Approximate score-based testing with application to multivariate trait association analysis.

For genome-wide association studies and DNA sequencing studies, several powerful score-based tests, such as kernel machine regression and sum of powered score tests, have been proposed in the last few years. However, extensions of these score-based tests to more complex models, such as mixed-effects models for analysis of multiple and correlated traits, have been hindered by the unavailability of the score vector, due to either no output from statistical software or no closed-form solution at all. We propose a simple and general method to asymptotically approximate the score vector based on an asymptotically normal and consistent estimate of a parameter vector to be tested and its (consistent) covariance matrix. The proposed method is applicable to both maximum-likelihood estimation and estimating function-based approaches. We use the derived approximate score vector to extend several score-based tests to mixed-effects models. We demonstrate the feasibility and possible power gains of these tests in association analysis of multiple and correlated quantitative or binary traits with both real and simulated data. The proposed method is easy to implement with a wide applicability.

Testing for polygenic effects in genome-wide association studies.

To confirm associations with a large number of single nucleotide polymorphisms (SNPs), each with only a small effect size, as hypothesized in the polygenic theory for schizophrenia, the International Schizophrenia Consortium (2009, Nature 460:748-752) proposed a polygenic risk score (PRS) test and demonstrated its effectiveness when applied to psychiatric disorders. The basic idea of the PRS test is to use a half of the sample to select and up-weight those more likely to be associated SNPs, and then use the other half of the sample to test for aggregated effects of the selected SNPs. Intrigued by the novelty and increasing use of the PRS test, we aimed to evaluate and improve its performance for GWAS data. First, by an analysis of the PRS test, we point out its connection with the Sum test [Chapman and Whittaker, Genet Epidemiol 32:560-566; Pan, Genet Epidemiol 33:497-507]; given the known advantages and disadvantages of the Sum test, this connection motivated the development of several other polygenic tests, some of which may be more powerful than the PRS test under certain situations. Second, more importantly, to overcome the low statistical efficiency of the data-splitting strategy as adopted in the PRS test, we reformulate and thus modify the PRS test, obtaining several adaptive tests, which are closely related to the adaptive sum of powered score (SPU) test studied in the context of rare variant analysis [Pan et al., 2014, Genetics 197:1081-1095]. We use both simulated data and a real GWAS dataset of alcohol dependence to show dramatically improved power of the new tests over the PRS test; due to its superior performance and simplicity, we recommend the whole sample-based adaptive SPU test for polygenic testing. We hope to raise the awareness of the limitations of the PRS test and potential power gain of the adaptive SPU test.

Overlapping genetic susceptibility of seven autoimmune diseases:SPU tests based on genome-wide association summary statistics.

Autoimmune diseases are a heterogeneous group of diseases with an unclear aetiology. Genome-wide association studies (GWAS) and meta-analysis are inefficient in identifying shared variants. This study aims to identify shared genetic susceptibility for seven autoimmune diseases using sum of powered score (SPU) tests. GWAS summary statistics datasets of seven autoimmune diseases were downloaded from Open Targets Genetics, Dryad and International Multiple Sclerosis Genetics Consortium (IMSGC). The MTaSPUs was applied to confirm common single-nucleotide polymorphisms (SNP), MTaSPUsSet and aSPUs were performed to identify potential shared genes, and MTaSPUsPath was conducted to explore biological functions based on Kyoto encyclopedia of genes and genomes (KEGG) biological pathways. The MTaSPUs test found 104 pleiotropic SNPs (P < 1.19 × 10-6) in our study. The 38 of these SNPs were associated with at least one trait in the original GWAS study. A total of 56 genes associated with at least one trait (P < 4.98 × 10-6) were recognized by aSPUs test. The 45 potential pleiotropic genes (P < 4.98 × 10-6) were significant in MTaSPUsSet test. By aggregating results of aSPUs test and MTaSPUsSet test, we ascertained 38 pleiotropic genes. The 10 of these 38 pleiotropic genes have been reported in previous studies, while the remaining 28 genes were newly discovered. These 38 genes were matched in 14 significant KEGG pathways. We found new variants linked with complicated illnesses derived from several GWAS datasets using the SPU testing technique. The discovery of pleiotropic genes and shared pathways may aid in the development of common treatment approaches for autoimmune disorders.

Integrating brain imaging endophenotypes with GWAS for Alzheimer's disease.

Background: Genome wide association studies (GWAS) have identified many genetic variants associated with increased risk of Alzheimer's disease (AD). These susceptibility loci may effect AD indirectly through a combination of physiological brain changes. Many of these neuropathologic features are detectable via magnetic resonance imaging (MRI). Methods: In this study, we examine the effects of such brain imaging derived phenotypes (IDPs) with genetic etiology on AD, using and comparing the following methods: two-sample Mendelian randomization (2SMR), generalized summary statistics based Mendelian randomization (GSMR), transcriptome wide association studies (TWAS) and the adaptive sum of powered score (aSPU) test. These methods do not require individual-level genotypic and phenotypic data but instead can rely only on an external reference panel and GWAS summary statistics. Results: Using publicly available GWAS datasets from the International Genomics of Alzheimer's Project (IGAP) and UK Biobank's (UKBB) brain imaging initiatives, we identify 35 IDPs possibly associated with AD, many of which have well established or biologically plausible links to the characteristic cognitive impairments of this neurodegenerative disease. Conclusions: Our results highlight the increased power for detecting genetic associations achieved by multiple correlated SNP-based methods, i.e., aSPU, GSMR and TWAS, over MR methods based on independent SNPs (as instrumental variables).

Highly adaptive tests for group differences in brain functional connectivity.

Resting-state functional magnetic resonance imaging (rs-fMRI) and other technologies have been offering evidence and insights showing that altered brain functional networks are associated with neurological illnesses such as Alzheimer's disease. Exploring brain networks of clinical populations compared to those of controls would be a key inquiry to reveal underlying neurological processes related to such illnesses. For such a purpose, group-level inference is a necessary first step in order to establish whether there are any genuinely disrupted brain subnetworks. Such an analysis is also challenging due to the high dimensionality of the parameters in a network model and high noise levels in neuroimaging data. We are still in the early stage of method development as highlighted by Varoquaux and Craddock (2013) that "there is currently no unique solution, but a spectrum of related methods and analytical strategies" to learn and compare brain connectivity. In practice the important issue of how to choose several critical parameters in estimating a network, such as what association measure to use and what is the sparsity of the estimated network, has not been carefully addressed, largely because the answers are unknown yet. For example, even though the choice of tuning parameters in model estimation has been extensively discussed in the literature, as to be shown here, an optimal choice of a parameter for network estimation may not be optimal in the current context of hypothesis testing. Arbitrarily choosing or mis-specifying such parameters may lead to extremely low-powered tests. Here we develop highly adaptive tests to detect group differences in brain connectivity while accounting for unknown optimal choices of some tuning parameters. The proposed tests combine statistical evidence against a null hypothesis from multiple sources across a range of plausible tuning parameter values reflecting uncertainty with the unknown truth. These highly adaptive tests are not only easy to use, but also high-powered robustly across various scenarios. The usage and advantages of these novel tests are demonstrated on an Alzheimer's disease dataset and simulated data.