Rare variants in ischemic stroke

An exome pilot study

John W. Cole, O. Colin Stine, Xinyue Liu, Abhishek Pratap, Yuching Cheng, Luke J. Tallon, Lisa K. Sadzewicz, Nicole Dueker, Marcella A. Wozniak, Barney J. Stern, James F Meschia, Braxton D. Mitchell, Steven J. Kittner, Jeffrey R. O'Connell

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.

Original languageEnglish (US)
Article numbere35591
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 20 2012

Fingerprint

Exome
stroke
Genes
Stroke
Exons
Screening
African Americans
exons
genes
Polymorphism
screening
penetrance
Penetrance
DNA libraries
Genome-Wide Association Study
protein aggregates
Human Genome
Research
Single Nucleotide Polymorphism
analytical methods

ASJC Scopus subject areas

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

Cite this

Cole, J. W., Stine, O. C., Liu, X., Pratap, A., Cheng, Y., Tallon, L. J., ... O'Connell, J. R. (2012). Rare variants in ischemic stroke: An exome pilot study. PLoS One, 7(4), [e35591]. https://doi.org/10.1371/journal.pone.0035591

Rare variants in ischemic stroke : An exome pilot study. / Cole, John W.; Stine, O. Colin; Liu, Xinyue; Pratap, Abhishek; Cheng, Yuching; Tallon, Luke J.; Sadzewicz, Lisa K.; Dueker, Nicole; Wozniak, Marcella A.; Stern, Barney J.; Meschia, James F; Mitchell, Braxton D.; Kittner, Steven J.; O'Connell, Jeffrey R.

In: PLoS One, Vol. 7, No. 4, e35591, 20.04.2012.

Research output: Contribution to journalArticle

Cole, JW, Stine, OC, Liu, X, Pratap, A, Cheng, Y, Tallon, LJ, Sadzewicz, LK, Dueker, N, Wozniak, MA, Stern, BJ, Meschia, JF, Mitchell, BD, Kittner, SJ & O'Connell, JR 2012, 'Rare variants in ischemic stroke: An exome pilot study', PLoS One, vol. 7, no. 4, e35591. https://doi.org/10.1371/journal.pone.0035591
Cole JW, Stine OC, Liu X, Pratap A, Cheng Y, Tallon LJ et al. Rare variants in ischemic stroke: An exome pilot study. PLoS One. 2012 Apr 20;7(4). e35591. https://doi.org/10.1371/journal.pone.0035591
Cole, John W. ; Stine, O. Colin ; Liu, Xinyue ; Pratap, Abhishek ; Cheng, Yuching ; Tallon, Luke J. ; Sadzewicz, Lisa K. ; Dueker, Nicole ; Wozniak, Marcella A. ; Stern, Barney J. ; Meschia, James F ; Mitchell, Braxton D. ; Kittner, Steven J. ; O'Connell, Jeffrey R. / Rare variants in ischemic stroke : An exome pilot study. In: PLoS One. 2012 ; Vol. 7, No. 4.
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