Browsing by Author "Rinkel, Gabriel J.E."

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    Exome-chip association analysis of intracranial aneurysms
    (American Academy of Neurology, 2020-02-04) van 't Hof, Femke N.G.; Lai, Dongbing; van Setten, Jessica; Bots, Michiel L.; Vaartjes, Ilonca; Broderick, Joseph; Woo, Daniel; Foroud, Tatiana; Rinkel, Gabriel J.E.; de Bakker, Paul I.W.; Ruigrok, Ynte M.; Medical and Molecular Genetics, School of Medicine
    Objective: To investigate to what extent low-frequency genetic variants (with minor allele frequencies <5%) affect the risk of intracranial aneurysms (IAs). Methods: One thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis. Results: After QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 (FBLN2) (best p = 1 × 10-6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort (p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10-7 for the SKAT, MAC ≥1). Conclusion: Gene-based tests indicated an association for FBLN2, a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants.
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    Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis
    (MDPI, 2022-08-30) Morel, Sandrine; Hostettler, Isabel C.; Spinner, Georg R.; Bourcier, Romain; Pera, Joanna; Meling, Torstein R.; Alg, Varinder S.; Houlden, Henry; Bakker, Mark K.; van’t Hof, Femke; Rinkel, Gabriel J.E.; Foroud, Tatiana; Lai, Dongbing; Moomaw, Charles J.; Worrall, Bradford B.; Caroff, Jildaz; Constant-dits-Beaufils, Pacôme; Karakachoff, Matilde; Rimbert, Antoine; Rouchaud, Aymeric; Gaal-Paavola, Emilia I.; Kaukovalta, Hanna; Kivisaari, Riku; Laakso, Aki; Jahromi, Behnam Rezai; Tulamo, Riikka; Friedrich, Christoph M.; Dauvillier, Jerome; Hirsch, Sven; Isidor, Nathalie; Kulcsàr, Zolt; Lövblad, Karl O.; Martin, Olivier; Machi, Paolo; Pereira, Vitor Mendes; Rüfenacht, Daniel; Schaller, Karl; Schilling, Sabine; Slowik, Agnieszka; Jaaskelainen, Juha E.; von und zu Fraunberg, Mikael; Jiménez-Conde, Jordi; Cuadrado-Godia, Elisa; Soriano-Tárraga, Carolina; Millwood, Iona Y.; Walters, Robin G.; The @neurIST project; The ICAN Study Group; Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators; International Stroke Genetics Consortium (ISGC); Kim, Helen; Redon, Richard; Ko, Nerissa U.; Rouleau, Guy A.; Lindgren, Antti; Niemelä, Mika; Desal, Hubert; Woo, Daniel; Broderick, Joseph P.; Werring, David J.; Ruigrok, Ynte M.; Bijlenga, Philippe; Medical and Molecular Genetics, School of Medicine
    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.
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    Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
    (PLoS, 2015-03-24) Farlow, Janice L.; Lin, Hai; Sauerbeck, Laura; Lai, Dongbing; Koller, Daniel L.; Pugh, Elizabeth; Hetrick, Kurt; Ling, Hua; Kleinloog, Rachel; van der Vlies, Peter; Deelen, Patrick; Swertz, Morris A.; Verweij, Bon H.; Regli, Luca; Rinkel, Gabriel J.E.; Ruigrok, Ynte M.; Doheny, Kimberly; Liu, Yunlong; Broderick, Joseph; Foroud, Tatiana; Department of Medical and Molecular Genetics, IU School of Medicine
    Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.