How can genetics affect MS onset and progression?

Dr Yuan Zhou

Menzies Institute for Medical Research, TAS

| Causes and Prevention | Genetics | Fellowship | 2018 | Investigator Led Research |
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Summary

Over 100 genes have been linked to an increased risk of developing MS. We do not know the role of each individual gene, and which genes are involved in the progression and increase in disability associated with MS.

In this post-doctoral fellowship Dr Yuan Zhou aims to investigate some of these genes to determine what effect they have on the clinical course of MS. He plans to create a mathematical formula that includes genetic and environmental risk factors that can better predict the clinical course of MS in an individual person. This would enable the individual to better choose a therapy that would be most beneficial for them.

To achieve this, Dr Zhou will use data from around the world to determine the genetic factors that influence the onset and progression of MS. Part of this project will focus on genes located on the X chromosome. Females have two X chromosomes, and males have only one. By studying this chromosome, he may discover why more females than males develop MS. Along with understanding the clinical course of MS better, this work may also provide novel targets for future therapies.

Progress to Date

Through international collaborations, Dr Zhou has conducted a genome-wide association study (GWAS) analysis for Epstein Barr Virus (EBV) and Human Herpesvirus 6 (HHV-6), which are risk factors for the development of MS. This type of study involves searching all genes simultaneously for small genetic variations that may be responsible for increasing the risk of developing MS. Dr Zhou has now completed the analysis for EBV and HHV6 levels in 11,079 twin family samples as well as for EBV levels in approximately 9,000 UK biobank data. A group at the University of Bristol are continuing the analysis of approximately 11,000 people with measurements of EBV and HHV6 over a long period of time.

Dr Zhou has established a new collaboration at the Genome Institute of Singapore and Australian Animal Health Laboratory to perform large-scale EBV sequencing in the Tasmanian population, and has established a rapid, cost-effective technique that can be used by the clinical labs to detect EBV strains.

As part of the MS Research Australia Ian Ballard Travel Award, Dr Zhou travelled to Boston for collaborations at Brigham Women’s Hospital, Broad Institute of MIT and Harvard. During this time, he has developed a pipeline to analyse the genetic differences between males and females, which may shed light on why women are predisposed to MS.

A PhD student from Belgium that Dr Zhou is co-supervising visited the Menzies Institute for Medical Research in Tasmania to analyse the genetic variations predicting the clinical course of MS using a cohort of people from Belgium (527 people with MS with at least 3.95 years follow up). This analysis is based on a model that Dr Zhou has developed. The next step is to combine this with data from the Tasmanian population. Dr Zhou will help determine the functions of these genetic variations by looking at whether they cause changes to gene activity during MS progression using large datasets. He has now completed the quality control step to ensure this data is of high quality.

He is also creating a mathematical formula using these findings that includes genetic and environmental risk factors that can better predict the clinical course of MS and treatment response in an individual person. He will then test this model using MRI data which together may provide a more accurate prognosis for disease progression. He has now completed the quality control step of the MRI data.

It is hoped that a risk model will be created that will take into account both genetic and environmental risk factors that will be able to make better predictions of an individual’s MS activity and provide guidance for treatment choices.

Dr Zhou has presented this research at a national conference. This work has also led to Dr Zhou successfully securing a competitive NHMRC Investigator Grant ($562,013) to further his research for the next 5 years.

Publications

  • Zhou Y and Clafin S et al (2019). Redefining the Multiple Sclerosis Severity Score (MSSS): the effect of sex and onset phenotype, Scler. 1352458519881994
  • Zhang Y, Zhou Y, van der Mei IAF Ausimmune/AusLong Investigators Group, et al (2019). Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis, J Neurol Neurosurg Psychiatry. 90:636-641
  • Afrasiabi A, Parnell GP, Fewings N, Schibeci SD, Basuki MA, Chandramohan R, Zhou Y, Taylor B, Brown DA, Swaminathan S, McKay FC, Stewart GJ, Booth DR (2019). Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility. Genome Med. 11:26

Updated: 11 June 2020

Updated: 04 January, 2018

Investigator

  • Dr Yuan Zhou, Menzies Institute for Medical Research, TAS

Co-investigator

Grant Awarded

  • Postdoctoral Fellowship

Total Funding

  • $210,000

Duration

  • 3 years over 2018 - 2020

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