Rare variants: data types and analysis strategies.
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ABSTRACT:
SUBMITTER: Goswami C
PROVIDER: S-EPMC8267277 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Rare variants: data types and analysis strategies.
Goswami Chayanika C Chattopadhyay Amrita A Chuang Eric Y EY
Annals of translational medicine 20210601 12
Similar Datasets
Project description:The limitations of genome-wide association (GWA) studies that focus on the phenotypic influence of common genetic variants have motivated human geneticists to consider the contribution of rare variants to phenotypic expression. The increasing availability of high-throughput sequencing technologies has enabled studies of rare variants but these methods will not be sufficient for their success as appropriate analytical methods are also needed. We consider data analysis approaches to testing associations between a phenotype and collections of rare variants in a defined genomic region or set of regions. Ultimately, although a wide variety of analytical approaches exist, more work is needed to refine them and determine their properties and power in different contexts.
| S-EPMC3743540 | biostudies-other
Project description:Longitudinal genetic data provide more information regarding genetic effects over time compared with cross-sectional data. Coupled with next-generation sequencing technologies, it becomes reality to identify important genes containing both rare and common variants in a longitudinal design. In this work, we adopted a weighted sum statistic (WSS) to collapse multiple variants in a gene region to form a gene score. When multiple genes in a pathway were considered together, a penalized longitudinal model under the quadratic inference function (QIF) framework was applied for efficient gene selection. We evaluated the estimation accuracy and model selection performance under different model settings, then applied the method to a real dataset from the Genetic Analysis Workshop 18 (GAW18). Compared with the unpenalized QIF method, the penalized QIF (pQIF) method achieved better estimation accuracy and higher selection efficiency. The pQIF remained optimal even when the working correlation structure was mis-specified. The real data analysis identified one important gene, angiotensin II receptor type 1 (AGTR1), in the Ca2+/AT-IIR/α-AR signaling pathway. The estimated effect implied that AGTR1 may have a protective effect for hypertension. Our pQIF method provides a general tool for longitudinal sequencing studies involving large numbers of genetic variants.
| S-EPMC5429681 | biostudies-literature
Project description:Mass cytometry allows high-resolution dissection of the cellular composition of the immune system. However, the high-dimensionality, large size, and non-linear structure of the data poses considerable challenges for the data analysis. In particular, dimensionality reduction-based techniques like t-SNE offer single-cell resolution but are limited in the number of cells that can be analyzed. Here we introduce Hierarchical Stochastic Neighbor Embedding (HSNE) for the analysis of mass cytometry data sets. HSNE constructs a hierarchy of non-linear similarities that can be interactively explored with a stepwise increase in detail up to the single-cell level. We apply HSNE to a study on gastrointestinal disorders and three other available mass cytometry data sets. We find that HSNE efficiently replicates previous observations and identifies rare cell populations that were previously missed due to downsampling. Thus, HSNE removes the scalability limit of conventional t-SNE analysis, a feature that makes it highly suitable for the analysis of massive high-dimensional data sets.
| S-EPMC5700955 | biostudies-literature
Project description:Rare genetic variants may be responsible for a significant amount of the uncharacterized genetic risk underlying many diseases. An efficient approach to characterizing the disease burden of rare variants may be to impute them into existing large datasets. It is well known that the ability to impute a rare variant is dependent both on the array choice and number of individuals in the reference panel carrying that variant, although it is still unclear exactly how well imputation will work for rare variants. Here, we review the additional challenges that arise when imputing rare variants, looking at studies that have been able to impute rare variants, methods behind merging reference panels, approaches for imputing rare variants, and methods for analyzing rare variants.
| S-EPMC4600126 | biostudies-literature
Project description:Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.
| S-EPMC4703835 | biostudies-literature
Project description:BackgroundRare variants play an essential role in the etiology of cancer. In this study, we aim to characterize rare germline variants that impact the risk of cancer.MethodsWe performed a genome-wide rare variant analysis using germline whole exome sequencing (WES) data derived from the Geisinger MyCode initiative to discover cancer predisposition variants. The case-control association analysis was conducted by binning variants in 5,538 patients with cancer and 7,286 matched controls in a discovery set and 1,991 patients with cancer and 2,504 matched controls in a validation set across nine cancer types. Further, The Cancer Genome Atlas (TCGA) germline data were used to replicate the findings.ResultsWe identified 133 significant pathway-cancer pairs (85 replicated) and 90 significant gene-cancer pairs (12 replicated). In addition, we identified 18 genes and 3 pathways that were associated with survival outcome across cancers (Bonferroni P < 0.05).ConclusionsIn this study, we identified potential predisposition genes and pathways based on rare variants in nine cancers.ImpactThis work adds to the knowledge base and progress being made in precision medicine.
| S-EPMC8419143 | biostudies-literature
Project description:BackgroundAs several rare genomic variants have been shown to affect common phenotypes, rare variants association analysis has received considerable attention. Several efficient association tests using genotype and phenotype similarity measures have been proposed in the literature. The major advantages of similarity-based tests are their ability to accommodate multiple types of DNA variations within one association test, and to account for the possible interaction within a region. However, not much work has been done to compare the performance of similarity-based tests on rare variants association scenarios, especially when applied with different rare variants pooling strategies.ResultsBased on the population genetics simulations and analysis of a publicly-available sequencing data set, we compared the performance of four similarity-based tests and two rare variants pooling strategies. We showed that weighting approach outperforms collapsing under the presence of strong effect from rare variants and under the presence of moderate effect from common variants, whereas collapsing of rare variants is preferable when common variants possess a strong effect. We also demonstrated that the difference in statistical power between the two pooling strategies may be substantial. The results also highlighted consistently high power of two similarity-based approaches when applied with an appropriate pooling strategy.ConclusionsPopulation genetics simulations and sequencing data set analysis showed high power of two similarity-based tests and a substantial difference in power between the two pooling strategies.
| S-EPMC3600007 | biostudies-literature
Project description:BACKGROUND:With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants. RESULTS:Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes. CONCLUSION:The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.
| S-EPMC5861485 | biostudies-literature
Project description:The detection of rare deleterious variants is the preeminent current technical challenge in statistical genetics. Sorting the deleterious from neutral variants at a disease locus is challenging because of the sparseness of the evidence for each individual variant. Hierarchical modeling and Bayesian model uncertainty are two techniques that have been shown to be promising in pinpointing individual rare variants that may be driving the association. Interpreting the results from these techniques from the perspective of multiple testing is a challenge and the goal of this article is to better understand their false discovery properties. Using simulations, we conclude that accurate false discovery control cannot be achieved in this framework unless the magnitude of the variants' risk is large and the hierarchical characteristics have high accuracy in distinguishing deleterious from neutral variants.
| S-EPMC4711769 | biostudies-literature
Project description:Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.
| S-EPMC10983955 | biostudies-literature