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1.
PLoS Genet ; 14(8): e1007586, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30096133

RESUMO

For many complex traits, gene regulation is likely to play a crucial mechanistic role. How the genetic architectures of complex traits vary between populations and subsequent effects on genetic prediction are not well understood, in part due to the historical paucity of GWAS in populations of non-European ancestry. We used data from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort to characterize the genetic architecture of gene expression within and between diverse populations. Genotype and monocyte gene expression were available in individuals with African American (AFA, n = 233), Hispanic (HIS, n = 352), and European (CAU, n = 578) ancestry. We performed expression quantitative trait loci (eQTL) mapping in each population and show genetic correlation of gene expression depends on shared ancestry proportions. Using elastic net modeling with cross validation to optimize genotypic predictors of gene expression in each population, we show the genetic architecture of gene expression for most predictable genes is sparse. We found the best predicted gene in each population, TACSTD2 in AFA and CHURC1 in CAU and HIS, had similar prediction performance across populations with R2 > 0.8 in each population. However, we identified a subset of genes that are well-predicted in one population, but poorly predicted in another. We show these differences in predictive performance are due to allele frequency differences between populations. Using genotype weights trained in MESA to predict gene expression in independent populations showed that a training set with ancestry similar to the test set is better at predicting gene expression in test populations, demonstrating an urgent need for diverse population sampling in genomics. Our predictive models and performance statistics in diverse cohorts are made publicly available for use in transcriptome mapping methods at https://github.com/WheelerLab/DivPop.

2.
Nat Commun ; 9(1): 1825, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739930

RESUMO

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

3.
Nat Genet ; 50(1): 151-158, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29229983

RESUMO

The excision of introns from pre-mRNA is an essential step in mRNA processing. We developed LeafCutter to study sample and population variation in intron splicing. LeafCutter identifies variable splicing events from short-read RNA-seq data and finds events of high complexity. Our approach obviates the need for transcript annotations and circumvents the challenges in estimating relative isoform or exon usage in complex splicing events. LeafCutter can be used both to detect differential splicing between sample groups and to map splicing quantitative trait loci (sQTLs). Compared with contemporary methods, our approach identified 1.4-2.1 times more sQTLs, many of which helped us ascribe molecular effects to disease-associated variants. Transcriptome-wide associations between LeafCutter intron quantifications and 40 complex traits increased the number of associated disease genes at a 5% false discovery rate by an average of 2.1-fold compared with that detected through the use of gene expression levels alone. LeafCutter is fast, scalable, easy to use, and available online.

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