From the Department of Neurosurgery (J. Räsänen, K.M., V.E.K., M.O., J.E.J., V.L.), Kuopio University Hospital and Institute of Clinical Medicine-Neurosurgery, and Institute of Biomedicine (S. Heikkinen, K.M., A.L., T.K., M.H.), University of Eastern Finland, Kuopio; Institute for Molecular Medicine Finland (FIMM) (J.M., A.P.), Helsinki Institute of Life Science (HiLIFE), University of Helsinki; Department of Neurology (A.J.), Clinical Neurosciences, Helsinki University Hospital and University of Helsinki, Finland; Univ. Lille (B.G.-B., C.B., J.-C.L.), Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, France; Department of Neurosurgery (M.O., K.L., J.S.), University of Helsinki and Helsinki University Hospital; Clinical Neurosciences (C.A., J.F., A.K., J. Rinne), Department of Neurosurgery, University of Turku and Turku University Hospital; Department of Neurosurgery (A.R.), Tampere University Hospital; Unit of Clinical Neuroscience (M.K., M.v.u.z.F.), Neurosurgery, University of Oulu and Medical Research Center, Oulu University Hospital; Finnish Institute for Health and Welfare (THL) (M.P.); University of Helsinki (M.P.); Department of Neurosciences (A.M.K., A.M.P.), University of Helsinki; Department of Geriatrics (A.M.K.), Helsinki University Hospital; NeuroCenter (A.M.K.), Kuopio University Hospital; Institute of Clinical Medicine-Neurology (V.J., H.S.), University of Eastern Finland; School of Medicine (A.M.), Institute of Clinical Medicine, Pathology and Forensic Medicine, and Translational Cancer Research Area, University of Eastern Finland; Department of Clinical Pathology (A.M.), Kuopio University Hospital; Unit of Clinical Medicine (S. Helisalmi), University of Eastern Finland, Kuopio, Finland; Department of Neurosurgery (P.K.E.), Oslo University Hospital-Rikshospitalet; Institute of Clinical Medicine (P.K.E.), Faculty of Medicine, and KG Jebsen Centre for Brain Fluid Research (P.K.E.), University of Oslo, Norway; Analytical and Translational Genetics Unit (A.P., M.I.K.), Department of Medicine, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P., M.I.K.), and Stanley Center for Psychiatric Research (A.P., M.I.K.), Broad Institute for Harvard and MIT, Cambridge, MA.
Neurology. 2024 Sep 10;103(5):e209694. doi: 10.1212/WNL.0000000000209694. Epub 2024 Aug 14.
Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH).
We used a case-control study design implementing FinnGen data containing 473,691 Finns with genotypes and nationwide health records. Patients with NPH were selected based on G91.2 diagnosis. To select patients with idiopathic NPH (iNPH) for sensitivity analysis, we excluded patients with a potentially known etiology of the condition using an algorithm on their disease history. The controls were the remaining non-hydrocephalic participants. For a replication analysis, the NPH cohort from UK Biobank (UKBB) was used.
We included 1,522 patients with NPH (mean age 72.2 years, 53% women) and 451,091 controls (mean age 60.5 years, 44% women). In the GWAS comparing patients with NPH with the controls, we identified 6 gene regions significantly ( < 5.0e-8) associated with NPH that replicated in a meta-analysis with UKBB (NPH n = 173). The top loci near the following genes were rs7962263, (odds ratio [OR] 0.71, 95% CI 0.65-0.78, = 1.0e-14); rs798495, / (OR 1.29, 95% CI 1.20-1.39, = 2.9e-12); rs10828247, (OR 0.77, 95% CI 0.71-0.83, = 1.5e-11); rs561699566 and rs371919113, (OR 0.76, 95% CI 0.70-0.82, = 1.5e-11); rs56023709, (OR 1.24, 95% CI 1.16-1.33, = 3.0e-9); and rs62434144, (OR 1.23, 95% CI 1.14-1.32, = 1.4e-8). In the sensitivity analysis comparing only patients with iNPH (n = 1,055) with the controls (n = 451,091), 4 top loci near the following genes remained significant: rs7962263, (OR 0.70, 95% CI 0.63-0.78, = 2.1e-11); rs10828247, (OR 0.74, 95% CI 0.62-0.82, = 4.6e-10); rs798511, / (OR 1.28, 95% CI 1.17-1.39, = 1.7e-8); and rs56023709, (OR 1.28, 95% CI 1.17-1.39, = 1.7e-8).
We identified 6 loci significantly associated with NPH in the thus far largest GWAS in chronic hydrocephalus. The genes near the top loci have previously been associated with blood-brain barrier and blood-CSF barrier function and with increased lateral brain ventricle volume. The effect sizes and allele frequencies remained similar in NPH and iNPH cohorts, indicating the identified loci are risk determinants for iNPH and likely not explained by associations with other etiologies. However, the exact role of these loci is still unknown, warranting further studies.
目前缺乏对慢性脑积水的全基因组范围的大型研究。我们对正常压力脑积水（NPH）进行了全基因组关联研究（GWAS）。
我们使用病例对照研究设计，利用包含 473691 名芬兰人的 FinnGen 数据，这些人具有基因型和全国性健康记录。根据 G91.2 诊断选择 NPH 患者。为了进行敏感性分析，选择特发性 NPH（iNPH）患者，我们使用他们病史的算法排除具有该疾病潜在已知病因的患者。对照组是其余非脑积水的参与者。为了进行复制分析，使用了 UK Biobank（UKBB）的 NPH 队列。
我们纳入了 1522 名 NPH 患者（平均年龄 72.2 岁，53%为女性）和 451091 名对照（平均年龄 60.5 岁，44%为女性）。在比较 NPH 患者与对照组的 GWAS 中，我们在与 UKBB 的荟萃分析中鉴定出 6 个与 NPH 显著相关（<5.0e-8）的基因区域（NPH n = 173）。靠近以下基因的最高位点是 rs7962263、（优势比 [OR] 0.71，95%CI 0.65-0.78，= 1.0e-14）；rs798495、/（OR 1.29，95%CI 1.20-1.39，= 2.9e-12）；rs10828247、（OR 0.77，95%CI 0.71-0.83，= 1.5e-11）；rs561699566 和 rs371919113、（OR 0.76，95%CI 0.70-0.82，= 1.5e-11）；rs56023709、（OR 1.24，95%CI 1.16-1.33，= 3.0e-9）；rs62434144、（OR 1.23，95%CI 1.14-1.32，= 1.4e-8）。在仅比较 iNPH 患者（n = 1055）与对照组（n = 451091）的敏感性分析中，靠近以下基因的 4 个最高位点仍然显著：rs7962263、（OR 0.70，95%CI 0.63-0.78，= 2.1e-11）；rs10828247、（OR 0.74，95%CI 0.62-0.82，= 4.6e-10）；rs798511、/（OR 1.28，95%CI 1.17-1.39，= 1.7e-8）；和 rs56023709、（OR 1.28，95%CI 1.17-1.39，= 1.7e-8）。
我们在迄今为止最大的慢性脑积水 GWAS 中鉴定出 6 个与 NPH 显著相关的位点。靠近最高位点的基因先前与血脑屏障和血脑脊液屏障功能以及侧脑室体积增加有关。在 NPH 和 iNPH 队列中，效应大小和等位基因频率仍然相似，表明鉴定出的位点是 iNPH 的风险决定因素，并且不太可能与其他病因的关联有关。然而，这些位点的确切作用仍然未知，需要进一步研究。
