67 results found
Biffi C, Simoes Monteiro de Marvao A, Attard M, et al., 2017, Three-dimensional Cardiovascular Imaging-Genetics: A Mass Univariate Framework, Bioinformatics, ISSN: 1367-4803
Motivation: Left ventricular (LV) hypertrophy is a strong predictor of cardiovascular outcomes, but its genetic regulation remains largely unexplained. Conventional phenotyping relies on manual calculation of LV mass and wall thickness, but advanced cardiac image analysis presents an opportunity for highthroughput mapping of genotype-phenotype associations in three dimensions (3D).Results: High-resolution cardiac magnetic resonance images were automatically segmented in 1,124 healthy volunteers to create a 3D shape model of the heart. Mass univariate regression was used to plot a 3D effect-size map for the association between wall thickness and a set of predictors at each vertex in the mesh. The vertices where a significant effect exists were determined by applying threshold-free cluster enhancement to boost areas of signal with spatial contiguity. Experiments on simulated phenotypic signals and SNP replication show that this approach offers a substantial gain in statistical power for cardiac genotype-phenotype associations while providing good control of the false discovery rate. This framework models the effects of genetic variation throughout the heart and can be automatically applied to large population cohorts.Availability: The proposed approach has been coded in an R package freely available at https://doi.org/10.5281/zenodo.834610 together with the clinical data used in this work.
Whiffin N, Walsh R, Govind R, et al., 2017, CardioClassifier – demonstrating the power of disease- and gene-specific computational decision support for clinical genome interpretation, Publisher: Cold Spring Harbor Laboratory
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>Internationally-adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cardioclassifier.org">www.cardioclassifier.org</jats:ext-link>), a semi-automated decision-support tool for inherited cardiac conditions (ICCs).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support varian interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We benchmarked CardioClassifier on 57 expertly-curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically-actionable variants (64/219 vs 156/219, Fisher’s <jats:bold>P</jats:bold>=1.1x10-18), with important false positives; illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually-curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.</jats:p></jats:sec><jats:sec><jat
Tayal U, Newsome S, Walsh R, et al., 2017, Defining the genetic architecture of dilated cardiomyopathy- insights from population genetic variation and the role of titin, Publisher: OXFORD UNIV PRESS, Pages: 821-822, ISSN: 0195-668X
Tayal U, Buchan R, Whiffin N, et al., 2017, EVALUATION OF TITIN CARDIOMYOPATHY IN PATIENTS WITH DILATED CARDIOMYOPATHY REVEALS A BLUNTED HYPERTROPHIC RESPONSE, AN EARLY ARRHYTHMIC RISK AND A SIGNIFICANT INTERACTION WITH ALCOHOL, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 1355-6037
Whiffin N, Minikel E, Walsh R, et al., 2017, Using high-resolution variant frequencies to empower clinical genome interpretation, Genetics in Medicine, Vol: 19, Pages: 1151-1158, ISSN: 1530-0366
Purpose: Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.Methods: We present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.Results: Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false positive rate<0.001).Conclusion: We outline a statistically robust framework for assessing whether a variant is 'too common' to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Tayal U, Newsome S, Buchan R, et al., 2017, Truncating variants in titin independently predict early arrhythmias in patients with dilated cardiomyopathy, Journal of the American College of Cardiology, Vol: 69, Pages: 2466-2468, ISSN: 1558-3597
Tayal U, Newsome S, Voges I, et al., 2017, MULTIMODALITY ASSESSMENT OF RISK IN DILATED CARDIOMYOPATHY-THE IMPORTANCE OF CMR, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A4-A4, ISSN: 1355-6037
Tayal U, Newsome S, Whiffin N, et al., 2017, PRECISE PHENOTYPING WITH CMR IDENTIFIES MODERATE ALCOHOL CONSUMPTION AS AN IMPORTANT PHENOTYPIC MODIFIER OF TITIN CARDIOMYOPATHY, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 1355-6037
Tayal U, Buchan R, Whiffin N, et al., 2017, INTEGRATED ANALYSIS OF THE CLINICAL MANIFESTATIONS AND PHENOTYPIC DRIVERS OF TITIN CARDIOMYOPATHY, 66th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 2563-2563, ISSN: 0735-1097
Whiffin N, Minikel E, Walsh R, et al., 2016, Using high-resolution variant frequencies to empower clinical genome interpretation
Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Here we present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, and identifies 43 variants previously reported as pathogenic that can now be reclassified. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Tayal U, Newsome S, Buchan R, et al., 2016, Genetic determinants of arrhythmia in dilated cardiomyopathy, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 206-206, ISSN: 0195-668X
