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Identifying genetic variants and environmental factors influencing multiple sclerosis pathological processes

Zhou, Y 2016 , 'Identifying genetic variants and environmental factors influencing multiple sclerosis pathological processes', PhD thesis, University of Tasmania.

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Multiple sclerosis (MS) is a complex neurological disorder whose cause and subsequent clinical course are to a large part due to an interplay between environmental and genetic factors. Currently, apart from the well-known effects of MHC genetic risk loci, genome-wide association studies (GWAS) have identified 110 non-MHC risk loci. However, these findings can only explain part of the heritability of MS, leading to the question “where is the missing heritability”. This thesis presents a number of methodological analyses using different study designs to reveal, in part, the puzzle of the missing heritability. By examining the susceptibility genes for EBV infection and their roles in MS development, as well as evaluating genetic variations and key environmental factors in determining clinical course, the complex role of genetics in MS onset and progression might be better understood.
In Chapter 2, I performed a genome-wide association study (GWAS) of anti-Epstein Barr Nuclear Antigen-1 (EBNA-1) IgG titers in 3,599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. I then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (`N_(eff)) = 5,555`) and a large MS GWAS (`N_(eff)= 15,231`). I identified one locus of strong association within the human leukocyte antigen (HLA) region that associated with anti-EBNA-1 titers. By examining the shared polygenic risk, I show that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA loci (1p22.1, 3p24.1, 3q13.33 and 10p15.1).
In Chapter 3, I assessed whether SNPs within genes for relevant cytokines and their receptors modulate the associations of TNF-α and IFN-γ with relapse. I found variation within the gene, IL2RB, demonstrated a significant protective effect of TNF-α on relapse, while variation in the 3’ region of TNFRSF1B and variation in the 5’region of IL3 showed a strong association between IFN-γ and increased relapse risk.
In Chapter 4, I assessed whether genetic variation in the myelin basic protein gene may directly, or by interaction with anti-HHV6 or EBV serological titers, determine clinical outcomes (conversion to MS after a first demyelinating event (FDE), relapse rate and disability) using the Ausimmune/AusLong Study. I found one variant, rs12959006, predicted worse MS clinical course in three key metrics, namely conversion to MS, relapse risk and annualised disability progression. I also found a significant interaction between the risk genotype and baseline anti-HHV6 IgG in predicting conversion to MS and relapse. These results, if replicated, may aid in developing prognostic algorithms in the early disease period in MS as well as providing further mechanistic insights.
In Chapter 5, I addressed the key question regarding the role of epigenetics in the missing heritability of MS. For the first time, I assessed the effects of a functional genetic variant within the gene for miR-146a (a miRNA whose expression is strongly associated with MS disease activity) on MS clinical course in the Ausimmune/AusLong Study, a well-established FDE cohort. I found the risk genotype (GC+CC) of the miR-146a SNP rs2910164 not only itself significantly predicted relapse risk, but also showed significant additive interaction with markers of EBV infection in predicting CDMS and relapse, including anti-EBNA-1 and -2 IgG and history of infectious mononucleosis, such that the associations of these environmental risk factors were significantly more potent among those carrying the miR146a risk variant.
This thesis presents a range of studies that add significant information regarding the missing heritability of MS and provide more evidence for the role of classic genetic, epigenetic and environmental factors in the pathogenesis of MS. Additionally, this thesis demonstrates how genetic variants may influence MS clinical course and interact with environmental factors to enhance the effects of genetic variants in predicting critical MS progression metrics. This work will be useful for the scientific community in general, and will be of benefit for MS patients.

Item Type: Thesis - PhD
Authors/Creators:Zhou, Y
Keywords: Multiple sclerosis, genetics, environmental factors, clinical course
Copyright Information:

Copyright 2016 the author

Additional Information:

Chapter 2 appears to be the equivalent of a post-print version of an article published as: Zhou, Y. et al., 2016. Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis, Multiple sclerosis, 22(13), 1655-1664

Chapter 3 appears to be the equivalent of a pre-print version of an article published as: Zhou, Y. et al., 2016. Genetic variation in PBMC-produced IFN-γ and TNF-α associations with relapse in multiple sclerosis, Journal of the neurological sciences, 349(1-2), 40-44

Chapter 4 appears to be the equivalent of a post-print version of an article published as: Zhou, Y., Simpson, S. Jr,, Charlesworth, J. C. et al., 2017. Variation within MBP gene predicts disease course in multiple sclerosis, Brain and behavvior, 7(4), 1-6

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