PMID- 30653506
OWN - NLM
STAT- MEDLINE
DCOM- 20190311
LR  - 20221207
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 15
IP  - 1
DP  - 2019 Jan
TI  - Admixture mapping reveals evidence of differential multiple sclerosis risk by 
      genetic ancestry.
PG  - e1007808
LID - 10.1371/journal.pgen.1007808 [doi]
LID - e1007808
AB  - 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.
FAU - Chi, Calvin
AU  - Chi C
AUID- ORCID: 0000-0002-4757-0559
AD  - Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, 
      Berkeley, California, United States of America.
AD  - Computational Biology Graduate Group, University of California, Berkeley, 
      Berkeley, California, United States of America.
FAU - Shao, Xiaorong
AU  - Shao X
AD  - Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, 
      Berkeley, California, United States of America.
FAU - Rhead, Brooke
AU  - Rhead B
AUID- ORCID: 0000-0002-1839-4883
AD  - Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, 
      Berkeley, California, United States of America.
AD  - Computational Biology Graduate Group, University of California, Berkeley, 
      Berkeley, California, United States of America.
FAU - Gonzales, Edlin
AU  - Gonzales E
AD  - Department of Research & Evaluation, Kaiser Permanente Southern California, Los 
      Angeles, California, United States of America.
FAU - Smith, Jessica B
AU  - Smith JB
AD  - Department of Research & Evaluation, Kaiser Permanente Southern California, Los 
      Angeles, California, United States of America.
FAU - Xiang, Anny H
AU  - Xiang AH
AD  - Department of Research & Evaluation, Kaiser Permanente Southern California, Los 
      Angeles, California, United States of America.
FAU - Graves, Jennifer
AU  - Graves J
AD  - Department of Neurology, University of California, San Francisco, San Francisco, 
      California, United States of America.
FAU - Waldman, Amy
AU  - Waldman A
AD  - Leukodystrophy Center, Children's Hospital of Philadelphia, Philadelphia, 
      Pennsylvania, United States of America.
FAU - Lotze, Timothy
AU  - Lotze T
AD  - Neurology and Developmental Neuroscience Department, Texas Children's Hospital, 
      Houston, Texas, United States of America.
FAU - Schreiner, Teri
AU  - Schreiner T
AD  - University of Colorado School of Medicine, Aurora, Colorado, United States of 
      America.
FAU - Weinstock-Guttman, Bianca
AU  - Weinstock-Guttman B
AUID- ORCID: 0000-0001-6732-151X
AD  - Department of Neurology, State University of New York, Buffalo, Buffalo, New 
      York, United States of America.
FAU - Aaen, Gregory
AU  - Aaen G
AD  - Loma Linda University, Loma Linda, California, United States of America.
FAU - Tillema, Jan-Mendelt
AU  - Tillema JM
AD  - Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of 
      America.
FAU - Ness, Jayne
AU  - Ness J
AD  - Children's of Alabama, Birmingham, Alabama, United States of America.
FAU - Candee, Meghan
AU  - Candee M
AD  - Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Krupp, Lauren
AU  - Krupp L
AD  - Department of Neurology, NYU Langone Health, New York, New York, United States of 
      America.
FAU - Gorman, Mark
AU  - Gorman M
AD  - Boston Children's Hospital, Boston, Massachusetts, United States of America.
FAU - Benson, Leslie
AU  - Benson L
AD  - Boston Children's Hospital, Boston, Massachusetts, United States of America.
FAU - Chitnis, Tanuja
AU  - Chitnis T
AD  - MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, 
      Massachusetts, United States of America.
FAU - Mar, Soe
AU  - Mar S
AD  - Department of Neurology, Washington University School of Medicine in St. Louis, 
      St. Louis, Missouri, United States of America.
FAU - Belman, Anita
AU  - Belman A
AD  - Department of Neurology, NYU Langone Health, New York, New York, United States of 
      America.
