Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A probabilistic method for identifying rare variants underlying complex traits.

ABSTRACT: BACKGROUND: Identifying the genetic variants that contribute to disease susceptibilities is important both for developing methodologies and for studying complex diseases in molecular biology. It has been demonstrated that the spectrum of minor allelic frequencies (MAFs) of risk genetic variants ranges from common to rare. Although association studies are shifting to incorporate rare variants (RVs) affecting complex traits, existing approaches do not show a high degree of success, and more efforts should be considered. RESULTS: In this article, we focus on detecting associations between multiple rare variants and traits. Similar to RareCover, a widely used approach, we assume that variants located close to each other tend to have similar impacts on traits. Therefore, we introduce elevated regions and background regions, where the elevated regions are considered to have a higher chance of harboring causal variants. We propose a hidden Markov random field (HMRF) model to select a set of rare variants that potentially underlie the phenotype, and then, a statistical test is applied. Thus, the association analysis can be achieved without pre-selection by experts. In our model, each variant has two hidden states that represent the causal/non-causal status and the region status. In addition, two Bayesian processes are used to compare and estimate the genotype, phenotype and model parameters. We compare our approach to the three current methods using different types of datasets, and though these are simulation experiments, our approach has higher statistical power than the other methods. The software package, RareProb and the simulation datasets are available at: http://www.engr.uconn.edu/~jiw09003.

SUBMITTER: Wang J

PROVIDER: S-EPMC3549819 | biostudies-other | 2013

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Probabilistic inference of the genetic architecture underlying functional enrichment of complex traits.

Project description:We develop a Bayesian model (BayesRR-RC) that provides robust SNP-heritability estimation, an alternative to marker discovery, and accurate genomic prediction, taking 22 seconds per iteration to estimate 8.4 million SNP-effects and 78 SNP-heritability parameters in the UK Biobank. We find that only ≤10% of the genetic variation captured for height, body mass index, cardiovascular disease, and type 2 diabetes is attributable to proximal regulatory regions within 10kb upstream of genes, while 12-25% is attributed to coding regions, 32-44% to introns, and 22-28% to distal 10-500kb upstream regions. Up to 24% of all cis and coding regions of each chromosome are associated with each trait, with over 3,100 independent exonic and intronic regions and over 5,400 independent regulatory regions having ≥95% probability of contributing ≥0.001% to the genetic variance of these four traits. Our open-source software (GMRM) provides a scalable alternative to current approaches for biobank data.

| S-EPMC8633298 | biostudies-literature

Probabilistic colocalization of genetic variants from complex and molecular traits: promise and limitations.

Project description:Colocalization analysis has emerged as a powerful tool to uncover the overlapping of causal variants responsible for both molecular and complex disease phenotypes. The findings from colocalization analysis yield insights into the molecular pathways of complex diseases. In this paper, we conduct an in-depth investigation of the promise and limitations of the available colocalization analysis approaches. Focusing on variant-level colocalization approaches, we first establish the connections between various existing methods. We proceed to discuss the impacts of various controllable analytical factors and uncontrollable practical factors on outcomes of colocalization analysis through realistic simulations and real data examples. We identify a single analytical factor, the specification of prior enrichment levels, which can lead to severe inflation of false-positive colocalization findings. Meanwhile, the combination of many other analytical and practical factors all lead to diminished power. Consequently, we recommend the following strategies for the best practice of colocalization analysis: (1) estimating prior enrichment level from the observed data and (2) separating fine-mapping and colocalization analysis. Our analysis of 4,091 complex traits and the multi-tissue expression quantitative trait loci (eQTL) data from the GTEx (v.8) suggests that colocalizations of molecular QTLs and causal complex trait associations are widespread. However, only a small proportion can be confidently identified from currently available data due to a lack of power. Our findings set a benchmark for current and future integrative genetic association analysis applications.

| S-EPMC7820626 | biostudies-literature

A data-driven method for identifying rare variants with heterogeneous trait effects.

