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PLoS Genet. 2019 Jan 17;15(1):e1007808. doi: 10.1371/journal.pgen.1007808. eCollection 2019 Jan.

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.

Author information

1
Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, Berkeley, California, United States of America.
2
Computational Biology Graduate Group, University of California, Berkeley, Berkeley, California, United States of America.
3
Department of Research & Evaluation, Kaiser Permanente Southern California, Los Angeles, California, United States of America.
4
Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
5
Leukodystrophy Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
6
Neurology and Developmental Neuroscience Department, Texas Children's Hospital, Houston, Texas, United States of America.
7
University of Colorado School of Medicine, Aurora, Colorado, United States of America.
8
Department of Neurology, State University of New York, Buffalo, Buffalo, New York, United States of America.
9
Loma Linda University, Loma Linda, California, United States of America.
10
Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
11
Children's of Alabama, Birmingham, Alabama, United States of America.
12
Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
13
Department of Neurology, NYU Langone Health, New York, New York, United States of America.
14
Boston Children's Hospital, Boston, Massachusetts, United States of America.
15
MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
16
Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
17
Department of Neurology, University of Utah, Salt Lake City, Utah, United States of America.
18
Center for Pediatric Neurosciences, Cleveland Clinic, Cleveland, Ohio, United States of America.
19
Mellen Center, Cleveland Clinic, Cleveland, Ohio, United States of America.
20
Neurology & Neurotherapeutics, University of Texas Southwestern, Dallas, Texas, United States of America.
21
Children's National Medical Center, Northwest Washington, D.C., United States of America.
22
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
23
Kaiser Permanente Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America.
24
Kaiser Permanente, Southern California Permanente Medical Group, Pasadena, California, United States of America.
25
Los Angeles Medical Center, Neurology Department, Los Angeles, California, United States of America.

Abstract

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

PMID:
30653506
PMCID:
PMC6353231
DOI:
10.1371/journal.pgen.1007808
[Indexed for MEDLINE]
Free PMC Article

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