背景:偏头痛是一种具有重要遗传成分的神经系统疾病,其特征是头痛的反复发作和长时间发作。先前的流行病学研究报道偏头痛患者患痴呆症的风险更高。神经影像学研究还显示了偏头痛和痴呆常见区域的结构性脑萎缩。然而,这些研究是观察性的,不能确定因果关系。本研究旨在探讨偏头痛与痴呆的遗传因果关系,以及使用孟德尔随机化(MR)的大脑结构变化在这种关联中的中介作用。
方法:我们收集了偏头痛及其两种亚型的全基因组关联研究(GWAS)汇总统计,以及四种常见的痴呆症,包括阿尔茨海默病(AD),血管性痴呆,额颞叶痴呆,和路易体痴呆.此外,我们收集了7项纵向脑测量值的GWAS汇总统计,这些测量值表征了脑结构随年龄的改变.利用这些GWAS,我们进行了双样本MR分析,以研究偏头痛及其两种亚型对痴呆和脑结构改变的因果影响.探讨脑结构改变在偏头痛和痴呆之间的可能中介作用。我们进行了两步MR中介分析.
结果:MR分析表明遗传预测的偏头痛与AD风险增加之间存在显着关联(OR=1.097,95%CI=[1.040,1.158],p=7.03×10-4)。此外,偏头痛显着加速了总皮质表面积的年度萎缩(每年-65.588cm2,95%CI=[-103.112,-28.064],p=6.13×10-4)和丘脑体积(每年-9.507cm3,95%CI=[-15.512,-3.502],p=1.91×10-3)。无先兆偏头痛(MO)亚型增加AD的风险(OR=1.091,95%CI=[1.059,1.123],p=6.95×10-9)和总皮质表面积的加速年度萎缩(-31.401cm2/年,95%CI=[-43.990,-18.811],p=1.02×10-6)。两步MR介导分析显示,丘脑萎缩部分介导了偏头痛对AD的因果效应,占总效应的28.2%。
结论:这项全面的MR研究为偏头痛对AD的因果效应提供了遗传学证据,并确定纵向丘脑萎缩是这种关联的潜在介质。这些发现可以告知脑干预目标,以预防偏头痛患者的AD风险。
BACKGROUND: Migraine is a neurological disease with a significant genetic component and is characterized by recurrent and prolonged episodes of headache. Previous epidemiological studies have reported a higher risk of dementia in migraine patients. Neuroimaging studies have also shown structural brain atrophy in regions that are common to migraine and dementia. However, these studies are observational and cannot establish causality. The present study aims to explore the genetic causal relationship between migraine and dementia, as well as the mediation roles of brain structural changes in this association using Mendelian randomization (MR).
METHODS: We collected the genome-wide association study (GWAS) summary statistics of migraine and its two subtypes, as well as four common types of dementia, including Alzheimer\'s disease (AD), vascular dementia, frontotemporal dementia, and Lewy body dementia. In addition, we collected the GWAS summary statistics of seven longitudinal brain measures that characterize brain structural alterations with age. Using these GWAS, we performed Two-sample MR analyses to investigate the causal effects of migraine and its two subtypes on dementia and brain structural changes. To explore the possible mediation of brain structural changes between migraine and dementia, we conducted a two-step MR mediation analysis.
RESULTS: The MR analysis demonstrated a significant association between genetically predicted migraine and an increased risk of AD (OR = 1.097, 95% CI = [1.040, 1.158], p = 7.03 × 10- 4). Moreover, migraine significantly accelerated annual atrophy of the total cortical surface area (-65.588 cm2 per year, 95% CI = [-103.112, -28.064], p = 6.13 × 10- 4) and thalamic volume (-9.507 cm3 per year, 95% CI = [-15.512, -3.502], p = 1.91 × 10- 3). The migraine without aura (MO) subtype increased the risk of AD (OR = 1.091, 95% CI = [1.059, 1.123], p = 6.95 × 10- 9) and accelerated annual atrophy of the total cortical surface area (-31.401 cm2 per year, 95% CI = [-43.990, -18.811], p = 1.02 × 10- 6). The two-step MR mediation analysis revealed that thalamic atrophy partly mediated the causal effect of migraine on AD, accounting for 28.2% of the total effect.
CONCLUSIONS: This comprehensive MR study provided genetic evidence for the causal effect of migraine on AD and identified longitudinal thalamic atrophy as a potential mediator in this association. These findings may inform brain intervention targets to prevent AD risk in migraine patients.