title: 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.
authors.affiliation: 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.
authors.forename: Noriko
authors.initials: N
authors.lastname: Isobe
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Lohith
authors.initials: L
authors.lastname: Madireddy
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Pouya
authors.initials: P
authors.lastname: Khankhanian
authors.affiliation: 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.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Jayaji M
authors.initials: JM
authors.lastname: Moré
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: 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.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.affiliation: 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.
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Beecham
authors.affiliation: 5 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Piccio
authors.affiliation: 6 Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Herbert
authors.affiliation: 7 Multiple Sclerosis Centre and The Sastry Foundation Advanced Imaging Laboratory, Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Khan
authors.affiliation: 8 Mellen Centre for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.affiliation: 8 Mellen Centre for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Lael
authors.initials: L
authors.lastname: Stone
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Santaniello
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Bruce A C
authors.initials: BA
authors.lastname: Cree
authors.affiliation: 9 Centre for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: 9 Centre for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: 10 Department of Clinical Neurosciences, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: 1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA Jorge.Oksenberg@ucsf.edu.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: African Americans; ImmunoChip; linkage disequilibrium; multiple sclerosis
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