PUMAS: fine-tuning polygenic risk scores with GWAS summary statistics.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhao Z
PROVIDER: S-EPMC8419981 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait's heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.
| S-EPMC7332650 | biostudies-literature
Project description:Polygenic scores quantify the genetic risk associated with a given phenotype and are widely used to predict the risk of complex diseases. There has been recent interest in developing methods to construct polygenic risk scores using summary statistic data. We propose a method to construct polygenic risk scores via penalized regression using summary statistic data and publicly available reference data. Our method bears similarity to existing method LassoSum, extending their framework to the Truncated Lasso Penalty (TLP) and the elastic net. We show via simulation and real data application that the TLP improves predictive accuracy as compared to the LASSO while imposing additional sparsity where appropriate. To facilitate model selection in the absence of validation data, we propose methods for estimating model fitting criteria AIC and BIC. These methods approximate the AIC and BIC in the case where we have a polygenic risk score estimated on summary statistic data and no validation data. Additionally, we propose the so-called quasi-correlation metric, which quantifies the predictive accuracy of a polygenic risk score applied to out-of-sample data for which we have only summary statistic information. In total, these methods facilitate estimation and model selection of polygenic risk scores on summary statistic data, and the application of these polygenic risk scores to out-of-sample data for which we have only summary statistic information. We demonstrate the utility of these methods by applying them to GWA studies of lipids, height, and lung cancer.
| S-EPMC7553329 | biostudies-literature
Project description:The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using 12 real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and meta-PRS. We find that, when large individual-level data are available, the linear combination of PRSs (meta-PRS) is both a simple alternative to meta-GWAS and often more accurate.
| S-EPMC8206385 | biostudies-literature
Project description:Genetic risk prediction is an important problem in human genetics, and accurate prediction can facilitate disease prevention and treatment. Calculating polygenic risk score (PRS) has become widely used due to its simplicity and effectiveness, where only summary statistics from genome-wide association studies are needed in the standard method. Recently, several methods have been proposed to improve standard PRS by utilizing external information, such as linkage disequilibrium and functional annotations. In this paper, we introduce EB-PRS, a novel method that leverages information for effect sizes across all the markers to improve prediction accuracy. Compared to most existing genetic risk prediction methods, our method does not need to tune parameters nor external information. Real data applications on six diseases, including asthma, breast cancer, celiac disease, Crohn's disease, Parkinson's disease and type 2 diabetes show that EB-PRS achieved 307.1%, 42.8%, 25.5%, 3.1%, 74.3% and 49.6% relative improvements in terms of predictive r2 over standard PRS method with optimally tuned parameters. Besides, compared to LDpred that makes use of LD information, EB-PRS also achieved 37.9%, 33.6%, 8.6%, 36.2%, 40.6% and 10.8% relative improvements. We note that our method is not the first method leveraging effect size distributions. Here we first justify our method by presenting theoretical optimal property over existing methods in this class of methods, and substantiate our theoretical result with extensive simulation results. The R-package EBPRS that implements our method is available on CRAN.
| S-EPMC7039528 | biostudies-literature
Project description:The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher's infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.
| S-EPMC7431089 | biostudies-literature
Project description:MotivationFine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients ([Formula: see text]) of the variants. However, haplotypes rather than pairwise [Formula: see text], are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel.ResultsSimulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization).Availability and implementationThe HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ CONTACT: : jie.zheng@bristol.ac.uk or tom.gaunt@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
| S-EPMC5544112 | biostudies-literature
Project description:Gestational diabetes Mellitus (GDM) affects 1 in 7 births and is associated with numerous adverse health outcomes for both mother and child. GDM is suspected to share a large common genetic background with type 2 diabetes (T2D). The aim of our study was to characterize different GDM polygenic risk scores (PRSs) and test their association with GDM using data from the South Asian Birth Cohort (START). PRSs were derived for 832 South Asian women from START using the pruning and thresholding (P?+?T), LDpred, and GraBLD methods. Weights were derived from a multi-ethnic and a white Caucasian study of the DIAGRAM consortium. GDM status was defined using South Asian-specific glucose values in response to an oral glucose tolerance test. Association with GDM was tested using logistic regression. Results were replicated in South Asian women from the UK Biobank (UKB) study. The top ranking P?+?T, LDpred and GraBLD PRSs were all based on DIAGRAM's multi-ethnic study. The best PRS was highly associated with GDM in START (AUC?=?0.62, OR?=?1.60 [95% CI?=?1.44-1.69]), and in South Asian women from UKB (AUC?=?0.65, OR?=?1.69 [95% CI?=?1.28-2.24]). Our results highlight the importance of combining genome-wide genotypes and summary statistics from large multi-ethnic studies to optimize PRSs in South Asians.
