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9 results on '"FIA Study Investigators"'

1. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

Author

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, Joseph Broderick, Tatiana Foroud, and FIA Study Investigators

Subjects
Medicine, Science
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
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2. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

Author

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 JE, Ruigrok, Ynte M, Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators

Subjects
FIA Study Investigators, Humans, Intracranial Aneurysm, Genetic Predisposition to Disease, Membrane Proteins, Cohort Studies, Chromosome Mapping, Pedigree, Sequence Analysis, DNA, Computational Biology, Base Sequence, Phenotype, Molecular Sequence Data, Genetic Variation, Exome, Sequence Analysis, DNA, General Science & Technology
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

3. Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk

Author

Foroud, Tatiana, Koller, Daniel L, Lai, Dongbing, Sauerbeck, Laura, Anderson, Craig, Ko, Nerissa, Deka, Ranjan, Mosley, Thomas H, Fornage, Myriam, Woo, Daniel, Moomaw, Charles J, Hornung, Richard, Huston, John, Meissner, Irene, Bailey-Wilson, Joan E, Langefeld, Carl, Rouleau, Guy, Connolly, E Sander, Worrall, Bradford B, Kleindorfer, Dawn, Flaherty, Matthew L, Martini, Sharyl, Mackey, Jason, De Los Rios La Rosa, Felipe, Brown, Robert D, Broderick, Joseph P, and FIA Study Investigators

Subjects
genome-wide association study, Neurology & Neurosurgery, Genotype, Prevention, Smoking, Human Genome, Clinical Sciences, Neurosciences, Intracranial Aneurysm, Single Nucleotide, Cardiorespiratory Medicine and Haematology, Brain Disorders, FIA Study Investigators, Risk Factors, Clinical Research, SOXF Transcription Factors, Genetics, RNA, Humans, 2.1 Biological and endogenous factors, Long Noncoding, Genetic Predisposition to Disease, Polymorphism, Aetiology
Abstract

BackgroundGenomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA.MethodWe utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis.ResultsThere was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype.ConclusionsIn addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

Published
2012

4. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Author

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, Broderick, Joseph, Foroud, Tatiana, FIA Study Investigators, 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, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators

Published
2015

5. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

Author

Li, Y, 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, Broderick, J, Foroud, T, FIA Study Investigators, Li, Y, 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, Broderick, J, Foroud, T, and FIA Study Investigators

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

6. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Author

ZL Cerebrovasculaire Ziekten Medisch, Brain, Circulatory Health, Neurologie, 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, Broderick, Joseph, Foroud, Tatiana, FIA Study Investigators, ZL Cerebrovasculaire Ziekten Medisch, Brain, Circulatory Health, Neurologie, 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, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators

Published
2015

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