Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Mary K. Horton; Joan E. Shim; Amelia Wallace; Jennifer S. Graves; Gregory Aaen; Benjamin Greenberg; Soe Mar; Yolanda Wheeler; Bianca Weinstock-Guttman; Amy Waldman; Teri Schreiner; Moses Rodriguez; Jan Mendelt Tillema; Tanuja Chitnis; Lauren Krupp; T. Charles Casper; Mary Rensel; Janace Hart; Hong L. Quach; Diana L. Quach; Catherine Schaefer; Emmanuelle Waubant; Lisa F. Barcellos

doi:10.1177/13524585221150736

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Mary K. Horton, Joan E. Shim, Amelia Wallace, Jennifer S. Graves, Gregory Aaen, Benjamin Greenberg, Soe Mar, Yolanda Wheeler, Bianca Weinstock-Guttman, Amy Waldman, Teri Schreiner, Moses Rodriguez, Jan Mendelt Tillema, Tanuja Chitnis, Lauren Krupp, T. Charles Casper, Mary Rensel, Janace Hart, Hong L. Quach, Diana L. QuachCatherine Schaefer, Emmanuelle Waubant, Lisa F. Barcellos

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10⁻³) and two MHC genes (BRD2, p = 5.89 × 10⁻⁵ and AGER, p = 7.96 × 10⁻⁵) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Original language	English (US)
Pages (from-to)	505-511
Number of pages	7
Journal	Multiple Sclerosis Journal
Volume	29
Issue number	4-5
DOIs	https://doi.org/10.1177/13524585221150736
State	Published - Apr 2023

Keywords

GWAS
Multiple sclerosis
POMS
pediatric-onset
rare variants

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1177/13524585221150736

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Horton, M. K., Shim, J. E., Wallace, A., Graves, J. S., Aaen, G., Greenberg, B., Mar, S., Wheeler, Y., Weinstock-Guttman, B., Waldman, A., Schreiner, T., Rodriguez, M., Tillema, J. M., Chitnis, T., Krupp, L., Casper, T. C., Rensel, M., Hart, J., Quach, H. L., ... Barcellos, L. F. (2023). Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis. Multiple Sclerosis Journal, 29(4-5), 505-511. https://doi.org/10.1177/13524585221150736

Horton, MK, Shim, JE, Wallace, A, Graves, JS, Aaen, G, Greenberg, B, Mar, S, Wheeler, Y, Weinstock-Guttman, B, Waldman, A, Schreiner, T, Rodriguez, M, Tillema, JM, Chitnis, T, Krupp, L, Casper, TC, Rensel, M, Hart, J, Quach, HL, Quach, DL, Schaefer, C, Waubant, E & Barcellos, LF 2023, 'Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis', Multiple Sclerosis Journal, vol. 29, no. 4-5, pp. 505-511. https://doi.org/10.1177/13524585221150736

@article{d296f18a1ef04521ac65ca7ca0627dd0,

title = "Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis",

abstract = "Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10−3) and two MHC genes (BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.",

keywords = "GWAS, Multiple sclerosis, POMS, pediatric-onset, rare variants",

author = "Horton, {Mary K.} and Shim, {Joan E.} and Amelia Wallace and Graves, {Jennifer S.} and Gregory Aaen and Benjamin Greenberg and Soe Mar and Yolanda Wheeler and Bianca Weinstock-Guttman and Amy Waldman and Teri Schreiner and Moses Rodriguez and Tillema, {Jan Mendelt} and Tanuja Chitnis and Lauren Krupp and Casper, {T. Charles} and Mary Rensel and Janace Hart and Quach, {Hong L.} and Quach, {Diana L.} and Catherine Schaefer and Emmanuelle Waubant and Barcellos, {Lisa F.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), 2023.",

year = "2023",

month = apr,

doi = "10.1177/13524585221150736",

language = "English (US)",

volume = "29",

pages = "505--511",

journal = "Multiple Sclerosis Journal",

issn = "1352-4585",

publisher = "SAGE Publications Ltd",

number = "4-5",

}

TY - JOUR

T1 - Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

AU - Horton, Mary K.

AU - Shim, Joan E.

AU - Wallace, Amelia

AU - Graves, Jennifer S.

AU - Aaen, Gregory

AU - Greenberg, Benjamin

AU - Mar, Soe

AU - Wheeler, Yolanda

AU - Weinstock-Guttman, Bianca

AU - Waldman, Amy

AU - Schreiner, Teri

AU - Rodriguez, Moses

AU - Tillema, Jan Mendelt

AU - Chitnis, Tanuja

AU - Krupp, Lauren

AU - Casper, T. Charles

AU - Rensel, Mary

AU - Hart, Janace

AU - Quach, Hong L.

AU - Quach, Diana L.

AU - Schaefer, Catherine

AU - Waubant, Emmanuelle

AU - Barcellos, Lisa F.

PY - 2023/4

Y1 - 2023/4

N2 - Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10−3) and two MHC genes (BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

AB - Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10−3) and two MHC genes (BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

KW - GWAS

KW - Multiple sclerosis

KW - POMS

KW - pediatric-onset

KW - rare variants

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U2 - 10.1177/13524585221150736

DO - 10.1177/13524585221150736

M3 - Article

C2 - 36755464

AN - SCOPUS:85150660764

SN - 1352-4585

VL - 29

SP - 505

EP - 511

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

IS - 4-5

ER -

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

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