Biology subjects

McPeek, M. S.

Publications and source records attributed to McPeek, M. S..

5 recordsLinked to original sources

bioRxiv2024

ADELLE: A global testing method for Trans-eQTL mapping

Understanding the genetic regulatory mechanisms of gene expression is a challenging and ongoing problem. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%-2% of 10,000 traits, among the 7 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.

genetics↗

bioRxiv2024

Overcoming the "feast or famine" effect: improved interaction testing in genome-wide association studies

In genetic association analysis of complex traits, detection of interaction (either GxG or GxE) can help to elucidate the genetic architecture and biological mechanisms underlying the trait. Detection of interaction in a genome-wide interaction study (GWIS) can be methodologically challenging for various reasons, including a high burden of multiple comparisons when testing for epistasis between all possible pairs of a set of genomewide variants, as well as heteroscedasticity effects occurring in the presence of GxG or GxE interaction. In this paper, we address the problem of an even more striking phenomenon that we call the "feast or famine" effect that occurs when testing interaction in a genomewide context. We show that in any given GxE GWIS, the type 1 error of standard interaction tests performed genomewide can vary widely from the nominal level, where the actual type 1 error in any given GWIS varies as a predictable function of the observed trait and environmental values. Using standard methods, some GWISs will have systematically underinflated p-values ("feast"), and others will have systematically overinflated p-values ("famine"), which can lead to false detection of interaction, reduced power, inconsistent results across studies, and failure to replicate true signal. This startling phenomenon is specific to detection of interaction in a GWIS, and it may partly explain why such detection has often proved challenging and difficult to replicate. We show that the feast or famine effect occurs across a wide range of GxE analysis methods, including but not limited to (1) testing interaction in a linear or linear mixed model (LMM) using standard approaches such as t-tests/Wald tests, likelihood ratio tests, or score tests; (2) doing a combined interaction-association test in a linear model or LMM using standard approaches; (3) testing interaction with multiple environments or multiple SNPs, where these are modeled as random effects in a LMM using standard approaches; (4) performing tests of interaction in a GWIS where significance is assessed using permutation of the trait residuals. We show theoretically that the key cause of this phenomenon is which variables are conditioned on in the analysis. Using this insight, we have developed (i) a diagnostic ratio to detect which GWASs are subject to a strong "feast or famine" effect and (ii) the TINGA method to adjust the interaction test statistics to make their p-values approximately uniform under the null hypothesis. In simulations we show that TINGA both controls type 1 error and improves power. TINGA allows for covariates and population structure through use of a linear mixed model and accounts for heteroscedasticity. We apply TINGA to detection of epistasis in a study of flowering time in Arabidopsis thaliana. Author summaryTesting for interactions in GWAS can lead to insight into biological mechanisms, but poses greater challenges than ordinary genetic association GWAS. When testing for interaction in a GWAS setting with one fixed SNP or environmental variable, the standard test statistics may not have the expected statistical properties under the null hypothesis, which can lead to false detection of interaction, inconsistent results across studies, reduced power, and failure to replicate true signal. We propose the TINGA method to adjust the test statistics so that the null distribution of their p-values is closer to uniform. Through simulations and real data analysis, we illustrate the problems with the standard analysis and the improvement of our proposed method.

genetics↗

bioRxiv2023

JASPER: fast, powerful, multitrait association testing in structured samples gives insight on pleiotropy in gene expression

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits and microbiome abundances. It allows for covariates, ascertainment and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, some of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples.

genetics↗

bioRxiv2018

Permutation methods for assessing significance in binary trait association mapping with structured samples

