With increasing biobanking efforts connecting electronic health records and national registries to germline genetics, the time-to-event data analysis has attracted increasing attention in the ...genetics studies of human diseases. In time-to-event data analysis, the Cox proportional hazards (PH) regression model is one of the most used approaches. However, existing methods and tools are not scalable when analyzing a large biobank with hundreds of thousands of samples and endpoints, and they are not accurate when testing low-frequency and rare variants. Here, we propose a scalable and accurate method, SPACox (a saddlepoint approximation implementation based on the Cox PH regression model), that is applicable for genome-wide scale time-to-event data analysis. SPACox requires fitting a Cox PH regression model only once across the genome-wide analysis and then uses a saddlepoint approximation (SPA) to calibrate the test statistics. Simulation studies show that SPACox is 76–252 times faster than other existing alternatives, such as gwasurvivr, 185–511 times faster than the standard Wald test, and more than 6,000 times faster than the Firth correction and can control type I error rates at the genome-wide significance level regardless of minor allele frequencies. Through the analysis of UK Biobank inpatient data of 282,871 white British European ancestry samples, we show that SPACox can efficiently analyze large sample sizes and accurately control type I error rates. We identified 611 loci associated with time-to-event phenotypes of 12 common diseases, of which 38 loci would be missed within a logistic regression framework with a binary phenotype defined as event occurrence status during the follow-up period.
Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common ...variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep-resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT.
We propose a general statistical framework for meta-analysis of gene- or region-based multimarker rare variant association tests in sequencing association studies. In genome-wide association studies, ...single-marker meta-analysis has been widely used to increase statistical power by combining results via regression coefficients and standard errors from different studies. In analysis of rare variants in sequencing studies, region-based multimarker tests are often used to increase power. We propose meta-analysis methods for commonly used gene- or region-based rare variants tests, such as burden tests and variance component tests. Because estimation of regression coefficients of individual rare variants is often unstable or not feasible, the proposed method avoids this difficulty by calculating score statistics instead that only require fitting the null model for each study and then aggregating these score statistics across studies. Our proposed meta-analysis rare variant association tests are conducted based on study-specific summary statistics, specifically score statistics for each variant and between-variant covariance-type (linkage disequilibrium) relationship statistics for each gene or region. The proposed methods are able to incorporate different levels of heterogeneity of genetic effects across studies and are applicable to meta-analysis of multiple ancestry groups. We show that the proposed methods are essentially as powerful as joint analysis by directly pooling individual level genotype data. We conduct extensive simulations to evaluate the performance of our methods by varying levels of heterogeneity across studies, and we apply the proposed methods to meta-analysis of rare variant effects in a multicohort study of the genetics of blood lipid levels.
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, the ...linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.
Delta age is a biomarker of brain aging that captures differences between the chronological age and the predicted biological brain age. Using multimodal data of brain MRI, genomics, and blood-based ...biomarkers and metabolomics in UK Biobank, this study investigates an explainable and causal basis of high delta age. A visual saliency map of brain regions showed that lower volumes in the fornix and the lower part of the thalamus are key predictors of high delta age. Genome-wide association analysis of the delta age using the SNP array data identified associated variants in gene regions such as KLF3-AS1 and STX1. GWAS was also performed on the volumes in the fornix and the lower part of the thalamus, showing a high genetic correlation with delta age, indicating that they share a genetic basis. Mendelian randomization (MR) for all metabolomic biomarkers and blood-related phenotypes showed that immune-related phenotypes have a causal impact on increasing delta age. Our analysis revealed regions in the brain that are susceptible to the aging process and provided evidence of the causal and genetic connections between immune responses and brain aging.
Meta-analysis of trans-ethnic genome-wide association studies (GWAS) has proven to be a practical and profitable approach for identifying loci that contribute to the risk of complex diseases. ...However, the expected genetic effect heterogeneity cannot easily be accommodated through existing fixed-effects and random-effects methods. In response, we propose a novel random effect model for trans-ethnic meta-analysis with flexible modeling of the expected genetic effect heterogeneity across diverse populations. Specifically, we adopt a modified random effect model from the kernel regression framework, in which genetic effect coefficients are random variables whose correlation structure reflects the genetic distances across ancestry groups. In addition, we use the adaptive variance component test to achieve robust power regardless of the degree of genetic effect heterogeneity. Simulation studies show that our proposed method has well-calibrated type I error rates at very stringent significance levels and can improve power over the traditional meta-analysis methods. We reanalyzed the published type 2 diabetes GWAS meta-analysis (Consortium et al., 2014) and successfully identified one additional SNP that clearly exhibits genetic effect heterogeneity across different ancestry groups. Furthermore, our proposed method provides scalable computing time for genome-wide datasets, in which an analysis of one million SNPs would require less than 3 hours.
