Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0121104 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850125437517168640 |
|---|---|
| author | 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 Joseph Broderick Tatiana Foroud FIA Study Investigators |
| author_facet | 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 Joseph Broderick Tatiana Foroud FIA Study Investigators |
| author_sort | Janice L Farlow |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0d9ffcc547fe408595dcf0bded78c1a9 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-0d9ffcc547fe408595dcf0bded78c1a92025-08-20T02:34:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e012110410.1371/journal.pone.0121104Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.Janice L FarlowHai LinLaura SauerbeckDongbing LaiDaniel L KollerElizabeth PughKurt HetrickHua LingRachel KleinloogPieter van der VliesPatrick DeelenMorris A SwertzBon H VerweijLuca RegliGabriel J E RinkelYnte M RuigrokKimberly DohenyYunlong LiuJoseph BroderickTatiana ForoudFIA Study InvestigatorsGenetic 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.https://doi.org/10.1371/journal.pone.0121104 |
| spellingShingle | 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 Joseph Broderick Tatiana Foroud FIA Study Investigators Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. PLoS ONE |
| title | Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. |
| title_full | Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. |
| title_fullStr | Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. |
| title_full_unstemmed | Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. |
| title_short | Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. |
| title_sort | lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder intracranial aneurysm |
| url | https://doi.org/10.1371/journal.pone.0121104 |
| work_keys_str_mv | AT janicelfarlow lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT hailin lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT laurasauerbeck lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT dongbinglai lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT daniellkoller lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT elizabethpugh lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT kurthetrick lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT hualing lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT rachelkleinloog lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT pietervandervlies lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT patrickdeelen lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT morrisaswertz lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT bonhverweij lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT lucaregli lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT gabrieljerinkel lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT yntemruigrok lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT kimberlydoheny lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT yunlongliu lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT josephbroderick lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT tatianaforoud lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm AT fiastudyinvestigators lessonslearnedfromwholeexomesequencinginmultiplexfamiliesaffectedbyacomplexgeneticdisorderintracranialaneurysm |