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, Joseph Broderick & 59 others Daniel Woo, Brett Kissela, Dawn Kleindorfer, Alex Schneider, Mario Zuccarello, Andrew Ringer, Ranjan Deka, Robert D. Brown, John Huston, Irene Mesissner, David Wiebers, Adnan I. Qureshi, Peter A. Rasmussen, E. Sander Connolly, Ralph L. Sacco, Marc Malkaff, Troy D. Payner, Gary G. Ferguson, E. Francois Aldrich, Guy Rouleau, Craig S. Anderson, Edward W. Mee, Graeme J. Hankey, Neville Knuckey, Peter L. Reilly, John D. Laidlaw, Paul D'Urso, Jeffrey V. Rosenfeld, Michael K. Morgan, Nicholas Dorsch, Michael Besser, H. Hunt Batjer, Michael T. Richard, Amin Kassam, Gary K. Steinberg, S. Claiborne Johnston, Nerissa U. Ko, Steven L. Giannotta, Neal F. Kassell, Bradford B. Worrall, Kenneth C. Lui, Aaron Dumont, David L. Tirschell, Anthony M. Kaufmann, Winfield S. Fisher, Khaled Mohamed Abdel Aziz, Arthur L. Day, Rose Du, Christopher Ogilvy, Stephen B. Lewis, Kieran P. Murphy, Martin Radvany, Dheerah Gandhi, Lynda Lisabeth, Aditya Pandey, Lewis Morgenstern, Colin Derdeyn, Carl Langefeld, Joan Bailey-Wilson

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0121104
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 24 2015

Fingerprint

Exome
aneurysm
Inborn Genetic Diseases
Intracranial Aneurysm
genetic disorders
Genes
genes
prioritization
Gene Expression Profiling
transcriptomics
linkage (genetics)
Virulence
Tissue
risk factors
pathogenicity
experimental design
sampling
prediction

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Farlow, J. L., Lin, H., Sauerbeck, L., Lai, D., Koller, D. L., Pugh, E., ... Bailey-Wilson, J. (2015). Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. PLoS One, 10(3), [e0121104]. https://doi.org/10.1371/journal.pone.0121104

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. / Farlow, Janice L.; Lin, Hai; Sauerbeck, Laura; Lai, Dongbing; Koller, Daniel L.; Pugh, Elizabeth; Hetrick, Kurt; Ling, Hua; Kleinloog, Rachel; Van Der Vlies, Pieter; Deelen, Patrick; Swertz, Morris A.; Verweij, Bon H.; Regli, Luca; Rinkel, Gabriel J E; Ruigrok, Ynte M.; Doheny, Kimberly; Liu, Yunlong; Foroud, Tatiana; Broderick, Joseph; Woo, Daniel; Kissela, Brett; Kleindorfer, Dawn; Schneider, Alex; Zuccarello, Mario; Ringer, Andrew; Deka, Ranjan; Brown, Robert D.; Huston, John; Mesissner, Irene; Wiebers, David; Qureshi, Adnan I.; Rasmussen, Peter A.; Connolly, E. Sander; Sacco, Ralph L.; Malkaff, Marc; Payner, Troy D.; Ferguson, Gary G.; Aldrich, E. Francois; Rouleau, Guy; Anderson, Craig S.; Mee, Edward W.; Hankey, Graeme J.; Knuckey, Neville; Reilly, Peter L.; Laidlaw, John D.; D'Urso, Paul; Rosenfeld, Jeffrey V.; Morgan, Michael K.; Dorsch, Nicholas; Besser, Michael; Batjer, H. Hunt; Richard, Michael T.; Kassam, Amin; Steinberg, Gary K.; Johnston, S. Claiborne; Ko, Nerissa U.; Giannotta, Steven L.; Kassell, Neal F.; Worrall, Bradford B.; Lui, Kenneth C.; Dumont, Aaron; Tirschell, David L.; Kaufmann, Anthony M.; Fisher, Winfield S.; Aziz, Khaled Mohamed Abdel; Day, Arthur L.; Du, Rose; Ogilvy, Christopher; Lewis, Stephen B.; Murphy, Kieran P.; Radvany, Martin; Gandhi, Dheerah; Lisabeth, Lynda; Pandey, Aditya; Morgenstern, Lewis; Derdeyn, Colin; Langefeld, Carl; Bailey-Wilson, Joan.

In: PLoS One, Vol. 10, No. 3, e0121104, 24.03.2015.

