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

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 – 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 ( N 1 =1803, N 2 =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; p FDR = 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.