17. pmc Revealing the genetic basis of multiple sclerosis: are we there yet?
    Sergio E Baranzini
    Department of Neurology, School of Medicine, University of California San Francisco, 513 Parnassus Ave, Room S 256, San Francisco, CA 94143 0435, United States
    Curr Opin Genet Dev 21:317-24. 2011
    ....
  18. pmc A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility
    W S Bush
    Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232 0700, USA
    Genes Immun 12:335-40. 2011
    ..Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS...
  19. pmc Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex
    Rebecca L Zuvich
    Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232 0700, USA
    Hum Mol Genet 20:3517-24. 2011
    ..These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS...
  20. pmc Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come
    William S Bush
    Vanderbilt University, USA
    Am J Hum Genet 86:621-5. 2010
    ....
  21. pmc A non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis
    M Ban
    Department of Clinical Neuroscience, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Genes Immun 11:660-4. 2010
    ..A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻⁶) in MS susceptibility...
  22. pmc Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures
    D T Okuda
    UCSF Multiple Sclerosis Center, University of California, San Francisco, San Francisco, California 94117, USA
    Brain 132:250-9. 2009
    ....
  23. pmc IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production
    Lisa M Maier
    Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS Genet 5:e1000322. 2009
    ..We demonstrate that multiple variants independently correlate with sIL-2RA levels...
  24. pmc Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses
    Lisa M Maier
    Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Immunol 182:1541-7. 2009
    ..In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS...
  25. pmc The role of the CD58 locus in multiple sclerosis
    Philip L De Jager
    Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 106:5264-9. 2009
    ....
  26. pmc Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor
    Maria Ban
    Department of Clinical Neuroscience, Addenbrooke s, Hospital, University of Cambridge, Cambridge, UK
    Eur J Hum Genet 17:1309-13. 2009
    ....
  27. pmc Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures
    E M Mowry
    Department of Neurology, University of California, San Francisco, 94117, USA
    Neurology 72:1760-5. 2009
    ..Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy...
  28. pmc Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
    Philip L De Jager
    Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA, USA
    Nat Genet 41:776-82. 2009
    ....
  29. pmc Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility
    Rebecca L Zuvich
    Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232 0700, USA
    Hum Genet 127:525-35. 2010
    ..2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease...
  30. pmc No evidence of association of the rare nsSNP rs35667974 in IFIH1 with multiple sclerosis
    Laura Bergamaschi
    Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy
    J Neuroimmunol 221:112-4. 2010
    ..This study has 99% power to demonstrate an association at the 5% level with this rare variant. Our analysis shows that the nsSNP rs35667974/Ile923Val does not have a role in susceptibility to MS...
  31. pmc Bayes factors in complex genetics
    Stephen Sawcer
    Department of Clinical Neuroscience, University of Cambridge, Addenbrooke s, Cambridge, UK
    Eur J Hum Genet 18:746-50. 2010
    ..In this review, the basic foundations of association testing are explained from a Bayesian perspective and the potential benefits of Bayes factors as a means of measuring the weight of evidence in support of an association are described...
  32. pmc What role for genetics in the prediction of multiple sclerosis?
    Stephen Sawcer
    Department of Clinical Neurosciences, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Ann Neurol 67:3-10. 2010
    ..There is an inevitable feeling that the same should be true in complex disease, but is it?..
  33. pmc CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis
    Paola G Bronson
    Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720 7356, USA
    Hum Mol Genet 19:2331-40. 2010
    ..15-1.95, P = 2.3 x 10(-3)) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501...
  34. pmc An application of Random Forests to a genome-wide association dataset: methodological considerations & new findings
    Benjamin A Goldstein
    Division of Biostatistics, School of Public Health, University of California, Berkeley, CA, USA
    BMC Genet 11:49. 2010
    ..One such approach is the Random Forests (RF) algorithm. The use of RF for SNP discovery related to human disease has grown in recent years; however, most work has focused on small datasets or simulation studies which are limited...
  35. pmc When is the absence of evidence, evidence of absence? Use of equivalence-based analyses in genetic epidemiology and a conclusion for the KIF1B rs10492972*C allelic association in multiple sclerosis
    Pierre Antoine Gourraud
    Department of Neurology, School of Medicine, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0435, USA
    Genet Epidemiol 35:568-71. 2011
    ..The data gathered for KIF1B in MS also underscore the need for very large sample sizes with the appropriate equivalence statistical methods in order to exclude reported false-positive results...