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dc.contributor.authorFarlow, JL
dc.contributor.authorLin, H
dc.contributor.authorSauerbeck, L
dc.contributor.authorLai, D
dc.contributor.authorKoller, DL
dc.contributor.authorPugh, E
dc.contributor.authorHetrick, K
dc.contributor.authorLing, H
dc.contributor.authorKleinloog, R
dc.contributor.authorvan der Vlies, P
dc.contributor.authorDeelen, P
dc.contributor.authorSwertz, MA
dc.contributor.authorVerweij, BH
dc.contributor.authorRegli, L
dc.contributor.authorRinkel, GJE
dc.contributor.authorRuigrok, YM
dc.contributor.authorDoheny, K
dc.contributor.authorLiu, Y
dc.contributor.authorBroderick, J
dc.contributor.authorForoud, T
dc.contributor.authorFIA Study Investigators,
dc.date.accessioned2020-12-21T01:04:38Z
dc.date.available2020-12-21T01:04:38Z
dc.date.issued2015
dc.identifierpii: PONE-D-14-33401
dc.identifier.citationFarlow, J. L., Lin, H., Sauerbeck, L., Lai, D., Koller, D. L., Pugh, E., Hetrick, K., Ling, H., Kleinloog, R., van der Vlies, P., Deelen, P., Swertz, M. A., Verweij, B. H., Regli, L., Rinkel, G. J. E., Ruigrok, Y. M., Doheny, K., Liu, Y., Broderick, J. ,... 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), pp.e0121104-. https://doi.org/10.1371/journal.pone.0121104.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11343/256356
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.
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleLessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pone.0121104
melbourne.affiliation.departmentSurgery (RMH)
melbourne.source.titlePLoS One
melbourne.source.volume10
melbourne.source.issue3
melbourne.source.pagese0121104-
dc.rights.licenseCC BY
melbourne.elementsid1218345
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372548
melbourne.contributor.authorLaidlaw, John
dc.identifier.eissn1932-6203
melbourne.accessrightsOpen Access


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