Melanie D Laarman1, Marit W Vermunt1, Rachel Kleinloog1, Jelkje J de Boer-Bergsma1, Netherlands Brain Bank1, Gabriël J E Rinkel1, Menno P Creyghton1, Michal Mokry1, Jeroen Bakkers1, Ynte M Ruigrok2. 1. From the Department of Neurology and Neurosurgery (M.D.L., R.K., G.J.E., Y.M.R.), Hubrecht Institute-KNAW, and Division of Heart and Lungs, Department of Medical Physiology (J.B.), University Medical Center Utrecht, the Netherlands (M.D.L., M.W.V., M.P.C., J.B.); Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (J.J.d.B.-B.); Netherlands Institute for Neuroscience, Amsterdam (N.B.B.); and Division of Pediatrics, Wilhelmina Children's Hospital, Utrecht, the Netherlands (M.M.). 2. From the Department of Neurology and Neurosurgery (M.D.L., R.K., G.J.E., Y.M.R.), Hubrecht Institute-KNAW, and Division of Heart and Lungs, Department of Medical Physiology (J.B.), University Medical Center Utrecht, the Netherlands (M.D.L., M.W.V., M.P.C., J.B.); Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (J.J.d.B.-B.); Netherlands Institute for Neuroscience, Amsterdam (N.B.B.); and Division of Pediatrics, Wilhelmina Children's Hospital, Utrecht, the Netherlands (M.M.). ij.m.ruigrok@umcutrecht.nl.
Abstract
BACKGROUND AND PURPOSE: Genome-wide association studies significantly link intracranial aneurysm (IA) to single-nucleotide polymorphisms (SNPs) in 6 genomic loci. To gain insight into the relevance of these IA-associated SNPs, we aimed to identify regulatory regions and analyze overall gene expression in the human circle of Willis (CoW), on which these aneurysms develop. METHODS: We performed chromatin immunoprecipitation and sequencing for histone modifications H3K4me1 and H3K27ac to identify regulatory regions, including distal enhancers and active promoters, in postmortem specimens of the human CoW. These experiments were complemented with RNA sequencing on the same specimens. We determined whether these regulatory regions overlap with IA-associated SNPs, using computational methods. By combining our results with publicly available data, we investigated the effect of IA-associated SNPs on the newly identified regulatory regions and linked them to potential target genes. RESULTS: We find that IA-associated SNPs are significantly enriched in CoW regulatory regions. Some of the IA-associated SNPs that overlap with a regulatory region are likely to alter transcription factor binding, and in proximity to these regulatory regions are 102 genes that are expressed in the CoW. In addition, gene expression in the CoW is enriched for genes related to cell adhesion and the extracellular matrix. CONCLUSIONS: CoW regulatory regions link IA-associated SNPs to genes with a potential role in the development of IAs. Our data refine previous predictions on SNPs associated with IA and provide a substantial resource from which candidates for follow-up studies can be prioritized.
BACKGROUND AND PURPOSE: Genome-wide association studies significantly link intracranial aneurysm (IA) to single-nucleotide polymorphisms (SNPs) in 6 genomic loci. To gain insight into the relevance of these IA-associated SNPs, we aimed to identify regulatory regions and analyze overall gene expression in the human circle of Willis (CoW), on which these aneurysms develop. METHODS: We performed chromatin immunoprecipitation and sequencing for histone modifications H3K4me1 and H3K27ac to identify regulatory regions, including distal enhancers and active promoters, in postmortem specimens of the humanCoW. These experiments were complemented with RNA sequencing on the same specimens. We determined whether these regulatory regions overlap with IA-associated SNPs, using computational methods. By combining our results with publicly available data, we investigated the effect of IA-associated SNPs on the newly identified regulatory regions and linked them to potential target genes. RESULTS: We find that IA-associated SNPs are significantly enriched in CoW regulatory regions. Some of the IA-associated SNPs that overlap with a regulatory region are likely to alter transcription factor binding, and in proximity to these regulatory regions are 102 genes that are expressed in the CoW. In addition, gene expression in the CoW is enriched for genes related to cell adhesion and the extracellular matrix. CONCLUSIONS:CoW regulatory regions link IA-associated SNPs to genes with a potential role in the development of IAs. Our data refine previous predictions on SNPs associated with IA and provide a substantial resource from which candidates for follow-up studies can be prioritized.
Authors: Melanie D Laarman; Geert Geeven; Phil Barnett; Gabriël J E Rinkel; Wouter de Laat; Ynte M Ruigrok; Jeroen Bakkers Journal: J Am Heart Assoc Date: 2019-05-07 Impact factor: 5.501
Authors: Kerry E Poppenberg; Kaiyu Jiang; Michael K Tso; Kenneth V Snyder; Adnan H Siddiqui; John Kolega; James N Jarvis; Hui Meng; Vincent M Tutino Journal: BMC Med Genomics Date: 2019-10-30 Impact factor: 3.063