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Bayesian Detection of Causal Rare Variants under Posterior Consistency  [PDF]
Faming Liang, Momiao Xiong
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069633
Abstract: Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small--large- situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small--large- situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.
Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype  [PDF]
Saumya Gupta?,Aparna Radhakrishnan?,Pandu Raharja-Liu?,Gen Lin?,Lars M. Steinmetz?,Julien Gagneur?,Himanshu Sinha
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005195
Abstract: Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression.
Robustly Leveraging Prior Knowledge in Text Classification  [PDF]
Biao Liu,Minlie Huang
Computer Science , 2015,
Abstract: Prior knowledge has been shown very useful to address many natural language processing tasks. Many approaches have been proposed to formalise a variety of knowledge, however, whether the proposed approach is robust or sensitive to the knowledge supplied to the model has rarely been discussed. In this paper, we propose three regularization terms on top of generalized expectation criteria, and conduct extensive experiments to justify the robustness of the proposed methods. Experimental results demonstrate that our proposed methods obtain remarkable improvements and are much more robust than baselines.
Re-Ranking Sequencing Variants in the Post-GWAS Era for Accurate Causal Variant Identification  [PDF]
Laura L. Faye,Mitchell J. Machiela,Peter Kraft on behalf of the Breast and Prostate Cancer Cohort Consortium,Shelley B. Bull,Lei Sun
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003609
Abstract: Next generation sequencing has dramatically increased our ability to localize disease-causing variants by providing base-pair level information at costs increasingly feasible for the large sample sizes required to detect complex-trait associations. Yet, identification of causal variants within an established region of association remains a challenge. Counter-intuitively, certain factors that increase power to detect an associated region can decrease power to localize the causal variant. First, combining GWAS with imputation or low coverage sequencing to achieve the large sample sizes required for high power can have the unintended effect of producing differential genotyping error among SNPs. This tends to bias the relative evidence for association toward better genotyped SNPs. Second, re-use of GWAS data for fine-mapping exploits previous findings to ensure genome-wide significance in GWAS-associated regions. However, using GWAS findings to inform fine-mapping analysis can bias evidence away from the causal SNP toward the tag SNP and SNPs in high LD with the tag. Together these factors can reduce power to localize the causal SNP by more than half. Other strategies commonly employed to increase power to detect association, namely increasing sample size and using higher density genotyping arrays, can, in certain common scenarios, actually exacerbate these effects and further decrease power to localize causal variants. We develop a re-ranking procedure that accounts for these adverse effects and substantially improves the accuracy of causal SNP identification, often doubling the probability that the causal SNP is top-ranked. Application to the NCI BPC3 aggressive prostate cancer GWAS with imputation meta-analysis identified a new top SNP at 2 of 3 associated loci and several additional possible causal SNPs at these loci that may have otherwise been overlooked. This method is simple to implement using R scripts provided on the author's website.
Incorporating Causal Prior Knowledge as Path-Constraints in Bayesian Networks and Maximal Ancestral Graphs  [PDF]
Giorgos Borboudakis,Ioannis Tsamardinos
Computer Science , 2012,
Abstract: We consider the incorporation of causal knowledge about the presence or absence of (possibly indirect) causal relations into a causal model. Such causal relations correspond to directed paths in a causal model. This type of knowledge naturally arises from experimental data, among others. Specifically, we consider the formalisms of Causal Bayesian Networks and Maximal Ancestral Graphs and their Markov equivalence classes: Partially Directed Acyclic Graphs and Partially Oriented Ancestral Graphs. We introduce sound and complete procedures which are able to incorporate causal prior knowledge in such models. In simulated experiments, we show that often considering even a few causal facts leads to a significant number of new inferences. In a case study, we also show how to use real experimental data to infer causal knowledge and incorporate it into a real biological causal network. The code is available at mensxmachina.org.
Association Testing of Clustered Rare Causal Variants in Case-Control Studies  [PDF]
Wan-Yu Lin
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094337
Abstract: Biological evidence suggests that multiple causal variants in a gene may cluster physically. Variants within the same protein functional domain or gene regulatory element would locate in close proximity on the DNA sequence. However, spatial information of variants is usually not used in current rare variant association analyses. We here propose a clustering method (abbreviated as “CLUSTER”), which is extended from the adaptive combination of P-values. Our method combines the association signals of variants that are more likely to be causal. Furthermore, the statistic incorporates the spatial information of variants. With extensive simulations, we show that our method outperforms several commonly-used methods in many scenarios. To demonstrate its use in real data analyses, we also apply this CLUSTER test to the Dallas Heart Study data. CLUSTER is among the best methods when the effects of causal variants are all in the same direction. As variants located in close proximity are more likely to have similar impact on disease risk, CLUSTER is recommended for association testing of clustered rare causal variants in case-control studies.
The Power of Gene-Based Rare Variant Methods to Detect Disease-Associated Variation and Test Hypotheses About Complex Disease  [PDF]
Loukas Moutsianas?,Vineeta Agarwala?,Christian Fuchsberger?,Jason Flannick?,Manuel A. Rivas?,Kyle J. Gaulton?,Patrick K. Albers?,GoT2D Consortium?,Gil McVean?,Michael Boehnke
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005165
Abstract: Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a) generate sequence variation at human genes in up to 10K case-control samples, and (b) quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α=2.5×10-6) in 3K individuals; even in 10K samples, power is modest (~60%). The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci.
Genetic variant selection: learning across traits and sites  [PDF]
Laurel Stell,Chiara Sabatti
Statistics , 2015,
Abstract: We consider resequencing studies of associated loci and the problem of prioritizing sequence variants for functional follow-up. Working within the multivariate linear regression framework helps us to account for correlation across variants, and adopting a Bayesian approach naturally leads to posterior probabilities that incorporate all information about the variants' function. We describe two novel prior distributions that facilitate learning the role of each variant by borrowing evidence across phenotypes and across mutations in the same gene. We illustrate their potential advantages with simulations and re-analyzing a dataset of sequencing variants.
Adaptive Ridge Regression for Rare Variant Detection  [PDF]
Haimao Zhan, Shizhong Xu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044173
Abstract: It is widely believed that both common and rare variants contribute to the risks of common diseases or complex traits and the cumulative effects of multiple rare variants can explain a significant proportion of trait variances. Advances in high-throughput DNA sequencing technologies allow us to genotype rare causal variants and investigate the effects of such rare variants on complex traits. We developed an adaptive ridge regression method to analyze the collective effects of multiple variants in the same gene or the same functional unit. Our model focuses on continuous trait and incorporates covariate factors to remove potential confounding effects. The proposed method estimates and tests multiple rare variants collectively but does not depend on the assumption of same direction of each rare variant effect. Compared with the Bayesian hierarchical generalized linear model approach, the state-of-the-art method of rare variant detection, the proposed new method is easy to implement, yet it has higher statistical power. Application of the new method is demonstrated using the well-known data from the Dallas Heart Study.
Identification of Rare Causal Variants in Sequence-Based Studies: Methods and Applications to VPS13B, a Gene Involved in Cohen Syndrome and Autism  [PDF]
Iuliana Ionita-Laza equal contributor ,Marinela Capanu equal contributor,Silvia De Rubeis,Kenneth McCallum,Joseph D. Buxbaum
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004729
Abstract: Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.
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