BACKGROUND AND OBJECTIVES 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. METHODS 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. RESULTS 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. DISCUSSION 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.

中文翻译：

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多基因风险评分与基于人群的出生年份队列中患多发性硬化症的终生风险的关联。


背景和目标 超过 200 种遗传变异与多发性硬化症 (MS) 易感性相关。然而，尚不清楚遗传因素在多大程度上影响多发性硬化症的终生风险。通过基于人群的出生年份队列，我们​​研究了遗传学对 MS 终生风险的影响。方法 在 Y 项目研究中，我们追踪了荷兰自 1966 年出生以来几乎所有 MS (pwMS) 患者。作为对照参与者，我们包括来自 Project Y 队列（1965-1967 年出生于荷兰）的非 MS 参与者和来自 1963 年至 1969 年之间出生的阿姆斯特丹痴呆队列的非 MS 参与者。与 MS 相关的遗传变异在 pwMS 和使用基因分型或插补方法控制参与者。根据最大的多发性硬化症遗传研究的变异和权重，计算每个参与者的多基因风险评分 (PRS)，并根据对照参与者的 PRS 分布将其分配到十分位。我们检查了每个十分位的终生风险以及 PRS 和 MS 疾病变量之间的关联，包括发病年龄和继发进展时间。结果 计算了 285 名 pwMS（平均年龄 53.0 ± 0.9 岁，72.3% 女性）和 267 名对照参与者（平均年龄 51.8 ± 3.2 岁，58.1% 女性）的 MS-PRS。根据终生风险估计，我们观察到，遗传风险最低 30% 的女性中有 1:2,739 患 MS，而遗传风险最高 10% 的女性中有 1:92 患 MS。对于男性来说，在最低 30% 遗传风险组中，只有 1:7,900 人患 MS，而在最高 10% 遗传风险组中，这一比例为 1:293。无论男女，PRS 与发病年龄和继发进展时间均无显着相关性。 讨论 我们的结果表明，多发性硬化症的终生风险很大程度上受遗传因素影响。我们的研究结果有可能支持疑似多发性硬化症个体的诊断确定性：高 PRS 可以加强诊断，但尤其是来自 PRS 分布最低尾部的 PRS 应被视为危险信号，并可以防止误诊模仿多发性硬化症的情况。