Division of Molecular Neuroscience, Department of Biomedicine, University of Basel, CH-4055 Basel, Switzerland; Research Cluster Molecular and Cognitive Neurosciences, Department of Biomedicine, University of Basel, CH-4055 Basel, Switzerland.
Division of Cognitive Neuroscience, Department of Biomedicine, University of Basel, CH-4055 Basel, Switzerland; Research Cluster Molecular and Cognitive Neurosciences, Department of Biomedicine, University of Basel, CH-4055 Basel, Switzerland.
J Neurol Sci. 2024 Aug 15;463:123138. doi: 10.1016/j.jns.2024.123138. Epub 2024 Jul 15.
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, N = 1803, N = 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 = 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.
多发性硬化症（MS）是一种具有较高遗传率的复杂疾病。除了运动和感觉缺陷等典型临床表现外，MS 还表现为结构和功能脑异常，以及认知障碍，如工作记忆（WM）表现下降。
我们研究了多发性硬化症多基因风险与健康成年人（18-35 岁）WM 表现之间的可能联系。此外，我们还探讨了多发性硬化症多基因风险与白质各向异性分数（FA）之间的关系。
我们生成了多发性硬化症易感性的多基因风险评分（PRS），并在 3282 名健康成年人（两个子样本，N=1803，N=1479）中研究了其与 WM 表现的关系。在第二个子样本中研究了 MS-PRS 与 FA 的关系。还研究了 MS 严重程度 PRS 与 WM 和 FA 测量值的关系。
MS-PRS 与 10% WM 表现最低的个体的 WM 表现显著相关（p=0.001；p=0.018）。它与任何研究的 FA 测量值均无显著相关性。MS 严重程度 PRS 与脑广泛平均 FA 显著相关（p=0.041），并与其他 FA 测量值显示出暗示性关联。
通过确定 MS 与 WM 表现之间的遗传联系，本研究有助于理解 MS 的遗传复杂性，并有望确定与 MS 认知障碍相关的分子途径。它还有助于理解与 MS 严重程度相关的遗传关联，因为与总体 MS 发病风险相关的遗传变异相比，这些关联似乎涉及不同的生物学途径。