Project description:Collapsing multiple variants into one variable and testing their collective effect is a useful strategy for rare variant association analysis. Direct collapsing, however, is not valid or may significantly lose power when a group of variants to be collapsed have heterogeneous effects on target traits (i.e. some positive and some negative). This could be especially true for quantitative traits (such as blood pressure and body mass index), regardless of whether subjects are sampled randomly from a population or selectively from two extreme tails of the trait distribution. To deal with this problem, we propose a novel, data-driven method, the P-value Weighted Sum Test (PWST), which allows each variant to be individually weighted according to the evidence of association from the data itself. Specifically, both significance and direction of individual variant effects are used to calculate a single weighted sum score based on rescaled left-tail P-values from single-variant analysis, after which a permutation test of association is performed between the score and the trait. Our simulation under different sampling strategies shows that PWST significantly increases statistical power when there are heterogeneous variant effects. The appeal of the PWST approach is illustrated in an application to sequence data by detecting the collective effect of variants in the peroxisome proliferator-activated receptor alpha (PPAR?) gene on triglycerides (TG) response to fenofibrate treatment from 300 subjects in the Genetics of Lipid Lowering and Diet Network study.

| S-EPMC3201701 | biostudies-literature

Detecting rare variants for complex traits using family and unrelated data.

Project description:Large genome-wide association studies (GWAS) have been performed to detect common genetic variants involved in common diseases, but most of the variants found this way account for only a small portion of the trait variance. Furthermore, candidate gene-based resequencing suggests that many rare genetic variants contribute to the trait variance of common diseases. Here we propose two designs, sibpair and unrelated-case designs, to detect rare genetic variants in either a candidate gene-based or genome-wide association analysis. First we show that we can detect and classify together rare risk haplotypes using a relatively small sample with either of these designs, and then have increased power to test association in a larger case-control sample. This method can also be applied to resequencing data. Next we apply the method to the Wellcome Trust Case Control Consortium (WTCCC) coronary artery disease (CAD) and hypertension (HT) data, the latter being the only trait for which no genome-wide association evidence was reported in the original WTCCC study, and identify one interesting gene associated with HT and four associated with CAD at a genome-wide significance level of 5%. These results suggest that searching for rare genetic variants is feasible and can be fruitful in current GWAS, candidate gene studies or resequencing studies.

| S-EPMC2811752 | biostudies-literature

Gene-based segregation method for identifying rare variants in family-based sequencing studies.

Project description:Whole-exome sequencing using family data has identified rare coding variants in Mendelian diseases or complex diseases with Mendelian subtypes, using filters based on variant novelty, functionality, and segregation with the phenotype within families. However, formal statistical approaches are limited. We propose a gene-based segregation test (GESE) that quantifies the uncertainty of the filtering approach. It is constructed using the probability of segregation events under the null hypothesis of Mendelian transmission. This test takes into account different degrees of relatedness in families, the number of functional rare variants in the gene, and their minor allele frequencies in the corresponding population. In addition, a weighted version of this test allows incorporating additional subject phenotypes to improve statistical power. We show via simulations that the GESE and weighted GESE tests maintain appropriate type I error rate, and have greater power than several commonly used region-based methods. We apply our method to whole-exome sequencing data from 49 extended pedigrees with severe, early-onset chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD study (BEOCOPD) and identify several promising candidate genes. Our proposed methods show great potential for identifying rare coding variants of large effect and high penetrance for family-based sequencing data. The proposed tests are implemented in an R package that is available on CRAN (https://cran.r-project.org/web/packages/GESE/).

| S-EPMC5397337 | biostudies-literature

A general framework for identifying oligogenic combinations of rare variants in complex disorders.

Project description:Genetic studies of complex disorders such as autism and intellectual disability (ID) are often based on enrichment of individual rare variants or their aggregate burden in affected individuals compared to controls. However, these studies overlook the influence of combinations of rare variants that may not be deleterious on their own due to statistical challenges resulting from rarity and combinatorial explosion when enumerating variant combinations, limiting our ability to study oligogenic basis for these disorders. Here, we present RareComb, a framework that combines the Apriori algorithm and statistical inference to identify specific combinations of mutated genes associated with complex phenotypes. RareComb overcomes computational barriers and exhaustively evaluates variant combinations to identify nonadditive relationships between simultaneously mutated genes. Using RareComb, we analyzed 6189 individuals with autism and identified 718 combinations significantly associated with ID, and carriers of these combinations showed lower IQ than expected in an independent cohort of 1878 individuals. These combinations were enriched for nervous system genes such as NIN and NGF, showed complex inheritance patterns, and were depleted in unaffected siblings. We found that an affected individual can carry many oligogenic combinations, each contributing to the same phenotype or distinct phenotypes at varying effect sizes. We also used this framework to identify combinations associated with multiple comorbid phenotypes, including mutations of COL28A1 and MFSD2B for ID and schizophrenia and ABCA4, DNAH10 and MC1R for ID and anxiety/depression. Our framework identifies a key component of missing heritability and provides a novel paradigm to untangle the genetic architecture of complex disorders.

| S-EPMC9104696 | biostudies-literature

Testing cross-phenotype effects of rare variants in longitudinal studies of complex traits.