| S-EPMC7265287 | biostudies-literature
Project description:Polygenic risk scores (PRS) from genome-wide association studies (GWAS) are increasingly used to predict disease risks. However some included variants could be false positives and the raw estimates of effect sizes from them may be subject to selection bias. In addition, the standard PRS approach requires testing over a range of p-value thresholds, which are often chosen arbitrarily. The prediction error estimated from the optimized threshold may also be subject to an optimistic bias. To improve genomic risk prediction, we proposed new empirical Bayes approaches to recover the underlying effect sizes and used them as weights to construct PRS. We applied the new PRS to twelve cardio-metabolic traits in the Northern Finland Birth Cohort and demonstrated improvements in predictive power (in R2) when compared to standard PRS at the best p-value threshold. Importantly, for eleven out of the twelve traits studied, the predictive performance from the entire set of genome-wide markers outperformed the best R2 from standard PRS at optimal p-value thresholds. Our proposed methodology essentially enables an automatic PRS weighting scheme without the need of choosing tuning parameters. The new method also performed satisfactorily in simulations. It is computationally simple and does not require assumptions on the effect size distributions.
| S-EPMC5286518 | biostudies-literature
Project description:A common strategy for the functional interpretation of genome-wide association study (GWAS) findings has been the integrative analysis of GWAS and expression data. Using this strategy, many association methods (e.g., PrediXcan and FUSION) have been successful in identifying trait-associated genes via mediating effects on RNA expression. However, these approaches often ignore the effects of splicing, which can carry as much disease risk as expression. Compared to expression data, one challenge to detect associations using splicing data is the large multiple testing burden due to multidimensional splicing events within genes. Here, we introduce a multidimensional splicing gene (MSG) approach, which consists of two stages: 1) we use sparse canonical correlation analysis (sCCA) to construct latent canonical vectors (CVs) by identifying sparse linear combinations of genetic variants and splicing events that are maximally correlated with each other; and 2) we test for the association between the genetically regulated splicing CVs and the trait of interest using GWAS summary statistics. Simulations show that MSG has proper type I error control and substantial power gains over existing multidimensional expression analysis methods (i.e., S-MultiXcan, UTMOST, and sCCA+ACAT) under diverse scenarios. When applied to the Genotype-Tissue Expression Project data and GWAS summary statistics of 14 complex human traits, MSG identified on average 83%, 115%, and 223% more significant genes than sCCA+ACAT, S-MultiXcan, and UTMOST, respectively. We highlight MSG's applications to Alzheimer's disease, low-density lipoprotein cholesterol, and schizophrenia, and found that the majority of MSG-identified genes would have been missed from expression-based analyses. Our results demonstrate that aggregating splicing data through MSG can improve power in identifying gene-trait associations and help better understand the genetic risk of complex traits.
| S-EPMC9278751 | biostudies-literature
Project description:For over a decade, genome-wide association studies (GWAS) have been a major tool for detecting genetic variants underlying complex traits. Recent studies have demonstrated that the same variant or gene can be associated with multiple traits, and such associations are termed cross-phenotype (CP) associations. CP association analysis can improve statistical power by searching for variants that contribute to multiple traits, which is often relevant to pleiotropy. In this chapter, we discuss existing statistical methods for analyzing association between a single marker and multivariate phenotypes, we introduce a general approach, CPASSOC, to detect the CP associations, and explain how to conduct the analysis in practice.
| S-EPMC6417431 | biostudies-literature