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An ImmunoChip study of multiple sclerosis risk in African Americans.

Abstract

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA 2 Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Saga 849-8501, Japan.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA 3 Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    4 John P. Hussman Institute for Human Genomics and The Dr John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

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    4 John P. Hussman Institute for Human Genomics and The Dr John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

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    5 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA.

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    6 Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.

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    7 Multiple Sclerosis Centre and The Sastry Foundation Advanced Imaging Laboratory, Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

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    8 Mellen Centre for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA.

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    8 Mellen Centre for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    9 Centre for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.

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    9 Centre for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.

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    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.

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    10 Department of Clinical Neurosciences, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.

    1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA Jorge.Oksenberg@ucsf.edu.

    Source

    Brain : a journal of neurology 138:Pt 6 2015 Jun pg 1518-30

    MeSH

    African Americans
    Alleles
    Case-Control Studies
    Genetic Predisposition to Disease
    Genome-Wide Association Study
    Genotype
    Humans
    Linkage Disequilibrium
    Multiple Sclerosis
    Oligonucleotide Array Sequence Analysis
    Polymorphism, Single Nucleotide

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25818868

    Citation

    Isobe, Noriko, et al. "An ImmunoChip Study of Multiple Sclerosis Risk in African Americans." Brain : a Journal of Neurology, vol. 138, no. Pt 6, 2015, pp. 1518-30.
    Isobe N, Madireddy L, Khankhanian P, et al. An ImmunoChip study of multiple sclerosis risk in African Americans. Brain. 2015;138(Pt 6):1518-30.
    Isobe, N., Madireddy, L., Khankhanian, P., Matsushita, T., Caillier, S. J., Moré, J. M., ... Oksenberg, J. R. (2015). An ImmunoChip study of multiple sclerosis risk in African Americans. Brain : a Journal of Neurology, 138(Pt 6), pp. 1518-30. doi:10.1093/brain/awv078.
    Isobe N, et al. An ImmunoChip Study of Multiple Sclerosis Risk in African Americans. Brain. 2015;138(Pt 6):1518-30. PubMed PMID: 25818868.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - An ImmunoChip study of multiple sclerosis risk in African Americans. AU - Isobe,Noriko, AU - Madireddy,Lohith, AU - Khankhanian,Pouya, AU - Matsushita,Takuya, AU - Caillier,Stacy J, AU - Moré,Jayaji M, AU - Gourraud,Pierre-Antoine, AU - McCauley,Jacob L, AU - Beecham,Ashley H, AU - ,, AU - Piccio,Laura, AU - Herbert,Joseph, AU - Khan,Omar, AU - Cohen,Jeffrey, AU - Stone,Lael, AU - Santaniello,Adam, AU - Cree,Bruce A C, AU - Onengut-Gumuscu,Suna, AU - Rich,Stephen S, AU - Hauser,Stephen L, AU - Sawcer,Stephen, AU - Oksenberg,Jorge R, Y1 - 2015/03/28/ PY - 2014/11/20/received PY - 2015/01/26/accepted PY - 2015/3/31/entrez PY - 2015/3/31/pubmed PY - 2015/8/8/medline KW - African Americans KW - ImmunoChip KW - linkage disequilibrium KW - multiple sclerosis SP - 1518 EP - 30 JF - Brain : a journal of neurology JO - Brain VL - 138 IS - Pt 6 N2 - The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/25818868/An_ImmunoChip_study_of_multiple_sclerosis_risk_in_African_Americans_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awv078 DB - PRIME DP - Unbound Medicine ER -