Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

dc.contributor.authorFarlow, Janice L.
dc.contributor.authorLin, Hai
dc.contributor.authorSauerbeck, Laura
dc.contributor.authorLai, Dongbing
dc.contributor.authorKoller, Daniel L.
dc.contributor.authorPugh, Elizabeth
dc.contributor.authorHetrick, Kurt
dc.contributor.authorLing, Hua
dc.contributor.authorKleinloog, Rachel
dc.contributor.authorvan der Vlies, Peter
dc.contributor.authorDeelen, Patrick
dc.contributor.authorSwertz, Morris A.
dc.contributor.authorVerweij, Bon H.
dc.contributor.authorRegli, Luca
dc.contributor.authorRinkel, Gabriel J.E.
dc.contributor.authorRuigrok, Ynte M.
dc.contributor.authorDoheny, Kimberly
dc.contributor.authorLiu, Yunlong
dc.contributor.authorBroderick, Joseph
dc.contributor.authorForoud, Tatiana
dc.contributor.departmentDepartment of Medical and Molecular Genetics, IU School of Medicineen_US
dc.date.accessioned2016-06-17T15:48:40Z
dc.date.available2016-06-17T15:48:40Z
dc.date.issued2015-03-24
dc.description.abstractGenetic 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.en_US
dc.identifier.citationFarlow, J. L., Lin, H., Sauerbeck, L., Lai, D., Koller, D. L., Pugh, E., … FIA Study Investigators. (2015). Lessons Learned from Whole Exome Sequencing in Multiplex Families Affected by a Complex Genetic Disorder, Intracranial Aneurysm. PLoS ONE, 10(3), e0121104. http://doi.org/10.1371/journal.pone.0121104en_US
dc.identifier.urihttps://hdl.handle.net/1805/10026
dc.language.isoen_USen_US
dc.publisherPLoSen_US
dc.relation.isversionof10.1371/journal.pone.0121104en_US
dc.relation.journalPLoS ONEen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectBase sequenceen_US
dc.subjectChromosome mappingen_US
dc.subjectIntracranial aneurysmen_US
dc.subjectMembrane proteinsen_US
dc.titleLessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysmen_US
dc.typeArticleen_US
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