FAU - Casper, Theron Charles
AU  - Casper TC
AD  - Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Rose, John
AU  - Rose J
AD  - Department of Neurology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Moodley, Manikum
AU  - Moodley M
AD  - Center for Pediatric Neurosciences, Cleveland Clinic, Cleveland, Ohio, United 
      States of America.
FAU - Rensel, Mary
AU  - Rensel M
AD  - Mellen Center, Cleveland Clinic, Cleveland, Ohio, United States of America.
FAU - Rodriguez, Moses
AU  - Rodriguez M
AD  - Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of 
      America.
FAU - Greenberg, Benjamin
AU  - Greenberg B
AUID- ORCID: 0000-0002-2091-8201
AD  - Neurology & Neurotherapeutics, University of Texas Southwestern, Dallas, Texas, 
      United States of America.
FAU - Kahn, Llana
AU  - Kahn L
AUID- ORCID: 0000-0002-0510-0276
AD  - Children's National Medical Center, Northwest Washington, D.C., United States of 
      America.
FAU - Rubin, Jennifer
AU  - Rubin J
AD  - Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United 
      States of America.
FAU - Schaefer, Catherine
AU  - Schaefer C
AD  - Kaiser Permanente Division of Research, Kaiser Permanente Northern California, 
      Oakland, California, United States of America.
FAU - Waubant, Emmanuelle
AU  - Waubant E
AD  - Department of Neurology, University of California, San Francisco, San Francisco, 
      California, United States of America.
FAU - Langer-Gould, Annette
AU  - Langer-Gould A
AD  - Kaiser Permanente, Southern California Permanente Medical Group, Pasadena, 
      California, United States of America.
AD  - Los Angeles Medical Center, Neurology Department, Los Angeles, California, United 
      States of America.
FAU - Barcellos, Lisa F
AU  - Barcellos LF
AUID- ORCID: 0000-0002-0303-3479
AD  - Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, 
      Berkeley, California, United States of America.
LA  - eng
GR  - R01 NS071463/NS/NINDS NIH HHS/United States
GR  - R01 NS049510/NS/NINDS NIH HHS/United States
GR  - F31 NS096885/NS/NINDS NIH HHS/United States
GR  - R01 ES017080/ES/NIEHS NIH HHS/United States
GR  - RC2 AG036607/AG/NIA NIH HHS/United States
GR  - R01 AI076544/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190117
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (HLA-A*03:01 antigen)
RN  - 0 (HLA-A3 Antigen)
RN  - 0 (HLA-B*07:02 antigen)
RN  - 0 (HLA-B7 Antigen)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*15:01 antigen)
RN  - 0 (Transcription Factors)
RN  - 0 (ZNF597 protein, human)
SB  - IM
MH  - Black or African American
MH  - Alleles
MH  - Asian
MH  - Female
MH  - *Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - HLA-A3 Antigen/genetics
MH  - HLA-B7 Antigen/genetics
MH  - HLA-DRB1 Chains/*genetics
MH  - Haplotypes
MH  - Hispanic or Latino
MH  - Humans
MH  - Male
MH  - Multiple Sclerosis/*genetics/pathology
MH  - Polymorphism, Single Nucleotide
MH  - Transcription Factors/*genetics
MH  - White People
PMC - PMC6353231
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/01/18 06:00
MHDA- 2019/03/12 06:00
PMCR- 2019/01/17
CRDT- 2019/01/18 06:00
PHST- 2018/05/25 00:00 [received]
PHST- 2018/11/02 00:00 [accepted]
PHST- 2019/01/30 00:00 [revised]
PHST- 2019/01/18 06:00 [pubmed]
PHST- 2019/03/12 06:00 [medline]
PHST- 2019/01/18 06:00 [entrez]
PHST- 2019/01/17 00:00 [pmc-release]
AID - PGENETICS-D-18-01075 [pii]
AID - 10.1371/journal.pgen.1007808 [doi]
PST - epublish
SO  - PLoS Genet. 2019 Jan 17;15(1):e1007808. doi: 10.1371/journal.pgen.1007808. 
      eCollection 2019 Jan.