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; Joseph Broderick; Tatiana Foroud; FIA Study Investigators

doi:10.1371/journal.pone.0121104

Back

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

Journal article

Open access

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, …

PloS one, Vol.10(3), pp.e0121104-e0121104

2015

DOI: https://doi.org/10.1371/journal.pone.0121104

PMCID: PMC4372548

PMID: 25803036

Appears in UM Open Access Research Published in PloS

Abstract

Genetic Predisposition to Disease - genetics

Intracranial Aneurysm - genetics

Membrane Proteins - genetics

Humans

Computational Biology

Molecular Sequence Data

Chromosome Mapping

Sequence Analysis, DNA

Genetic Variation

Exome - genetics

Phenotype

Pedigree

Base Sequence

Intracranial Aneurysm - pathology

Cohort Studies

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.

Files and links (1)

url

https://doi.org/10.1371/journal.pone.0121104View

Published (Version of record) Open

Metrics

8 Record Views

26 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.105 Strokes; 1.105.514 Subarachnoid Hemorrhage
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
Creators: Janice L Farlow - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Hai Lin - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Laura Sauerbeck - Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America
Dongbing Lai - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Daniel L Koller - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Elizabeth Pugh - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America
Kurt Hetrick - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America
Hua Ling - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America
Rachel Kleinloog - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Pieter van der Vlies - Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Patrick Deelen - 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
Morris A Swertz - 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
Bon H Verweij - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Luca Regli - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
Gabriel J E Rinkel - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Ynte M Ruigrok - Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Kimberly Doheny - Center for Inherited Disease Research, Johns Hopkins University; Baltimore, Maryland, United States of America
Yunlong Liu - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Joseph Broderick - Department of Neurology and Rehabilitation Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America
Tatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
FIA Study Investigators
Publication Details: PloS one, Vol.10(3), pp.e0121104-e0121104
Grant note: R03NS083468 / NINDS NIH HHS HHSN268200782096C / PHS HHS R01NS39512 / NINDS NIH HHS R01 NS039512 / NINDS NIH HHS HHSN268200782096C / NHGRI NIH HHS T32 GM077229 / NIGMS NIH HHS HHSN268201200008I / NHLBI NIH HHS R03 NS083468 / NINDS NIH HHS HHSN268201100011I / PHS HHS HHSN268201200008I / PHS HHS HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS TL1 TR000162 / NCATS NIH HHS HHSN268201200008C / NHLBI NIH HHS
Language: English
Resource Type: Journal article
PMID: 25803036
PMCID: PMC4372548
Record Identifier: 991031600280302976