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

Lin X, Deng FY, Lu X, Lei SF - J Clin Neurol (2015)

Bottom Line: The aim of this study was to identify more genes associated with MS.A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40×10⁻⁴).The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, People's Republic of China.

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<1.40×10⁻⁴). 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.

No MeSH data available.


Related in: MedlinePlus

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.
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Figure 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.

Mentions: Quantile-quantile plots of the association results for the original genome scan and the present gene-based GWAS are shown in Fig. 1, in which probability values (shown as -log10 values) for all 20,761 genes and all SNPs are plotted against the expected distribution. The tail of the distribution of gene-based probability values deviated more significantly than those of SNPs inside or outside of the gene. The distribution of the probability values for the present gene-based GWAS is shown in Fig. 2.


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

Lin X, Deng FY, Lu X, Lei SF - J Clin Neurol (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596110&req=5

Figure 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.
Mentions: Quantile-quantile plots of the association results for the original genome scan and the present gene-based GWAS are shown in Fig. 1, in which probability values (shown as -log10 values) for all 20,761 genes and all SNPs are plotted against the expected distribution. The tail of the distribution of gene-based probability values deviated more significantly than those of SNPs inside or outside of the gene. The distribution of the probability values for the present gene-based GWAS is shown in Fig. 2.

Bottom Line: The aim of this study was to identify more genes associated with MS.A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40×10⁻⁴).The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, People's Republic of China.

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<1.40×10⁻⁴). 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.

No MeSH data available.


Related in: MedlinePlus