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

Janice L. Farlow, Hai Lin, Laura Sauerbeck, Dongbing Lai, Daniel L. Koller, Elizabeth Pugh, Kurt Hetrick, Hua Ling, Rachel Kleinloog, Pieter Van Der Vlies, Patrick Deelen, Morris A. Swertz, Bon H. Verweij, Luca Regli, Gabriel J E Rinkel, Ynte M. Ruigrok, Kimberly Doheny, Yunlong Liu, Tatiana Foroud, FIA Study Investigators

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30 Citations (Scopus)


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.

Original languageEnglish
Article numbere0121104
Number of pages25
JournalPLoS ONE
Issue number3
Publication statusPublished - 24 Mar 2015
Externally publishedYes

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