Tayal U, Newsome S, Buchan R, et al., 2016, Defining titin cardiomyopathy: genotype- phenotype correlations in a large prospective cohort of dilated cardiomyopathy patients, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 365-365, ISSN: 0195-668X
Tayal U, Buchan RJ, Whiffin N, et al., 2016, Clinical and Genetic Characteristics of Familial Dilated Cardiomyopathy in a Large UK Prospective Cohort, Annual Conference of the British Cardiovascular Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A103-A103, ISSN: 1355-6037
Tayal U, Buchan RJ, Whiffin N, et al., 2016, Effects of Truncating Variants in Titin on Cardiac Phenotype and Left Ventricular Remodelling in Dilated Cardiomyopathy, Annual Conference of the British Cardiovascular Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A102-A103, ISSN: 1355-6037
Tayal U, Newsome S, Buchan R, et al., 2016, The presence of a truncating mutation in titin independently associates with arrhythmic burden in patients with dilated cardiomyopathy, Heart Failure 2016 Conference, Publisher: Wiley, Pages: 156-156, ISSN: 1879-0844
Pua CJ, Bhalshankar J, Miao K, et al., 2016, Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Journal of Cardiovascular Translational Research, Vol: 9, Pages: 3-11, ISSN: 1937-5395
Inherited cardiac conditions (ICCs) are characterisedby marked genetic and allelic heterogeneity and require extensivesequencing for genetic characterisation. We iterativelyoptimised a targeted gene capture panel for ICCs that includesdisease-causing, putatively pathogenic, research and phenocopygenes (n = 174 genes). We achieved high coverage ofthe target region on both MiSeq (>99.8 % at ≥20× read depth,n= 12) and NextSeq (>99.9 % at ≥20×, n= 48) platforms with100 % sensitivity and precision for single nucleotide variantsand indels across the protein-coding target on the MiSeq. In thefinal assay, 40 out of 43 established ICC genes informative inclinical practice achieved complete coverage (100 % at ≥20×).By comparison, whole exome sequencing (WES; ∼80×),deep WES (∼500×) and whole genome sequencing(WGS; ∼70×) had poorer performance (88.1, 99.2 and99.3 % respectively at ≥20×) across the ICC target. Theassay described here delivers highly accurate and affordablesequencing of ICC genes, complemented by accessiblecloud-based computation and informatics.
Cheng THT, Thompson D, Painter J, et al., 2015, Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1, Scientific Reports, Vol: 5, ISSN: 2045-2322
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers.
Timofeeva MN, Kinnersley B, Farrington SM, et al., 2015, Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer, Scientific Reports, Vol: 5, ISSN: 2045-2322
Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
Al-Tassan NA, Whiffin N, Hosking FJ, et al., 2015, A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer (vol 5, 10442, 2015), SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322
Al-Tassan NA, Whiffin N, Hosking FJ, et al., 2015, A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322
Freitag DF, Butterworth AS, Willeit P, et al., 2015, Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis, LANCET DIABETES & ENDOCRINOLOGY, Vol: 3, Pages: 243-253, ISSN: 2213-8587
Morris EJA, Penegar S, Whiffin N, et al., 2015, A Retrospective Observational Study of the Relationship between Single Nucleotide Polymorphisms Associated with the Risk of Developing Colorectal Cancer and Survival, PLOS ONE, Vol: 10, ISSN: 1932-6203
Jaeger R, Migliorini G, Henrion M, et al., 2015, Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Jaeger R, Migliorini G, Henrion M, et al., 2014, Targeted Hi-C and integrative analyses reveal functionality of colorectal cancer risk loci, 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Whiffin N, Hosking FJ, Farrington SM, et al., 2014, Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 4729-4737, ISSN: 0964-6906
Ongen H, Andersen CL, Bramsen JB, et al., 2014, Putative cis-regulatory drivers in colorectal cancer, NATURE, Vol: 512, Pages: 87-90, ISSN: 0028-0836
Whiffin N, Houlston RS, 2014, Architecture of Inherited Susceptibility to Colorectal Cancer: A Voyage of Discovery, Genes, Vol: 5, Pages: 270-284, ISSN: 2073-4425
Whiffin N, Dobbins SE, Hosking FJ, et al., 2013, Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 5075-5082, ISSN: 0964-6906
Floyd S, Whiffin N, Gavilan MP, et al., 2013, Spatiotemporal organization of Aurora-B by APC/C-Cdh1 after mitosis coordinates cell spreading through FHOD1, JOURNAL OF CELL SCIENCE, Vol: 126, Pages: 2845-2856, ISSN: 0021-9533
Kinnersley B, Migliorini G, Broderick P, et al., 2012, The TERT variant rs2736100 is associated with colorectal cancer risk, BRITISH JOURNAL OF CANCER, Vol: 107, Pages: 1001-1008, ISSN: 0007-0920
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