Comparison of methods for estimating genetic correlation between complex traits using GWAS summary statistics.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8425307 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genome-wide association studies (GWAS) for complex diseases have focused primarily on single-trait analyses for disease status and disease-related quantitative traits. For example, GWAS on risk factors for coronary artery disease analyze genetic associations of plasma lipids such as total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides (TGs) separately. However, traits are often correlated and a joint analysis may yield increased statistical power for association over multiple univariate analyses. Recently several multivariate methods have been proposed that require individual-level data. Here, we develop metaUSAT (where USAT is unified score-based association test), a novel unified association test of a single genetic variant with multiple traits that uses only summary statistics from existing GWAS. Although the existing methods either perform well when most correlated traits are affected by the genetic variant in the same direction or are powerful when only a few of the correlated traits are associated, metaUSAT is designed to be robust to the association structure of correlated traits. metaUSAT does not require individual-level data and can test genetic associations of categorical and/or continuous traits. One can also use metaUSAT to analyze a single trait over multiple studies, appropriately accounting for overlapping samples, if any. metaUSAT provides an approximate asymptotic P-value for association and is computationally efficient for implementation at a genome-wide level. Simulation experiments show that metaUSAT maintains proper type-I error at low error levels. It has similar and sometimes greater power to detect association across a wide array of scenarios compared to existing methods, which are usually powerful for some specific association scenarios only. When applied to plasma lipids summary data from the METSIM and the T2D-GENES studies, metaUSAT detected genome-wide significant loci beyond the ones identified by univariate analyses. Evidence from larger studies suggest that the variants additionally detected by our test are, indeed, associated with lipid levels in humans. In summary, metaUSAT can provide novel insights into the genetic architecture of a common disease or traits.
| S-EPMC5811402 | biostudies-literature
Project description:Genome-wide association studies (GWASs) have been successful in discovering SNP trait associations for many quantitative traits and common diseases. Typically, the effect sizes of SNP alleles are very small and this requires large genome-wide association meta-analyses (GWAMAs) to maximize statistical power. A trend towards ever-larger GWAMA is likely to continue, yet dealing with summary statistics from hundreds of cohorts increases logistical and quality control problems, including unknown sample overlap, and these can lead to both false positive and false negative findings. In this study, we propose four metrics and visualization tools for GWAMA, using summary statistics from cohort-level GWASs. We propose methods to examine the concordance between demographic information, and summary statistics and methods to investigate sample overlap. (I) We use the population genetics Fst statistic to verify the genetic origin of each cohort and their geographic location, and demonstrate using GWAMA data from the GIANT Consortium that geographic locations of cohorts can be recovered and outlier cohorts can be detected. (II) We conduct principal component analysis based on reported allele frequencies, and are able to recover the ancestral information for each cohort. (III) We propose a new statistic that uses the reported allelic effect sizes and their standard errors to identify significant sample overlap or heterogeneity between pairs of cohorts. (IV) To quantify unknown sample overlap across all pairs of cohorts, we propose a method that uses randomly generated genetic predictors that does not require the sharing of individual-level genotype data and does not breach individual privacy.
| S-EPMC5159754 | biostudies-literature
Project description:The polygenic risk score (PRS) is calculated as the weighted sum of an individual's genotypes and their estimated effect sizes, which is often used to estimate an individual's genetic susceptibility to complex traits and disorders. It is well known that some complex human traits or disorders have sex differences in trait distributions, disease onset, progression, and treatment response, although the underlying mechanisms causing these sex differences remain largely unknown. PRSs for these traits are often based on Genome-Wide Association Studies (GWAS) data with both male and female samples included, ignoring sex differences. In this study, we present a benchmark study using both simulations with various combinations of genetic correlation and sample size ratios between sexes and real data to investigate whether combining sex-specific PRSs can outperform sex-agnostic PRSs on traits showing sex differences. We consider two types of PRS models in our study: single-population PRS models (PRScs, LDpred2) and multiple-population PRS models (PRScsx). For each trait or disorder, the candidate PRSs were calculated based on sex-specific GWAS data and sex-agnostic GWAS data. The simulation results show that applying LDpred2 or PRScsx to sex-specific GWAS data and then combining sex-specific PRSs leads to the highest prediction accuracy when the genetic correlation between sexes is low and the sample sizes for both sexes are balanced and large. Otherwise, the PRS generated by applying LDpred2 or PRScs to sex-agnostic GWAS data is more appropriate. If the sample sizes between sexes are not too small and very unbalanced, combining LDpred2-based sex-specific PRSs to predict on the sex with a larger sample size and combining PRScsx-based sex-specific PRSs to predict on the sex with a smaller size are the preferred strategies. For real data, we considered 19 traits from Genetic Investigation of ANthropometric Traits (GIANT) consortium studies and UK Biobank with both sex-specific GWAS data and sex-agnostic GWAS data. We found that for waist-to-hip ratio (WHR) related traits, accounting for sex differences and incorporating information from the opposite sex could help improve PRS prediction accuracy. Taken together, our findings in this study provide guidance on how to calculate the best PRS for sex-differentiated traits or disorders, especially as the sample size of GWASs grows in the future.
