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

Calvin Chi*, Xiaorong Shao, Brooke Rhead, Edlin Gonzales, Jessica B. Smith, Anny H. Xiang, Jennifer Graves, Amy Waldman, Timothy Lotze, Teri Schreiner, Bianca Weinstock-Guttman, Gregory Aaen, Jan Mendelt Tillema, Jayne Ness, Meghan Candee, Lauren Krupp, Mark Gorman, Leslie Benson, Tanuja Chitnis, Soe MarAnita Belman, Theron Charles Casper, John Rose, Manikum Moodley, Mary Rensel, Moses Rodriguez, Benjamin Greenberg, Llana Kahn, Jennifer P Rubin, Catherine Schaefer, Emmanuelle Waubant, Annette Langer-Gould, Lisa F. Barcellos

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numbere1007808
JournalPLoS genetics
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

sclerosis
antigen
ancestry
Multiple Sclerosis
allele
HLA Antigens
Alleles
alleles
African American
African Americans
Haplotypes
haplotypes
Hispanic Americans
Population
Single Nucleotide Polymorphism
Asian Americans
ultraviolet radiation
antigens
risk factor
Chromosomes, Human, Pair 8

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Chi, C., Shao, X., Rhead, B., Gonzales, E., Smith, J. B., Xiang, A. H., ... Barcellos, L. F. (2019). Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. PLoS genetics, 15(1), [e1007808]. https://doi.org/10.1371/journal.pgen.1007808
Chi, Calvin ; Shao, Xiaorong ; Rhead, Brooke ; Gonzales, Edlin ; Smith, Jessica B. ; Xiang, Anny H. ; Graves, Jennifer ; Waldman, Amy ; Lotze, Timothy ; Schreiner, Teri ; Weinstock-Guttman, Bianca ; Aaen, Gregory ; Tillema, Jan Mendelt ; Ness, Jayne ; Candee, Meghan ; Krupp, Lauren ; Gorman, Mark ; Benson, Leslie ; Chitnis, Tanuja ; Mar, Soe ; Belman, Anita ; Casper, Theron Charles ; Rose, John ; Moodley, Manikum ; Rensel, Mary ; Rodriguez, Moses ; Greenberg, Benjamin ; Kahn, Llana ; Rubin, Jennifer P ; Schaefer, Catherine ; Waubant, Emmanuelle ; Langer-Gould, Annette ; Barcellos, Lisa F. / Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. In: PLoS genetics. 2019 ; Vol. 15, No. 1.
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title = "Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry",
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.",
author = "Calvin Chi and Xiaorong Shao and Brooke Rhead and Edlin Gonzales and Smith, {Jessica B.} and Xiang, {Anny H.} and Jennifer Graves and Amy Waldman and Timothy Lotze and Teri Schreiner and Bianca Weinstock-Guttman and Gregory Aaen and Tillema, {Jan Mendelt} and Jayne Ness and Meghan Candee and Lauren Krupp and Mark Gorman and Leslie Benson and Tanuja Chitnis and Soe Mar and Anita Belman and Casper, {Theron Charles} and John Rose and Manikum Moodley and Mary Rensel and Moses Rodriguez and Benjamin Greenberg and Llana Kahn and Rubin, {Jennifer P} and Catherine Schaefer and Emmanuelle Waubant and Annette Langer-Gould and Barcellos, {Lisa F.}",
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Chi, C, Shao, X, Rhead, B, Gonzales, E, Smith, JB, Xiang, AH, Graves, J, Waldman, A, Lotze, T, Schreiner, T, Weinstock-Guttman, B, Aaen, G, Tillema, JM, Ness, J, Candee, M, Krupp, L, Gorman, M, Benson, L, Chitnis, T, Mar, S, Belman, A, Casper, TC, Rose, J, Moodley, M, Rensel, M, Rodriguez, M, Greenberg, B, Kahn, L, Rubin, JP, Schaefer, C, Waubant, E, Langer-Gould, A & Barcellos, LF 2019, 'Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry', PLoS genetics, vol. 15, no. 1, e1007808. https://doi.org/10.1371/journal.pgen.1007808

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. / Chi, Calvin; Shao, Xiaorong; Rhead, Brooke; Gonzales, Edlin; Smith, Jessica B.; Xiang, Anny H.; Graves, Jennifer; Waldman, Amy; Lotze, Timothy; Schreiner, Teri; Weinstock-Guttman, Bianca; Aaen, Gregory; Tillema, Jan Mendelt; Ness, Jayne; Candee, Meghan; Krupp, Lauren; Gorman, Mark; Benson, Leslie; Chitnis, Tanuja; Mar, Soe; Belman, Anita; Casper, Theron Charles; Rose, John; Moodley, Manikum; Rensel, Mary; Rodriguez, Moses; Greenberg, Benjamin; Kahn, Llana; Rubin, Jennifer P; Schaefer, Catherine; Waubant, Emmanuelle; Langer-Gould, Annette; Barcellos, Lisa F.

In: PLoS genetics, Vol. 15, No. 1, e1007808, 01.01.2019.

Research output: Contribution to journalArticle

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 P

AU - Schaefer, Catherine

AU - Waubant, Emmanuelle

AU - Langer-Gould, Annette

AU - Barcellos, Lisa F.

PY - 2019/1/1

Y1 - 2019/1/1

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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