TY - JOUR
T1 - Rare variants in ischemic stroke
T2 - An exome pilot study
AU - Cole, John W.
AU - Stine, O. Colin
AU - Liu, Xinyue
AU - Pratap, Abhishek
AU - Cheng, Yuching
AU - Tallon, Luke J.
AU - Sadzewicz, Lisa K.
AU - Dueker, Nicole
AU - Wozniak, Marcella A.
AU - Stern, Barney J.
AU - Meschia, James F.
AU - Mitchell, Braxton D.
AU - Kittner, Steven J.
AU - O'Connell, Jeffrey R.
N1 - Funding Information:
While genome-wide association studies (GWAS) can identify common variants, they are not suited for situations where genetic architecture is such that multiple rare disease-causing variants contribute significantly to disease risk. This is because GWAS chips most often implement common variants as identified through the HapMap project and these variants do not serve as markers for rare variation . As such, we believe that sequencing will ultimately identify rare risk variants and that exome sequencing, given its ability to identify rare variants of high penetrance, is an excellent methodology to begin these efforts. Large scale exome projects are now well underway, most notably including the National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project (ESP). The ESP is funded by NHLBI and managed by both NHLBI and National Human Genome Research Institute (NHGRI). The goal of the ESP is to develop and validate a cost-effective, high-throughput sequencing application for all protein coding regions of the human genome in the study of several diseases, including ischemic stroke. The purpose of developing this resequencing application is to enable the sequencing of tens of thousands of individual samples from NHLBI's well-phenotyped populations in a cost-effective manner. These data will be publically-available and free to use by the scientific community. Among these there will be a deeply phenotyped reference sample not selected on basis of disease, consisting of 750 Caucasians of European origin and 250 African-Americans. The first samples have recently been submitted to dbGaP with many more over the next year.
PY - 2012/4/20
Y1 - 2012/4/20
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0035591
DO - 10.1371/journal.pone.0035591
M3 - Article
C2 - 22536414
AN - SCOPUS:84859983470
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 4
M1 - e35591
ER -