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Several biobanks, including UK Biobank (UKBB), are generating large-scale sequencing data. An existing method, SAIGE-GENE, performs well when testing variants with minor allele frequency (MAF) ≤ 1%, but inflation is observed in variance component set-based tests when restricting to variants with MAF ≤ 0.1% or 0.01%. Here, we propose SAIGE-GENE+ with greatly improved type I error control and computational efficiency to facilitate rare variant tests in large-scale data. We further show that incorp

Abstract In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, linear mixed model and the recently proposed logistic mixed model, perform poorly – producing large type I error rates – in the analysis of phenotypes with unbalanced case-control ratios. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approx

A number of settings arise in which it is of interest to predict Principal Component (PC) scores for new observations using data from an initial sample. In this paper, we demonstrate that naive approaches to PC score prediction can be substantially biased towards 0 in the analysis of large matrices. This phenomenon is largely related to known inconsistency results for sample eigenvalues and eigenvectors as both dimensions of the matrix increase. For the spiked eigenvalue model for random matrice

As most existing genome-wide association studies (GWASs) were conducted in European-ancestry cohorts, and as the existing polygenic risk score (PRS) models have limited transferability across ancestry groups, PRS research on non-European-ancestry groups needs to make efficient use of available data until we attain large sample sizes across all ancestry groups. Here we propose a PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PR

In genetic association analysis, a joint test of multiple distinct phenotypes can increase power to identify sets of trait-associated variants within genes or regions of interest. Existing multiphenotype tests for rare variants make specific assumptions about the patterns of association with underlying causal variants, and the violation of these assumptions can reduce power to detect association. Here, we develop a general framework for testing pleiotropic effects of rare variants on multiple co

For aggregation tests of genes or regions, the set of included variants often have small total minor allele counts (MACs), and this is particularly true when the most deleterious sets of variants are considered. When MAC is low, commonly used asymptotic tests are not well calibrated for binary phenotypes and can have conservative or anti-conservative results and potential power loss. Empirical p-values obtained via resampling methods are computationally costly for highly significant p-values and

Supplementary data are available at Bioinformatics online.

Abstract With very large sample sizes, population-based cohorts and biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, gene or region-based multiple variant aggregate tests are commonly used to increase association test power. However, due to the substantial computation cost, existing region-based rare variant tests cannot analyze hundreds of thousands of samples while accounting for confounders, such as population stratification

Unobserved environmental, demographic and technical factors canadversely affect the estimation and testing of the effects ofprimary variables. Surrogate variable analysis, proposed to tacklethis problem, has been widely used in genomic studies. To estimatehidden factors that are correlated with the primary variables,surrogate variable analysis performs principal component analysiseither on a subset of features or on all features, but weightingeach differently. However, existing approaches may fa

In genome-wide association studies, population stratification is recognized as producing inflated type I error due to the inflation of test statistics. Principal component-based methods applied to genotypes provide information about population structure, and have been widely used to control for stratification. Here we explore the precise relationship between genotype principal components and inflation of association test statistics, thereby drawing a connection between principal component-based

The etiology of most complex diseases involves genetic variants, environmental factors, and gene-environment interaction (G × E) effects. Compared with marginal genetic association studies, G × E analysis requires more samples and detailed measure of environmental exposures, and this limits the possible discoveries. Large-scale population-based biobanks with detailed phenotypic and environmental information, such as UK-Biobank, can be ideal resources for identifying G × E effects. However, due t