Background: Multiple sclerosis (MS) is a genetically complex disease with substantial heritability estimates. Besides typical clinical manifestations such as motor and sensory deficits, and fatigue, MS is characterized by structural and functional brain abnormalities, and by cognitive impairment such as decreased working memory (WM) performance. Objectives: This study investigates the possible link between the polygenic risk for MS and WM performance in healthy adults aged 18 to 35 years. Additionally, it addresses in the same population the relationship between polygenic risk for MS and brain white matter properties, as represented by measures of fractional anisotropy (FA). Methods: We generated a polygenic risk score (PRS) of MS and investigated its association with WM performance in a population of 3282 healthy adults, which consisted of two subsamples (N1=1803, N2=1479). The association between MS PRS and FA was studied in the second subsample. Results: MS PRS was significantly associated with WM performance within the 10% lowest WM performing individuals (p = 0.001; pFDR = 0.018). It was not significantly associated with any of the investigated FA measurements. Conclusions: By identifying a genetic link between MS and WM performance, this study contributes to the understanding of the genetic complexity of MS, and hopefully to the possible identification of molecular pathways linked to cognitive deficits in MS.

The authors have declared no competing interest.

This study was funded by intramural funds of the University of Basel.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of the Cantons of Basel Stadt and Basel Landschaft approved the study protocols.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The multiple sclerosis GWAS data can be obtained upon request at https://imsgc.net/. Other data used in this paper are available upon reasonable request to the authors.

https://imsgc.net/