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Study Description

Monozygotic (MZ) twins have been widely employed for dissection of the relative contributions of genetics and environment in disease. In multiple sclerosis (MS), an autoimmune demyelinating disease that commonly causes neurodegeneration and disability in young adults, disease discordance in MZ twins has been interpreted to indicate environmental importance in pathogenesis. However, genetic and epigenetic differences between MZ twins have been described, challenging the accepted experimental paradigm in disambiguating effects of nature and nurture. Here, we report the genome sequences of one MS-discordant MZ twin pair and messenger RNA (mRNA) transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant, MZ twin pairs. No reproducible differences were detected between co-twins among ~3.6 million single nucleotide polymorphisms (SNPs) or ~0.2 million insertion-deletion polymorphisms (indels). Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and indel genotypes, or expression of ~19,000 genes in CD4+ T cells. Only two to 176 differences in methylation of ~2 million CpG sites were detected between siblings of the three twin pairs, in contrast to ~800 differences in methylation between T cells of unrelated individuals and several thousand differences between tissues or normal and cancerous tissues. In the first systematic effort to estimate sequence variation among MZ co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first female, twin and autoimmune disease genome sequences reported.

  • Study Types: Case-Control, Monozygotic Twins
  • Number of study subjects that have individual level data available through Authorized Access: 6

Authorized Access
Publicly Available Data (Public ftp)

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Study Inclusion/Exclusion Criteria

Three pairs of adult monozygotic twins who were discordant for MS. Affected individuals fulfilled McDonald criteria for MS diagnosis. Lack of affectation in siblings was confirmed through clinical, magnetic resonance brain imaging, and cerebrospinal studies. Controls for reduced representation bisulphite sequencing were four tissue samples: one breast cancer, one normal breast tissue, one lung cancer, one normal lung tissue.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Illumina Genome Analyzer II N/A N/A
Whole Genome Genotyping Affymetrix AFFY_6.0 934940 52074
Exon Genotyping Affymetrix GeneChip Human Exon 1.0 ST Array N/A N/A
Selected publications
Diseases Related to Study (MESH terms)
Authorized Data Access Requests
Study Attribution
  • Principal Investigators
    • Stephen Kingsmore. National Center for Genome Resources, Santa Fe, NM, USA
    • Stephen Hauser. University of California-San Francisco, CA, USA
    • Jorge Oksenberg. University of California-San Francisco, CA, USA
    • Sergio Baranzini. University of California-San Francisco, CA, USA
  • Co-Investigator
    • Faye Schilkey. National Center for Genome Resources, Santa Fe, NM, USA
  • Institute
    • National Center for Genome Resources, Santa Fe, NM, USA
  • Funding Source
    • Small Ventures USA, Houston, TX, USA
    • A.J. Brass Foundation
    • Nancy Davis Foundation, Los Angelese, CA, USA
    • RR016480. National Center for Research Resources (NCRR), National Institutes of Health, Bethedsa, MD, USA
    • RO1NS26799. National Institutes of Health, Bethedsa, MD, USA
    • RG3060C8. National MS Society
    • RG2901D9. National MS Society
    • RO1NS46297. National Institutes of Health, Bethedsa, MD, USA
    • Harry Weaver Neuroscience Scholar. National MS Society