1. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
- Author
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Nerissa U. Ko, Kimberly F. Doheny, Robert D. Brown, Paul D'Urso, Khaled Aziz, Gary G. Ferguson, Yunlong Liu, Janice L. Farlow, Rachel Kleinloog, Dongbing Lai, Jeffrey V. Rosenfeld, Rose Du, Alex Schneider, Hua Ling, Dawn Kleindorfer, Andrew J. Ringer, Patrick Deelen, Neville W. Knuckey, Bradford B. Worrall, Michael K. Morgan, John Huston, Michael Besser, John Laidlaw, Luca Regli, Brett M. Kissela, Tatiana Foroud, Gabriel J.E. Rinkel, Steven L. Giannotta, Elizabeth W. Pugh, Bon H. Verweij, Troy D. Payner, E. Sander Connolly, Graeme J. Hankey, Ynte M. Ruigrok, Stephen B. Lewis, Joan E. Bailey-Wilson, Hai Lin, Lewis B. Morgenstern, E. Francois Aldrich, Martin G. Radvany, Aaron S. Dumont, Mario Zuccarello, Irene Mesissner, Edward W. Mee, Pieter van der Vlies, M. T. Richard, Colin P. Derdeyn, Ranjan Deka, Winfield S. Fisher, David O. Wiebers, Laura Sauerbeck, Anthony M. Kaufmann, H. Hunt Batjer, Lynda D. Lisabeth, David L. Tirschell, Nicholas W. C. Dorsch, Gary K. Steinberg, Peter L. Reilly, Amin B. Kassam, Craig S. Anderson, Aditya S. Pandey, Daniel L. Koller, Peter A. Rasmussen, Morris A. Swertz, Joseph P. Broderick, Guy A. Rouleau, Dheerah Gandhi, Ralph L. Sacco, Kurt N. Hetrick, S. Claiborne Johnston, Arthur L. Day, Marc Malkaff, Carl D. Langefeld, Kieran P. Murphy, Neal F. Kassell, Adnan I. Qureshi, Kenneth C. Lui, Christopher S. Ogilvy, Daniel Woo, University of Zurich, and Li, Yun
- Subjects
lcsh:Medicine ,Genome-wide association study ,Biochemistry ,DISEASE ,FIA Study Investigators ,Cohort Studies ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Exome ,Aetiology ,lcsh:Science ,Exome sequencing ,Genetics ,Medicine(all) ,0303 health sciences ,Multidisciplinary ,Agricultural and Biological Sciences(all) ,Genetic disorder ,Chromosome Mapping ,Pedigree ,Stroke ,Phenotype ,RARE VARIANTS ,POPULATIONS ,Sequence Analysis ,Research Article ,General Science & Technology ,Molecular Sequence Data ,610 Medicine & health ,1100 General Agricultural and Biological Sciences ,Biology ,DNA sequencing ,AORTIC-ANEURYSM ,03 medical and health sciences ,10180 Clinic for Neurosurgery ,Genetic linkage ,Clinical Research ,1300 General Biochemistry, Genetics and Molecular Biology ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,GENOME-WIDE ASSOCIATION ,SUBARACHNOID HEMORRHAGE ,METAANALYSIS ,030304 developmental biology ,1000 Multidisciplinary ,Base Sequence ,Biochemistry, Genetics and Molecular Biology(all) ,MUTATIONS ,lcsh:R ,Human Genome ,Neurosciences ,Computational Biology ,Genetic Variation ,Membrane Proteins ,Intracranial Aneurysm ,DNA ,Sequence Analysis, DNA ,medicine.disease ,FRAMEWORK ,RISK LOCI ,Brain Disorders ,lcsh:Q ,030217 neurology & neurosurgery ,Genetics and Molecular Biology(all) - Abstract
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.
- Published
- 2015