Project description:Many gene mapping studies of complex traits have identified genes or variants that influence multiple phenotypes. With the advent of next-generation sequencing technology, there has been substantial interest in identifying rare variants in genes that possess cross-phenotype effects. In the presence of such effects, modeling both the phenotypes and rare variants collectively using multivariate models can achieve higher statistical power compared to univariate methods that either model each phenotype separately or perform separate tests for each variant. Several studies collect phenotypic data over time and using such longitudinal data can further increase the power to detect genetic associations. Although rare-variant approaches exist for testing cross-phenotype effects at a single time point, there is no analogous method for performing such analyses using longitudinal outcomes. In order to fill this important gap, we propose an extension of Gene Association with Multiple Traits (GAMuT) test, a method for cross-phenotype analysis of rare variants using a framework based on the distance covariance. The approach allows for both binary and continuous phenotypes and can also adjust for covariates. Our simple adjustment to the GAMuT test allows it to handle longitudinal data and to gain power by exploiting temporal correlation. The approach is computationally efficient and applicable on a genome-wide scale due to the use of a closed-form test whose significance can be evaluated analytically. We use simulated data to demonstrate that our method has favorable power over competing approaches and also apply our approach to exome chip data from the Genetic Epidemiology Network of Arteriopathy.

| S-EPMC5980726 | biostudies-literature

Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants.

Project description:Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.

| S-EPMC9772568 | biostudies-literature

A Probabilistic Matrix Factorization Method for Identifying lncRNA-disease Associations.

Project description:Recently, an increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) can participate in various crucial biological processes and can also be used as the most promising biomarkers for the treatment of certain diseases such as coronary artery disease and various cancers. Due to costs and time complexity, the number of possible disease-related lncRNAs that can be verified by traditional biological experiments is very limited. Therefore, in recent years, it has been very popular to use computational models to predict potential disease-lncRNA associations. In this study, we constructed three kinds of association networks, namely the lncRNA-miRNA association network, the miRNA-disease association network, and the lncRNA-disease correlation network firstly. Then, through integrating these three newly constructed association networks, we constructed an lncRNA-disease weighted association network, which would be further updated by adopting the KNN algorithm based on the semantic similarity of diseases and the similarity of lncRNA functions. Thereafter, according to the updated lncRNA-disease weighted association network, a novel computational model called PMFILDA was proposed to infer potential lncRNA-disease associations based on the probability matrix decomposition. Finally, to evaluate the superiority of the new prediction model PMFILDA, we performed Leave One Out Cross-Validation (LOOCV) based on strongly validated data filtered from MNDR and the simulation results indicated that the performance of PMFILDA was better than some state-of-the-art methods. Moreover, case studies of breast cancer, lung cancer, and colorectal cancer were implemented to further estimate the performance of PMFILDA, and simulation results illustrated that PMFILDA could achieve satisfying prediction performance as well.

| S-EPMC6410097 | biostudies-literature

Association analysis of rare and common variants with multiple traits based on variable reduction method.

Project description:Pleiotropy, the effect of one variant on multiple traits, is widespread in complex diseases. Joint analysis of multiple traits can improve statistical power to detect genetic variants and uncover the underlying genetic mechanism. Currently, a large number of existing methods target one common variant or only rare variants. Increasing evidence shows that complex diseases are caused by common and rare variants. Here we propose a region-based method to test both rare and common variant associated multiple traits based on variable reduction method (abbreviated as MULVR). However, in the presence of noise traits, the MULVR method may lose power, so we propose the MULVR-O method, which jointly analyses the optimal number of traits associated with genetic variants by the MULVR method, to guard against the effect of noise traits. Extensive simulation studies show that our proposed method (MULVR-O) is applied to not only multiple quantitative traits but also qualitative traits, and is more powerful than several other comparison methods in most scenarios. An application to the two genes (SHBG and CHRM3) and two phenotypes (systolic blood pressure and diastolic blood pressure) from the GAW19 dataset illustrates that our proposed methods (MULVR and MULVR-O) are feasible and efficient as a region-based method.

| S-EPMC6865155 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data