With the advances in genotyping technologies and electronic health records (EHRs), large biobanks have been great resources to identify novel genetic associations and gene-environment interactions on ...a genome-wide and even a phenome-wide scale. To date, several phenome-wide association studies (PheWAS) have been performed on biobank data, which provides comprehensive insights into many aspects of human genetics and biology. Although inspiring, PheWAS on large-scale biobank data encounters new challenges including computational burden, unbalanced phenotypic distribution, and genetic relationship. In this paper, we first discuss these new challenges and their potential impact on data analysis. Then, we summarize approaches that are scalable and robust in GWAS and PheWAS. This review can serve as a practical guide for geneticists, epidemiologists, and other medical researchers to identify genetic variations associated with health-related phenotypes in large-scale biobank data analysis. Meanwhile, it can also help statisticians to gain a comprehensive and up-to-date understanding of the current technical tool development.
Genetic variants can contribute differently to trait heritability by their functional categories, and recent studies have shown that incorporating functional annotation can improve the predictive ...performance of polygenic risk scores (PRSs). In addition, when only a small proportion of variants are causal variants, PRS methods that employ a Bayesian framework with shrinkage can account for such sparsity. It is possible that the annotation group level effect is also sparse. However, the number of PRS methods that incorporate both annotation information and shrinkage on effect sizes is limited. We propose a PRS method, PRSbils, which utilizes the functional annotation information with a bilevel continuous shrinkage prior to accommodate the varying genetic architectures both on the variant-specific level and on the functional annotation level.
We conducted simulation studies and investigated the predictive performance in settings with different genetic architectures. Results indicated that when there was a relatively large variability of group-wise heritability contribution, the gain in prediction performance from the proposed method was on average 8.0% higher AUC compared to the benchmark method PRS-CS. The proposed method also yielded higher predictive performance compared to PRS-CS in settings with different overlapping patterns of annotation groups and obtained on average 6.4% higher AUC. We applied PRSbils to binary and quantitative traits in three real world data sources (the UK Biobank, the Michigan Genomics Initiative (MGI), and the Korean Genome and Epidemiology Study (KoGES)), and two sources of annotations: ANNOVAR, and pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and demonstrated that the proposed method holds the potential for improving predictive performance by incorporating functional annotations.
By utilizing a bilevel shrinkage framework, PRSbils enables the incorporation of both overlapping and non-overlapping annotations into PRS construction to improve the performance of genetic risk prediction. The software is available at https://github.com/styvon/PRSbils .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical utility of a type 2 diabetes mellitus (T2DM) polygenic risk score (PRS) in the East Asian population remains underexplored. We aimed to examine the potential prognostic value of a T2DM ...PRS and assess its viability as a clinical instrument. We first established a T2DM PRS for 5490 Korean individuals using East Asian Biobank data (269,487 samples). Subsequently, we assessed the predictive capability of this T2DM PRS in a prospective longitudinal study with baseline data and data from seven additional follow-ups. Our analysis showed that the T2DM PRS could predict the transition of glucose tolerance stages from normal glucose tolerance to prediabetes and from prediabetes to T2DM. Moreover, T2DM patients in the top-decile PRS group were more likely to be treated with insulin (hazard ratio = 1.69, p value = 2.31E-02) than were those in the remaining PRS groups. T2DM PRS values were significantly high in the severe diabetes subgroup, characterized by insulin resistance and
-cell dysfunction (p value = 0.0012). The prediction models with the T2DM PRS had significantly greater Harrel's C-indices than did corresponding models without it. By utilizing prospective longitudinal study data and extensive clinical risk factor information, our analysis provides valuable insights into the multifaceted clinical utility of the T2DM PRS.
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