In genetic association analysis of complex traits, permutation testing can be a valuable tool for assessing significance when the distribution of the test statistic is unknown or not well-approximated. This commonly arises, e.g, in tests of gene-set, pathway or genome-wide significance, or when the statistic is formed by machine learning or data adaptive methods. Existing applications include eQTL mapping, association testing with rare variants, inclusion of admixed individuals in genetic association analysis, and epistasis detection among many others. For genetic association testing in samples with population structure and/or relatedness, use of naive permutation can lead to inflated type 1 error. To address this in quantitative traits, the MVNpermute method was developed. However, for association mapping of a binary trait, the relationship between the mean and variance makes both naive permutation and the MVNpermute method invalid. We propose BRASS, a permutation method for binary traits, for use in association mapping in structured samples. In addition to modeling structure in the sample, BRASS allows for covariates, ascertainment and simultaneous testing of multiple markers, and it accommodates a wide range of test statistics. In simulation studies, we compare BRASS to other permutation and resampling-based methods in a range of scenarios that include population structure, familial relatedness, ascertainment and phenotype model misspecification. In these settings, we demonstrate the superior control of type 1 error by BRASS compared to the other 6 methods considered. We apply BRASS to assess genome-wide significance for association analyses in domestic dog for elbow dysplasia (ED) and idiopathic epilepsy (IE). For both traits we detect previously identified associations, and in addition, for ED, we detect significant association with a SNP on chromosome 35 that was not detected by previous analyses, demonstrating the potential of the method. Author summaryTo determine whether genetic association with a trait is significant, permutation methods are an attractive and popular approach when analytic methods based on distributional assumptions are not available, e.g., when applying machine learning or data adaptive methods, or when performing a multiple testing correction, e.g., to assess region-wide or genome-wide significance in association mapping studies. Existing applications include eQTL mapping, association testing with rare variants, inclusion of admixed individuals in genetic association analysis, and detection of genetic interaction among many others. However, when there is population structure in the sample, naive permutation of the data can lead to inflated significance of the association results. For continuous traits, linear mixed-model based approaches have been proposed for permutation-based tests that can also adjust for sample structure; however, these do not remain valid when applied to binary traits, as key features of binary data are not well accounted for. We propose BRASS, a permutation-based testing method for binary data that incorporates important characteristics of binary data in the trait model, can accommodate relevant covariates and ascertainment, and adjusts for the presence of structure in the sample. In simulations, we demonstrate the superior control of type 1 error by BRASS compared to other methods, and we apply BRASS in the context of correcting for multiple testing in two genome-wide association studies in domestic dog: one for elbow dysplasia and one for idiopathic epilepsy.

genetics↗

bioRxiv2018

Genome-Wide Control of Population Structure and Relatedness in Genetic Association Studies via Linear Mixed Models with Orthogonally Partitioned Structure

Linear mixed models (LMMs) have become the standard approach for genetic association testing in the presence of sample structure. However, the performance of LMMs has primarily been evaluated in relatively homogeneous populations of European ancestry, despite many of the recent genetic association studies including samples from worldwide populations with diverse ancestries. In this paper, we demonstrate that existing LMM methods can have systematic miscalibration of association test statistics genome-wide in samples with heterogenous ancestry, resulting in both increased type-I error rates and a loss of power. Furthermore, we show that this miscalibration arises due to varying allele frequency differences across the genome among populations. To overcome this problem, we developed LMM-OPS, an LMM approach which orthogonally partitions diverse genetic structure into two components: distant population structure and recent genetic relatedness. In simulation studies with real and simulated genotype data, we demonstrate that LMM-OPS is appropriately calibrated in the presence of ancestry heterogeneity and outperforms existing LMM approaches, including EMMAX, GCTA, and GEMMA. We conduct a GWAS of white blood cell (WBC) count in an admixed sample of 3,551 Hispanic/Latino American women from the Womens Health Initiative SNP Health Association Resource where LMM-OPS detects genome-wide significant associations with corresponding p-values that are one or more orders of magnitude smaller than those from competing LMM methods. We also identify a genome-wide significant association with regulatory variant rs2814778 in the DARC gene on chromosome 1, which generalizes to Hispanic/Latino Americans a previous association with reduced WBC count identified in African Americans.

genetics↗