title: Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.
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.
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Janice L
authors: JL
authors: Farlow
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Hai
authors: H
authors: Lin
authors: Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
authors: Laura
authors: L
authors: Sauerbeck
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Dongbing
authors: D
authors: Lai
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Daniel L
authors: DL
authors: Koller
authors: Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America.
authors: Elizabeth
authors: E
authors: Pugh
authors: Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America.
authors: Kurt
authors: K
authors: Hetrick
authors: Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America.
authors: Hua
authors: H
authors: Ling
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Rachel
authors: R
authors: Kleinloog
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Pieter
authors: P
authors: van der Vlies
authors: 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 Netherlands.
authors: Patrick
authors: P
authors: Deelen
authors: 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 Netherlands.
authors: Morris A
authors: MA
authors: Swertz
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Bon H
authors: BH
authors: Verweij
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
authors: Luca
authors: L
authors: Regli
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Gabriel J E
authors: GJ
authors: Rinkel
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Ynte M
authors: YM
authors: Ruigrok
authors: Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America.
authors: Kimberly
authors: K
authors: Doheny
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Yunlong
authors: Y
authors: Liu
authors: Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
authors: Joseph
authors: J
authors: Broderick
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Tatiana
authors: T
authors: Foroud
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D015331:Cohort Studies; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C000604779:TMEM132B protein, human