Time Series Analysis of Nonlinear Head Dynamics Using Synthetic Data Generated with a Variably Saturated Model.

The performance of time series models is assessed using synthetic head series simulated with a numerical model that solves Richards' equation for variably saturated flow. Heads were simulated in a homogeneous unconfined aquifer between two parallel canals; measured daily precipitation and potential evaporation are specified at the land surface and root water uptake is simulated. The head response to a precipitation event is nonlinear and depends on the saturation degree and rainfall before and after the precipitation event while evaporation reduction occurs during summers. Synthetic series were generated for 27 years and three different soil types; the unsaturated zone thickness varies between 0 and >5 m. The synthetic head series were simulated with a linear and nonlinear time series model. Performance of a linear time series model with four parameters, using a scaled Gamma response, gave R2 values ranging from 0.67 to 0.96. The nonlinear time series model with five parameters simulates recharge using a root zone reservoir after which the head response to recharge is simulated with a scaled Gamma response function. The nonlinear time series model was able to simulate all synthetic head series very well with R2 values above 0.9 for almost all models. The head response of the nonlinear model to a single precipitation event compares well to the response of the variably saturated groundwater model. The provided scripts may be used to simulate synthetic head series for other climates or for systems with additional complexity to assess the performance of other data-driven models.

Drug classes affecting intracranial aneurysm risk: Genetic correlation and Mendelian randomization.

INTRODUCTION: There is no non-invasive treatment to prevent aneurysmal subarachnoid hemorrhage (ASAH) caused by intracranial aneurysm (IA) rupture. We aimed to identify drug classes that may affect liability to IA using a genetic approach. PATIENTS AND METHODS: Using genome-wide association summary statistics we calculated genetic correlation between unruptured IA (N = 2140 cases), ASAH (N = 5140) or the combined group, and liability to drug usage from 23 drug classes (N up to 320,000) independent of the risk factor high blood pressure. Next, we evaluated the causality and therapeutic potential of correlated drug classes using three different Mendelian randomization frameworks. RESULTS: Correlations with IA were found for antidepressants, paracetamol, acetylsalicylic acid, opioids, beta-blockers, and peptic ulcer and gastro-esophageal reflux disease drugs. MR showed no evidence that genetically predicted usage of these drug classes caused IA. Genetically predicted high responders to antidepressant drugs were at higher risk of IA (odds ratio [OR] = 1.61, 95% confidence interval (CI) = 1.09-2.39, p = 0.018) and ASAH (OR = 1.68, 95% CI = 1.07-2.65, p = 0.024) if they used antidepressant drugs. This effect was absent in non-users. For beta-blockers, additional analyses showed that this effect was not independent of blood pressure after all. A complex and likely pleiotropic relationship was found between genetic liability to chronic multisite pain, pain medication usage (paracetamol, acetylsalicylic acid, and opioids), and IA. CONCLUSIONS: We did not find drugs decreasing liability to IA and ASAH but found that antidepressant drugs may increase liability. We observed pleiotropic relationships between IA and other drug classes and indications. Our results improve understanding of pathogenic mechanisms underlying IA.

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis.

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

The impact of health literacy: associations with disease activity and medication prescription in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to explore the longitudinal associations between health literacy profiles and disease activity and medication prescription in patients with RA. METHODS: Patients with RA who previously completed the Health Literacy Questionnaire (HLQ) and were assigned 1 of 10 distinct health literacy profiles based on cluster analysis were further aggregated into three groups: 'several health literacy limitations', 'some health literacy limitations' and 'good health literacy'. Linear mixed modelling (LMM) was used to analyse the association between health literacy groups and disease activity over the course of 1 year. Chi-squared tests and logistic regression analyses were used to compare medication prescriptions between the groups. RESULTS: A total of 108 patients with RA were included. LMM showed a significant effect of health literacy group on disease activity over time (P = 0.010). Patients with 'good health literacy' had significantly lower disease activity over time [28-joint DAS with ESR (DAS28-ESR) = 2.4] than patients with 'several health literacy limitations' (DAS28-ESR = 3.1), independent of age, gender and education level. Patients with 'good health literacy' were most often prescribed a biologic DMARD (50%), whereas patients with 'some health literacy limitations' more commonly received a conventional synthetic DMARD only [72.7%; odds ratio (OR) 4.24], and patients with 'several health literacy limitations' were more often prescribed prednisolone (52.4%; OR 3.56). CONCLUSION: Significant differences in longitudinal disease activity and medication prescription were observed between groups with different health literacy levels. These results stress the importance of insights into the role of health literacy in treatment and outcomes in patients with RA.

Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases.

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n ≤ 2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. We inferred brain cell types for 3,549 cis-eQTLs by interaction analysis. We prioritized 186 cis-eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis-eQTLs with an inferred cell type, such as a neuron-specific cis-eQTL (CYP24A1) for multiple sclerosis. We further describe 737 trans-eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity.

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (ß=-4.82×10-3 per year [95% CI, -6.49×10-3 to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Interaction Effects Between Aquifer Thermal Energy Storage Systems.

Aquifer thermal energy storage (ATES) is an energy efficient technique to provide heating and cooling to buildings by storage of warm and cold water in aquifers. In regions with large demand for ATES, ATES adoption has lead to congestion problems in aquifers. The recovery of thermal energy stored in aquifers can be increased by reducing the distance between wells of the same temperature while safeguarding individual system performance. Although this approach is implemented in practice, the understanding of how this affects both the recovery efficiency and the needed pumping energy is lacking. In this research, the effect of well placement on the performance of individual systems is quantified, and guidelines for planning and design are developed. Results show an increase in thermal recovery efficiency of individual systems when the thermal zones of wells of the same temperature are combined, which is explained by reduced surface area of the thermal zone over which losses occur. The highest increase of the thermal recovery efficiency is found for systems with a small storage volume and long well screens. The relative increase of the thermal recovery efficiency is 12% for average-sized systems with a storage volume of 250,000 m3 /year, and 25% for small systems (50,000 m3 /year). The optimal distance between wells of the same temperature is 0.5 times the thermal radius, following the trade-off between an increase of the thermal recovery efficiency and the increase in pumping energy. The distance between wells of opposite temperature must be larger than three times the thermal radius to avoid negative interaction.

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH. METHODS: Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools. RESULTS: One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12-1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis  = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL  = 1.3 × 10-7 ). CONCLUSIONS: The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

A Genome-Wide Association Study of Outcome After Aneurysmal Subarachnoid Haemorrhage: Discovery Analysis.

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10-4), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10-8) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment.

Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study.

BACKGROUND: In a genome-wide association study of intracranial aneurysms (IA), enrichment was found between genes associated with IA and genes encoding targets of effective anti-epileptic drugs. Our aim was to assess if this pleiotropy is driven by shared disease mechanisms that could potentially highlight a treatment strategy for IA. METHODS: Using 2-sample inverse-variance weighted Mendelian randomization and genetic colocalization analyses we assessed: (1) if epilepsy liability in general affects IA risk, and (2) whether changes in gene- and protein-expression levels of anti-epileptic drug targets in blood and arterial tissue may causally affect IA risk. RESULTS: We found no overall effect of epilepsy liability on IA. Expression of 21 genes and 13 proteins corresponding to anti-epileptic drug targets supported a causal effect (P<0.05) on IA risk. Of those genes and proteins, genetic variants affecting CNNM2 levels showed strong evidence for colocalization with IA risk (posterior probability>70%). Higher CNNM2 levels in arterial tissue were associated with increased IA risk (odds ratio, 3.02; [95% CI, 2.32-3.94]; P=3.39×10-16). CNNM2 expression was best proxied by rs11191580. The magnitude of the effect of this variant was greater than would be expected if systemic blood pressure was the sole IA-causing mechanism in this locus. CONCLUSIONS: CNNM2 is a driver of the pleiotropy between IA and anti-epileptic drug targets. Administration of the anti-epileptic drugs phenytoin, valproic acid, or carbamazepine may be expected to decrease CNNM2 levels and therefore subsequently decrease IA risk. CNNM2 is therefore an important target to investigate further for its role in the pathogenesis of IA.

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Consideration of health literacy in patient information: a mixed-methods study of COVID-19 crisis communication in Dutch rheumatology.