| S-EPMC9304553 | biostudies-literature
Project description:Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits' genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses, we demonstrate that our method provides accurate covariance estimates, thereby enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (Ntotal≈ 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimer disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOAD's correlation with cognitive traits and hints at an autoimmune component for ALS.
| S-EPMC5812911 | biostudies-literature
Project description:MotivationPleiotropic SNPs are associated with multiple traits. Such SNPs can help pinpoint biological processes with an effect on multiple traits or point to a shared etiology between traits. We present PolarMorphism, a new method for the identification of pleiotropic SNPs from genome-wide association studies (GWAS) summary statistics. PolarMorphism can be readily applied to more than two traits or whole trait domains. PolarMorphism makes use of the fact that trait-specific SNP effect sizes can be seen as Cartesian coordinates and can thus be converted to polar coordinates r (distance from the origin) and theta (angle with the Cartesian x-axis, in the case of two traits). r describes the overall effect of a SNP, while theta describes the extent to which a SNP is shared. r and theta are used to determine the significance of SNP sharedness, resulting in a P-value per SNP that can be used for further analysis.ResultsWe apply PolarMorphism to a large collection of publicly available GWAS summary statistics enabling the construction of a pleiotropy network that shows the extent to which traits share SNPs. We show how PolarMorphism can be used to gain insight into relationships between traits and trait domains and contrast it with genetic correlation. Furthermore, pathway analysis of the newly discovered pleiotropic SNPs demonstrates that analysis of more than two traits simultaneously yields more biologically relevant results than the combined results of pairwise analysis of the same traits. Finally, we show that PolarMorphism is more efficient and more powerful than previously published methods.Availability and implementationcode: https://github.com/UMCUGenetics/PolarMorphism, results: 10.5281/zenodo.5844193.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC9235478 | biostudies-literature
Project description:Genome-wide Association Studies (GWAS) result in millions of summary statistics ("z-scores") for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design. Here we present a parsimonious methodology for modeling effect sizes and replication probabilities, relying only on summary statistics from GWAS substudies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The four-parameter model allows for estimating the degree of polygenicity of the phenotype and predicting the proportion of chip heritability explainable by genome-wide significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (N = 82,315) and putamen volume (N = 12,596), with approximately 9.3 million SNP z-scores in both cases. We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We assess the degree to which effect sizes are over-estimated when based on linear-regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 10(6) and 10(5). The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation. The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures.
| S-EPMC4754432 | biostudies-literature
Project description:We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.
| S-EPMC3593158 | biostudies-literature
Project description:The increasing number of genetic association studies conducted in multiple populations provides an unprecedented opportunity to study how the genetic architecture of complex phenotypes varies between populations, a problem important for both medical and population genetics. Here, we have developed a method for estimating the transethnic genetic correlation: the correlation of causal-variant effect sizes at SNPs common in populations. This methods takes advantage of the entire spectrum of SNP associations and uses only summary-level data from genome-wide association studies. This avoids the computational costs and privacy concerns associated with genotype-level information while remaining scalable to hundreds of thousands of individuals and millions of SNPs. We applied our method to data on gene expression, rheumatoid arthritis, and type 2 diabetes and overwhelmingly found that the genetic correlation was significantly less than 1. Our method is implemented in a Python package called Popcorn.
| S-EPMC5005434 | biostudies-literature
Project description:There has been an increasing interest in joint association testing of multiple traits for possible pleiotropic effects. However, even in the presence of pleiotropy, most of the existing methods cannot distinguish direct and indirect effects of a genetic variant, say single-nucleotide polymorphism (SNP), on multiple traits, and a conditional analysis of a trait adjusting for other traits is perhaps the simplest and most common approach to addressing this question. However, without individual-level genotypic and phenotypic data but with only genome-wide association study (GWAS) summary statistics, as typical with most large-scale GWAS consortium studies, we are not aware of any existing method for such a conditional analysis. We propose such a conditional analysis, offering formulas of necessary calculations to fit a joint linear regression model for multiple quantitative traits. Furthermore, our method can also accommodate conditional analysis on multiple SNPs in addition to on multiple quantitative traits, which is expected to be useful for fine mapping. We provide numerical examples based on both simulated and real GWAS data to demonstrate the effectiveness of our proposed approach, and illustrate possible usefulness of conditional analysis by contrasting its result differences from those of standard marginal analyses.
| S-EPMC5536980 | biostudies-literature
Project description:Most existing tools for constructing genetic prediction models begin with the assumption that all genetic variants contribute equally towards the phenotype. However, this represents a suboptimal model for how heritability is distributed across the genome. Therefore, we develop prediction tools that allow the user to specify the heritability model. We compare individual-level data prediction tools using 14 UK Biobank phenotypes; our new tool LDAK-Bolt-Predict outperforms the existing tools Lasso, BLUP, Bolt-LMM and BayesR for all 14 phenotypes. We compare summary statistic prediction tools using 225 UK Biobank phenotypes; our new tool LDAK-BayesR-SS outperforms the existing tools lassosum, sBLUP, LDpred and SBayesR for 223 of the 225 phenotypes. When we improve the heritability model, the proportion of phenotypic variance explained increases by on average 14%, which is equivalent to increasing the sample size by a quarter.
| S-EPMC8263809 | biostudies-literature