TY - JOUR
T1 - Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry
AU - Chi, Calvin
AU - Shao, Xiaorong
AU - Rhead, Brooke
AU - Gonzales, Edlin
AU - Smith, Jessica B.
AU - Xiang, Anny H.
AU - Graves, Jennifer
AU - Waldman, Amy
AU - Lotze, Timothy
AU - Schreiner, Teri
AU - Weinstock-Guttman, Bianca
AU - Aaen, Gregory
AU - Tillema, Jan Mendelt
AU - Ness, Jayne
AU - Candee, Meghan
AU - Krupp, Lauren
AU - Gorman, Mark
AU - Benson, Leslie
AU - Chitnis, Tanuja
AU - Mar, Soe
AU - Belman, Anita
AU - Casper, Theron Charles
AU - Rose, John
AU - Moodley, Manikum
AU - Rensel, Mary
AU - Rodriguez, Moses
AU - Greenberg, Benjamin
AU - Kahn, Llana
AU - Rubin, Jennifer
AU - Schaefer, Catherine
AU - Waubant, Emmanuelle
AU - Langer-Gould, Annette
AU - Barcellos, Lisa F.
N1 - Funding Information:
This study was funded by National Institute of Health grants R01AI076544, R01NS049510, and R01ES017080 (https://www.nih.gov). Genotyping of the GERA cohort was supported by a grant (RC2 AG036607; C.S. and Neil Risch, PIs). Development of the Kaiser Permanente Research Program on Genes, Environment, and Health was supported by grants from the Wayne and Gladys Valley Foundation (http://fdnweb.org/wgvalley/), the Ellison Medical Foundation (http://www.ellisonfoundation.org), the Robert Wood Johnson Foundation (https://www.rwjf.org), and the Kaiser Permanente Community Benefit Program. C.C was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE 1106400 (https://www.nsf.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the IMSGC for providing genotype data from ImmunoChip for 1,265 African Americans.
Publisher Copyright:
© 2019 Chi et al.
PY - 2019
Y1 - 2019
N2 - 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.
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.
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U2 - 10.1371/journal.pgen.1007808
DO - 10.1371/journal.pgen.1007808
M3 - Article
C2 - 30653506
AN - SCOPUS:85060954585
SN - 1553-7390
VL - 15
JO - PLoS genetics
JF - PLoS genetics
IS - 1
M1 - e1007808
ER -