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  • Genetically determined serum serine level has a novel causal effect on multiple sclerosis risk and predicts disability progression

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Multiple sclerosis
Original research
Genetically determined serum serine level has a novel causal effect on multiple sclerosis risk and predicts disability progression
  1. Xin Lin1,
  2. Yuanhao Yang2,3,
  3. Valery Fuh-Ngwa1,
  4. Xianyong Yin4,
  5. Steve Simpson-Yap1,5,
  6. Ingrid van der Mei1,
  7. Simon A Broadley6,
  8. Anne-Louise Ponsonby7,8,
  9. Ausimmune/ AusLong Investigators Group,
  10. Kathryn P Burdon1,
  11. Bruce V Taylor1,
  12. Yuan Zhou1
    1. 1 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
    2. 2 Mater Research Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
    3. 3 Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
    4. 4 Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
    5. 5 Neuroepidemiology Unit, The University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia
    6. 6 School of Medicine, Griffith University, Gold Coast, Queensland, Australia
    7. 7 Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia
    8. 8 Neuroepidemiology Group, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
    1. Correspondence to Dr Yuan Zhou, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia; Yuan.Zhou{at}utas.edu.au

    Abstract

    Background There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management.

    Methods This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569–86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up.

    Results We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10−20), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10−4).

    Conclusions These findings support investigating serine as an important candidate biomarker for MS onset and disability progression.

    • multiple sclerosis
    • genetics

    Data availability statement

    Data are available in a public, open access repository. Data are available upon reasonable request. Summary statistics for MS GWAS are available through application from: https://imsgc.net/?page_id=31 Summary statistics for metabolites are available through an interactive web server (https://omicscience.org/apps/crossplatform/) as well as the GWAS Catalog database (https://www.ebi.ac.uk/gwas/, accession numbers GCST90010722–GCST90010862). The AusLong dataset is available from the authors upon reasonable request but is not publicly available due to ethical requirements.

    https://doi.org/10.1136/jnnp-2022-330259

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      Data availability statement

      Data are available in a public, open access repository. Data are available upon reasonable request. Summary statistics for MS GWAS are available through application from: https://imsgc.net/?page_id=31 Summary statistics for metabolites are available through an interactive web server (https://omicscience.org/apps/crossplatform/) as well as the GWAS Catalog database (https://www.ebi.ac.uk/gwas/, accession numbers GCST90010722–GCST90010862). The AusLong dataset is available from the authors upon reasonable request but is not publicly available due to ethical requirements.

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      Footnotes

      • Twitter @aydzhouyuan

      • Collaborators Authors listed below belong to the AusLong/Ausimmune Investigators Group, which contributed to the design and data collection of AusLong study:

        Keith Dear (University of Adelaide, Australia); Terry Dwyer (Oxford Martin School, University of Oxford, England); Leigh Blizzard (Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia); Robyn M Lucas (National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australian Capital Territory, Australia); Trevor Kilpatrick (Centre for Neurosciences, Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia); David Williams and Jeanette Lechner-Scott (University of Newcastle, Newcastle, Australia); Cameron Shaw and Caron Chapman (Barwon Health, Geelong, Australia); Alan Coulthard (University of Queensland, Brisbane, Australia); Michael P Pender (The University of Queensland, Brisbane, Australia) and Patricia Valery (QIMR Berghofer Medical Research Institute, Brisbane, Australia).

      • Contributors XL, BVT and YZ contributed to the conception and design of the study. XL, YY, VF-N and YZ contributed to the acquisition and analysis of data. AusLong Investigator Group contributed to the design and data collection of AusLong study. BVT and YZ supervised the study. XL, YY, VF-N, XY, SS-Y, IvdM, SAB, A-LP, AusLong Investigator Group, KB, BVT and YZ contributed to the interpretations of the findings and the critical revision of the manuscript. YZ is responsible for the overall content as the guarantor.

      • Funding This work was supported by funding from The Medical Research Future Fund (BVT), and the Australian National Health and Medical Research Council (BVT; YZ: GNT1173155). YY was supported by the Mater Foundation.

      • Competing interests BVT has received compensation for consulting, talks, and advisory/steering board activities for Merck, Novartis, Biogen, and Roche. He receives research funding support from MS Research Australia, Medical Research Future Fund Australia and the National Health & Medical Research Council Australia.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.