From the MS Center Amsterdam (F.C.L., E.M.M.S., B.U.), Neurology, Amsterdam Neuroscience, Genomics of Neurodegenerative Diseases and Aging (D.Á.S., N.T., H.H., A.N.S., M.H., S.J.V.D.L.), Human Genetics, and Alzheimer Center Amsterdam (H.H., S.J.V.D.L.), Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc; Delft Bioinformatics Lab (N.T., H.H.), Delft University of Technology; and Amsterdam Neuroscience (H.H., S.J.V.D.L.), Neurodegeneration, the Netherlands.
Neurology. 2024 Oct 8;103(7):e209663. doi: 10.1212/WNL.0000000000209663. Epub 2024 Sep 13.
More than 200 genetic variants have been associated with multiple sclerosis (MS) susceptibility. However, it is unclear to what extent genetic factors influence lifetime risk of MS. Using a population-based birth-year cohort, we investigate the effect of genetics on lifetime risk of MS.
In the Project Y study, we tracked down almost all persons with MS (pwMS) from birth year 1966 in the Netherlands. As control participants, we included non-MS participants from the Project Y cohort (born 1965-1967 in the Netherlands) and non-MS participants from the Amsterdam Dementia Cohort born between 1963 and 1969. Genetic variants associated with MS were determined in pwMS and control participants using genotyping or imputation methods. Polygenic risk scores (PRSs) based on variants and weights from the largest genetic study in MS were calculated for each participant and assigned into deciles based on the PRS distribution in the control participants. We examined the lifetime risk for each decile and the association between PRS and MS disease variables, including age at onset and time to secondary progression.
MS-PRS was calculated for 285 pwMS (mean age 53.0 ± 0.9 years, 72.3% female) and 267 control participants (mean age 51.8 ± 3.2 years, 58.1% female). Based on the lifetime risk estimation, we observed that 1:2,739 of the women with the lowest 30% genetic risk developed MS, whereas 1:92 of the women with the top 10% highest risk developed MS. For men, only 1:7,900 developed MS in the lowest 30% genetic risk group, compared with 1:293 men with the top 10% genetic risk. The PRS was not significantly associated with age at onset and time to secondary progression in both sexes.
Our results show that the lifetime risk of MS is strongly influenced by genetic factors. Our findings have the potential to support diagnostic certainty in individuals with suspected MS: a high PRS could strengthen a diagnosis, but especially a PRS from the lowest tail of the PRS distribution should be considered a red flag and could prevent misdiagnosing conditions that mimic MS.
已有 200 多种遗传变异与多发性硬化症（MS）易感性相关。然而，遗传因素对 MS 终生风险的影响程度尚不清楚。本研究使用基于人群的出生年份队列，调查遗传因素对 MS 终生风险的影响。
在 Project Y 研究中，我们从荷兰追踪了所有出生于 1966 年的 MS 患者（pwMS）。作为对照参与者，我们纳入了来自 Project Y 队列的非 MS 参与者（1965-1967 年出生于荷兰）和出生于 1963 年至 1969 年的阿姆斯特丹痴呆队列中的非 MS 参与者。使用基因分型或 imputation 方法，在 pwMS 和对照参与者中确定与 MS 相关的遗传变异。基于 MS 最大遗传研究中的变异和权重，为每位参与者计算多基因风险评分（PRS），并根据对照参与者中 PRS 的分布将其分配到十分位数。我们检查了每个十分位数的终生风险以及 PRS 与 MS 疾病变量（包括发病年龄和继发性进展时间）之间的关联。
为 285 名 pwMS（平均年龄 53.0±0.9 岁，72.3%为女性）和 267 名对照参与者（平均年龄 51.8±3.2 岁，58.1%为女性）计算了 MS-PRS。根据终生风险估计，我们观察到在遗传风险最低的 30%女性中，每 2739 人中就有 1 人患 MS，而遗传风险最高的 10%女性中，每 92 人就有 1 人患 MS。对于男性，只有遗传风险最低的 30%组中的 1/7900 人会患 MS，而遗传风险最高的 10%男性中，每 293 人就有 1 人患 MS。PRS 与两性的发病年龄和继发性进展时间均无显著相关性。
我们的研究结果表明，MS 的终生风险受遗传因素的强烈影响。我们的发现有可能支持对疑似 MS 个体的诊断确定性：高 PRS 可能会加强诊断，但特别是 PRS 来自 PRS 分布的最低尾部，应被视为一个危险信号，并可防止误诊类似于 MS 的疾病。
