Original Investigation

Human Genetics

, Volume 127, Issue 5, pp 525-535

First online:

Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility

  • Rebecca L. ZuvichAffiliated withCenter for Human Genetics Research, Vanderbilt University Medical Center Email author 
  • , Jacob L. McCauleyAffiliated withJohn P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami
  • , Jorge R. OksenbergAffiliated withDepartment of Neurology, School of Medicine, University of CaliforniaInstitute for Human Genetics, School of Medicine, University of California
  • , Stephen J. SawcerAffiliated withDepartment of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge
  • , Philip L. De JagerAffiliated withProgram in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s HospitalProgram in Medical and Population Genetics, Broad Institute of Harvard UniversityHarvard Medical SchoolMassachusetts Institute of Technology
  • , International Multiple Sclerosis Genetics Consortium
  • , Cristin AubinAffiliated withProgram in Medical and Population Genetics, Broad Institute of Harvard UniversityMassachusetts Institute of Technology
  • , Anne H. CrossAffiliated withDepartment of Neurology, Washington University
  • , Laura PiccioAffiliated withDepartment of Neurology, Washington University
    • , Neelum T. AggarwalAffiliated withRush Alzheimer Disease Center, Department of Neurological Sciences, Rush UniversityRush Institute for Healthy Aging, Rush University
    • , Denis EvansAffiliated withRush Alzheimer Disease Center, Department of Neurological Sciences, Rush UniversityRush Institute for Healthy Aging, Rush University
    • , David A. HaflerAffiliated withProgram in Medical and Population Genetics, Broad Institute of Harvard UniversityDepartment of Neurology, Yale School of MedicineMassachusetts Institute of Technology
    • , Alastair CompstonAffiliated withDepartment of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge
    • , Stephen L. HauserAffiliated withDepartment of Neurology, School of Medicine, University of California
    • , Margaret A. Pericak-VanceAffiliated withJohn P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami
    • , Jonathan L. HainesAffiliated withCenter for Human Genetics Research, Vanderbilt University Medical Center

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Abstract

Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large data sets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. in Nat Genet 39(9):1083–1091, 2007; International Multiple Sclerosis Genetics Consortium in N Engl J Med 357(9):851–862, 2007; Lundmark in Nat Genet 39(9):1108–1113, 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. in Nat Genet 39(9):1083–1091, 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case–control data sets, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case–control data set (4,831 samples) with joint p values as high as 8.29 × 10−6 and 3.48 × 10−7, respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p values reaching 3.47 × 10−4, and BCL2 with p values reaching 4.32 × 10−4. The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 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.