BACKGROUND: The rapid spread of COVID-19 required swift action to provide people with rheumatic and musculoskeletal diseases (RMDs) with reliable information. People with limited health literacy constitute a vulnerable group that might have difficulty accessing, understanding and applying health information, particularly in times of crisis. OBJECTIVES: This study explored (a) key aspects of crisis communication and (b) explicit consideration of people's health literacy needs in communication to people with RMDs during the first wave of COVID-19 in the Netherlands. METHODS: We conducted a convergent, qualitatively driven mixed-methods study comprising seven qualitative interviews with professional representatives of organisations responsible for information provision to people with RMDs, and quantitative analysis of 15 patient information materials distributed by these organisations. The study was guided by principles of crisis communication and health literacy. We assessed understandability and actionability of information materials using the Dutch version of the Patient Education Materials Assessment Tool (PEMAT, resulting in a percentage of quality criteria met), and language difficulty level using an online application (assessing difficult words, jargon, passive, complex and long sentences, long paragraphs, and difficulty levels according to the Common European Framework of Reference for Languages (CEFR, from A1 (basic) to C2 (proficient))). RESULTS: Respondents reported lack of preparedness, challenges related to scientific uncertainty and reaching the target group, difficulty simplifying information, and uncertainty regarding adequacy of the communication approach. Patient information materials (written and video) showed variation in actionability (range 60-100%) and understandability (range 58-100%), and 69% of written materials were too difficult, mostly due to the use of long sentences and difficult words. The quantitative findings were in coherence with the limitations in communication reported by respondents. Several potential improvements were formulated in 'lessons learned'. CONCLUSIONS: Although rheumatology organisations mostly adhered to principles of crisis communication and made efforts to adapt information to their audience's needs, we propose recommendations to improve preparedness, strategy, content, reach and consideration of health literacy needs in future crisis communication.

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis.

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

BACKGROUND: The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization). METHODS: We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG. RESULTS: Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05-1.34]; P=0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55-0.95]; P=0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05-1.40]; P=0.008). No other causal associations were identified. CONCLUSIONS: Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

Exploring discordance between Health Literacy Questionnaire scores of people with RMDs and assessment by treating health professionals.

OBJECTIVES: We studied discordance between health literacy of people with rheumatic and musculoskeletal diseases (RMDs) and assessment of health literacy by their treating health professionals, and explored whether discordance is associated with the patients' socioeconomic background. METHODS: Patients with RA, spondyloarthritis (SpA) or gout from three Dutch outpatient rheumatology clinics completed the nine-domain Health Literacy Questionnaire (HLQ). Treating health professionals assessed their patients on each HLQ domain. Discordance per domain was defined as a ≥2-point difference on a 0-10 scale (except if both scores were below three or above seven), leading to three categories: 'negative discordance' (i.e. professional scored lower), 'probably the same' or 'positive discordance' (i.e. professional scored higher). We used multivariable multilevel multinomial regression models with patients clustered by health professionals to test associations with socioeconomic factors (age, gender, education level, migration background, employment, disability for work, living alone). RESULTS: We observed considerable discordance (21-40% of patients) across HLQ domains. Most discordance occurred for 'Critically appraising information' (40.5%, domain 5). Comparatively, positive discordance occurred more frequently. Negative discordance was more frequently and strongly associated with socioeconomic factors, specifically lower education level and non-Western migration background (for five HLQ domains). Associations between socioeconomic factors and positive discordance were less consistent. CONCLUSION: Frequent discordance between patients' scores and professionals' estimations indicates there may be hidden challenges in communication and care, which differ between socioeconomic groups. Successfully addressing patients' health literacy needs cannot solely depend on health professionals' estimations but will require measurement and dialogue. VIDEO ABSTRACT: A video abstract of this article can be found at https://www.youtube.com/watch?v=ggnB1rATdQ4.

Genome-wide linkage analysis combined with genome sequencing in large families with intracranial aneurysms.

Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging variants for IA in three large Dutch families with multiple affected members with IA (N = 9, 11, and 6). By combining linkage analysis and genome sequencing (GS), we identified six rare and damaging variants for which all cases within one of the families were heterozygous. These variants were p.Tyr87Cys in SYCP1, p.Phe1077Leu in FMNL2, p.Thr754Lys in TBC1D2, p.Arg321His in ZNF782, p.Arg979Trp in CCDC180, and p.Val125Met in NCBP1. None of the variants showed association with IA status in a large cohort of 937 patients from the general IA patient population and 1046 controls. Gene expression in IA and cerebral artery tissue further prioritized FMNL2 and TBC1D2 as potential important players in IA pathophysiology. Further studies are needed to characterize the functional consequences of the identified variants and their role in the biological mechanisms of IA.