J Clin Neurol.  2015 Oct;11(4):311-318. 10.3988/jcn.2015.11.4.311.

Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

• Lin X
• Deng FY
• Lu X
• Lei SF

• KMID: 2179750
• DOI: http://doi.org/10.3988/jcn.2015.11.4.311

Abstract

BACKGROUND AND PURPOSE
Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS.
METHODS
Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets.
RESULTS
A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40x10(-4)). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both.
CONCLUSIONS
The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS.

Keyword

multiple sclerosis; gene-based GWAS; gene expression; human leukocyte antigen

MeSH Terms

Central Nervous System
Dataset
Gene Expression
Genome-Wide Association Study*
Genotype
Humans
Leukocytes
Major Histocompatibility Complex
Molecular Biology
Multiple Sclerosis*
Myelin-Oligodendrocyte Glycoprotein
Phenotype
Myelin-Oligodendrocyte Glycoprotein

Figure

• 

  Fig. 1 Quantile-quantile plots of the association results for the initial genome scan. The tail of the distribution of gene-based probability values deviated more significantly than those of SNPs inside or outside of the gene, which suggests that the power was higher for a gene-based association analysis than a single SNP-based GWAS in detecting associations. GWAS: genome-wide association study, SNP: single-nucleotide polymorphism.

• 

  Fig. 2 Manhattan plot of gene probability values on chromosomes. Most of the genes significantly associated with MS are mapped to the HLA region (chromosome 6). HLA: human leukocyte antigen, MS: multiple sclerosis.

• 

  Fig. 3 Protein-protein interactions between MS-associated genes. Only the connected genes are shown. The novel genes are labeled in red. Different line colors represent the types of evidence for the association. HLA class I cluster: major histocompatibility complex, class I, A (HLA-A), Major histocompatibility complex, class I, C (HLA-C), and major histocompatibility complex, class I, F (HLA-F); HLA class II cluster: major histocompatibility complex, class II, DQ alpha 1 (HLA-DQA1), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2), major histocompatibility complex, class II, DQ beta 2 (HLA-DQB2), major histocompatibility complex, class II, DR alha (HLA-DRA), major histocompatibility complex, class II, DO beta (HLA-DOB), major histocompatibility complex, class II, DM alpha (HLA-DMA), and major histocompatibility complex, class II, DM beta (HLA-DMB). HLA: human leukocyte antigen, MS: Multiple sclerosis.

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