Journal article
Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
PloS one, Vol.10(3), pp.e0121104-e0121104
2015
DOI: 10.1371/journal.pone.0121104
PMCID: PMC4372548
PMID: 25803036
Abstract
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.
Details
- Title: Subtitle
- Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
- Creators
- Hai Lin - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of AmericaLaura Sauerbeck - Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of AmericaDongbing Lai - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of AmericaDaniel L Koller - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of AmericaElizabeth Pugh - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of AmericaKurt Hetrick - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of AmericaHua Ling - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of AmericaRachel Kleinloog - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the NetherlandsPieter van der Vlies - Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsPatrick Deelen - Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsMorris A Swertz - Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsBon H Verweij - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the NetherlandsLuca Regli - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Neurosurgery, University Hospital Zurich, Zurich, SwitzerlandGabriel J E Rinkel - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the NetherlandsYnte M Ruigrok - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the NetherlandsKimberly Doheny - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of AmericaYunlong Liu - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of AmericaJoseph Broderick - Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of AmericaTatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of AmericaFIA Study InvestigatorsFamilial Intracranial Aneurysm (FIA) Study Investigators
- Contributors
- Colin P Derdeyn (Contributor) - University of Iowa, Radiology
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.10(3), pp.e0121104-e0121104
- DOI
- 10.1371/journal.pone.0121104
- PMID
- 25803036
- PMCID
- PMC4372548
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; United States
- Grant note
- R03NS083468 / NINDS NIH HHS HHSN268200782096C / PHS HHS R01NS39512 / NINDS NIH HHS R01 NS039512 / NINDS NIH HHS HHSN268200782096C / NHGRI NIH HHS T32 GM077229 / NIGMS NIH HHS HHSN268201200008I / NHLBI NIH HHS R03 NS083468 / NINDS NIH HHS HHSN268201100011I / PHS HHS HHSN268201200008I / PHS HHS HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS TL1 TR000162 / NCATS NIH HHS HHSN268201200008C / NHLBI NIH HHS
- Language
- English
- Date published
- 2015
- Academic Unit
- Neurology; Radiology; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984013113202771
Metrics
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