Research output: Contribution to journalArticle

Farlow, JL, Lin, H, Sauerbeck, L, Lai, D, Koller, DL, Pugh, E, Hetrick, K, Ling, H, Kleinloog, R, Van Der Vlies, P, Deelen, P, Swertz, MA, Verweij, BH, Regli, L, Rinkel, GJE, Ruigrok, YM, Doheny, K, Liu, Y, Foroud, T, Broderick, J, Woo, D, Kissela, B, Kleindorfer, D, Schneider, A, Zuccarello, M, Ringer, A, Deka, R, Brown, RD, Huston, J, Mesissner, I, Wiebers, D, Qureshi, AI, Rasmussen, PA, Connolly, ES, Sacco, RL, Malkaff, M, Payner, TD, Ferguson, GG, Aldrich, EF, Rouleau, G, Anderson, CS, Mee, EW, Hankey, GJ, Knuckey, N, Reilly, PL, Laidlaw, JD, D'Urso, P, Rosenfeld, JV, Morgan, MK, Dorsch, N, Besser, M, Batjer, HH, Richard, MT, Kassam, A, Steinberg, GK, Johnston, SC, Ko, NU, Giannotta, SL, Kassell, NF, Worrall, BB, Lui, KC, Dumont, A, Tirschell, DL, Kaufmann, AM, Fisher, WS, Aziz, KMA, Day, AL, Du, R, Ogilvy, C, Lewis, SB, Murphy, KP, Radvany, M, Gandhi, D, Lisabeth, L, Pandey, A, Morgenstern, L, Derdeyn, C, Langefeld, C & Bailey-Wilson, J 2015, 'Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm', PLoS One, vol. 10, no. 3, e0121104. https://doi.org/10.1371/journal.pone.0121104
Farlow, Janice L. ; Lin, Hai ; Sauerbeck, Laura ; Lai, Dongbing ; Koller, Daniel L. ; Pugh, Elizabeth ; Hetrick, Kurt ; Ling, Hua ; Kleinloog, Rachel ; Van Der Vlies, Pieter ; Deelen, Patrick ; Swertz, Morris A. ; Verweij, Bon H. ; Regli, Luca ; Rinkel, Gabriel J E ; Ruigrok, Ynte M. ; Doheny, Kimberly ; Liu, Yunlong ; Foroud, Tatiana ; Broderick, Joseph ; Woo, Daniel ; Kissela, Brett ; Kleindorfer, Dawn ; Schneider, Alex ; Zuccarello, Mario ; Ringer, Andrew ; Deka, Ranjan ; Brown, Robert D. ; Huston, John ; Mesissner, Irene ; Wiebers, David ; Qureshi, Adnan I. ; Rasmussen, Peter A. ; Connolly, E. Sander ; Sacco, Ralph L. ; Malkaff, Marc ; Payner, Troy D. ; Ferguson, Gary G. ; Aldrich, E. Francois ; Rouleau, Guy ; Anderson, Craig S. ; Mee, Edward W. ; Hankey, Graeme J. ; Knuckey, Neville ; Reilly, Peter L. ; Laidlaw, John D. ; D'Urso, Paul ; Rosenfeld, Jeffrey V. ; Morgan, Michael K. ; Dorsch, Nicholas ; Besser, Michael ; Batjer, H. Hunt ; Richard, Michael T. ; Kassam, Amin ; Steinberg, Gary K. ; Johnston, S. Claiborne ; Ko, Nerissa U. ; Giannotta, Steven L. ; Kassell, Neal F. ; Worrall, Bradford B. ; Lui, Kenneth C. ; Dumont, Aaron ; Tirschell, David L. ; Kaufmann, Anthony M. ; Fisher, Winfield S. ; Aziz, Khaled Mohamed Abdel ; Day, Arthur L. ; Du, Rose ; Ogilvy, Christopher ; Lewis, Stephen B. ; Murphy, Kieran P. ; Radvany, Martin ; Gandhi, Dheerah ; Lisabeth, Lynda ; Pandey, Aditya ; Morgenstern, Lewis ; Derdeyn, Colin ; Langefeld, Carl ; Bailey-Wilson, Joan. / Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. In: PLoS One. 2015 ; Vol. 10, No. 3.
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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.",
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AU - Lin, Hai

AU - Sauerbeck, Laura

AU - Lai, Dongbing

AU - Koller, Daniel L.

AU - Pugh, Elizabeth

AU - Hetrick, Kurt

AU - Ling, Hua

AU - Kleinloog, Rachel

AU - Van Der Vlies, Pieter

AU - Deelen, Patrick

AU - Swertz, Morris A.

AU - Verweij, Bon H.

AU - Regli, Luca

AU - Rinkel, Gabriel J E

AU - Ruigrok, Ynte M.

AU - Doheny, Kimberly

AU - Liu, Yunlong

AU - Foroud, Tatiana

AU - Broderick, Joseph

AU - Woo, Daniel

AU - Kissela, Brett

AU - Kleindorfer, Dawn

AU - Schneider, Alex

AU - Zuccarello, Mario

AU - Ringer, Andrew

AU - Deka, Ranjan

AU - Brown, Robert D.

AU - Huston, John

AU - Mesissner, Irene

AU - Wiebers, David

AU - Qureshi, Adnan I.

AU - Rasmussen, Peter A.

AU - Connolly, E. Sander

AU - Sacco, Ralph L.

AU - Malkaff, Marc

AU - Payner, Troy D.

AU - Ferguson, Gary G.

AU - Aldrich, E. Francois

AU - Rouleau, Guy

AU - Anderson, Craig S.

AU - Mee, Edward W.

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AU - Laidlaw, John D.

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AU - Steinberg, Gary K.

AU - Johnston, S. Claiborne

AU - Ko, Nerissa U.

AU - Giannotta, Steven L.

AU - Kassell, Neal F.

AU - Worrall, Bradford B.

AU - Lui, Kenneth C.

AU - Dumont, Aaron

AU - Tirschell, David L.

AU - Kaufmann, Anthony M.

AU - Fisher, Winfield S.

AU - Aziz, Khaled Mohamed Abdel

AU - Day, Arthur L.

AU - Du, Rose

AU - Ogilvy, Christopher

AU - Lewis, Stephen B.

AU - Murphy, Kieran P.

AU - Radvany, Martin

AU - Gandhi, Dheerah

AU - Lisabeth, Lynda

AU - Pandey, Aditya

AU - Morgenstern, Lewis

AU - Derdeyn, Colin

AU - Langefeld, Carl

AU - Bailey-Wilson, Joan

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N2 - 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.

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