Article

Rare Variants in Ischemic Stroke: An Exome Pilot Study

The University of Hong Kong, Hong Kong
PLoS ONE (Impact Factor: 3.53). 04/2012; 7(4):e35591. DOI: 10.1371/journal.pone.0035591
Source: PubMed

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.

Download full-text

Full-text

Available from: Braxton D Mitchell, Jun 27, 2015
2 Followers
 · 
180 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic risk factors that underlie many rare and common neurological diseases remain poorly understood because of the multi-factorial and heterogeneous nature of these disorders. Although genome-wide association studies (GWAS) have successfully uncovered numerous susceptibility genes for these diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. These results implicated that there are rare (present in <5% of the population) but not causative variants exist in the pathogenesis of these diseases, which usually have large effect size and cannot be captured by GWAS. With the decreasing cost of next-generation sequencing (NGS) technologies, whole-genome and whole-exome sequencing have enabled the rapid identification of rare variants with large effect size, which made huge progress in understanding the basis of many Mendelian neurological conditions as well as complex neurological diseases. In this article, recent NGS-based studies that aimed to investigate genetic causes for neurological diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis, stroke, amyotrophic lateral sclerosis and spinocerebellar ataxias, have been reviewed. In addition, we also discuss the future directions of NGS applications in this article.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Modifiable risk factors like obesity, hypertension, smoking, physical inactivity or atrial fibrillation account for a significant proportion of the risk for ischaemic stroke, but genetic variation is also believed to contribute to the risk, although few genetic risk variants were identified to date. Common clinical subtypes of stroke are caused by cardiac embolism, large artery atherosclerosis and small cerebral vessel disease. Each of these underlying pathologies may have a specific genetic architecture. Previous genome-wide association studies (GWAS) showed association of variants near PITX2 and ZFHX3 with atrial fibrillation and stroke. ANRIL (antisense Non-coding RNA in the INK4 Locus (harboring the CDKN2A/B genes)) variants were related to a variety of vascular diseases (myocardial infarction, aortic and intracranial aneurysm), including ischaemic stroke. Now a recent GWAS published in Nature Genetics confirmed these previous associations, analyzed the specificity of the previous associations with particular stroke subtypes and identified a new association between HDAC9 and large vessel stroke. The findings suggest that well-recognized clinical stroke subtypes correspond to distinct aetiological entities. However, the molecular pathways that are affected by the identified genetic variants are not yet pinpointed, and the observed associations apply only for some, but not all victims of a specific stroke aetiology.
    BMC Medicine 07/2012; 10:70. DOI:10.1186/1741-7015-10-70 · 7.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To summarize is to review recent progress in 'genomic' science and how this may be applied to the perioperative environment. Although investigations that relate genetic variation to perioperative outcomes continue, it is increasingly apparent that epigenetic mechanisms may contribute to much of the observed variation in complex outcomes not otherwise explained by differences in genetic sequence. Examples of recent findings relating to the role of epigenetic modifications in complex disease and outcomes are derived from research into type 1 diabetes, pain, and the hypoxic response. These studies provide models for future cohort study design, potential perioperative drug targets, and hypothesis development. Genetic and epigenetic factors combine to alter both gene expression and drug responses at both pharmacokinetic and pharmacodynamic levels. These factors impact on the efficacy and safety of multiple drug classes used in perioperative medicine. Enhancing our understanding of the way in which patients as genomic organisms interact with the perioperative environment requires a more sophisticated appreciation of the factors governing gene expression than has been the case to date. Epigenetic mechanisms are sure to play a pivotal role in what is essentially an acquired phenotype.
    Current opinion in critical care 08/2012; 18(5):548-54. DOI:10.1097/MCC.0b013e328357af6d · 3.18 Impact Factor