Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort

Abstract

Background and objectives: Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH).

Methods: 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 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.

Results: 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 (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 the following genes remained significant: rs7962263, SLCO1A2 (OR 0.70, 95% CI 0.63-0.78, p = 2.1e-11); rs10828247, MLLT10 (OR 0.74, 95% CI 0.62-0.82, p = 4.6e-10); rs798511, AMZ1/GNA12 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8); and rs56023709, C16orf95 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8).

Discussion: 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.

Figure 1. Flowchart of Participant Selection for the NPH GWAS and the Exclusion of the Potential sNPH Cases for the Sensitivity Analysis With iNPH and Shunted iNPH Cohorts

GWAS = genome-wide association study; (i)NPH = (idiopathic) normal pressure hydrocephalus; QC = quality control; TBI = traumatic brain injury. *Cases of the FinnGen G6_HYDROCEPH end point.

Figure 2. Manhattan Plot* of the NPH GWAS

*The nearest genes of the top associated loci (p < 5.0e-8) replicating (black) and failing to replicate (gray) with the UKBB data, and the previously iNPH associated genes (in red) are indicated in the plot. The y-axis displays −log10 p-values with the dotted line indicating the location of the untransformed limit of genome-wide significance (p = 5.0e-8). The x-axis displays the chromosome number. NPH n = 1,522 and controls n = 451,091. GWAS = genome-wide association study; NPH = normal pressure hydrocephalus; UKBB = UK Biobank.

Figure 3. Regional Association Plots of the 3 Top NPH-Associated Loci* at (A) 12p12.1, (B) 7p22.3, and (C) 10p12.31

*Fine-mapped leading variants are indicated in their respective loci with rsid. The purple dot represents the leading variant of each credible set, and the surrounding variants are colored according to pairwise genotype correlation R2 with the leading variant. The y-axis displays the −log10 p-values and x-axis the chromosome position and gene annotations in GRCh38 coordinates. NPH = normal pressure hydrocephalus.