Risk Variants Associated With Normal Pressure Hydrocephalus
Joel Räsänen, Sami Heikkinen, Kiira Mäklin, Anssi Lipponen, Teemu Kuulasmaa, Juha Mehtonen, Ville E. Korhonen, Antti Junkkari, Benjamin Grenier‐Boley, Céline Bellenguez, Minna Oinas, Cecilia Avellan, Janek Frantzén, Anna Kotkansalo, Jaakko Rinne, Antti Ronkainen, Mikko Kauppinen, Mikael von und zu Fraunberg, Kimmo Lönnrot, Jarno Satopää, Markus Perola, Anne M. Koivisto, Valtteri Julkunen, Anne M. Portaankorva, Arto Mannermaa, Hilkka Soininen, Seppo Helisalmi, Juha E. Jääskeläinen, Jean‐Charles Lambert, Per Kristian Eide, for FinnGen, Aarno Palotie, Mitja Kurki, Mikko Hiltunen, Ville Leinonen
Abstract
Background and ObjectivesLarge-scale genome-wide studies of chronic hydrocephalus have been lacking.We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH). MethodsWe 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 ICD-10 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. ResultsWe 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 (p < 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, SLCO1A2 (odds ratio [OR] 0.71, 95% CI 0.65-0.78,p = 1.0e-14); rs798495, AMZ1/GNA12 (OR 1.29, 95% CI 1.20-1.39,p = 2.9e-12); rs10828247, MLLT10 (OR 0.77, 95% CI 0.71-0.83,p = 1.5e-11); rs561699566 and rs371919113, CDCA2 (OR 0.76, 95% CI 0.70-0.82,p = 1.5e-11); rs56023709, C16orf95 (OR 1.24, 95% CI 1.16-1.33,p = 3.0e-9); and rs62434144, PLEKHG1 (OR 1.23, 95% CI 1.14-1.32,p = 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