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Transcript specific regulation of expression influences susceptibility to multiple sclerosis.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Ban, Maria 
Liao, Wenjia 
Baker, Amie 
Compston, Alastair 
Thorpe, John 

Abstract

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10-24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.

Description

Keywords

Adaptor Proteins, Vesicular Transport, Adult, Alleles, Genetic Predisposition to Disease, Humans, Middle Aged, Multiple Sclerosis, Open Reading Frames, Polymorphism, Genetic, RNA, Messenger

Journal Title

Eur J Hum Genet

Conference Name

Journal ISSN

1018-4813
1476-5438

Volume Title

28

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (G1100125)
MULTIPLE SCLEROSIS SOCIETY (39)
Wellcome Trust (105924/Z/14/Z)