Polygenic susceptibility for multiple sclerosis is associated with working memory in low-performing young adults

Multiple sclerosis (MS) is a complex disease with substantial heritability estimates. Besides typical clinical manifestations such as motor and sensory deficits, MS is characterized by structural and functional brain abnormalities, and by cognitive impairment such as decreased working memory (WM) performance.

We investigated the possible link between the polygenic risk for MS and WM performance in healthy adults (18-35 years). Additionally, we addressed the relationship between polygenic risk for MS and white matter fractional anisotropy (FA).

We generated a polygenic risk score (PRS) of MS susceptibility and investigated its association with WM performance in 3282 healthy adults (two subsamples, N₁ = 1803, N₂ = 1479). The association between MS-PRS and FA was studied in the second subsample. MS severity PRS associations were also investigated for the WM and FA measurements.

MS-PRS was significantly associated with WM performance within the 10% lowest WM-performing individuals (p = 0.001; p_FDR = 0.018). It was not significantly associated with any of the investigated FA measurements. MS severity PRS was significantly associated with brain-wide mean FA (p = 0.041) and showed suggestive associations with additional FA measurements.

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. It also contributes to the understanding of genetic associations with MS severity, as these associations seem to involve distinct biological pathways compared to genetic variants linked to the overall risk of developing MS.