Multivariable cis-Mendelian randomization (cis-MVMR) has become an effective approach for identifying therapeutic targets that influence disease susceptibility. However, biases from invalid instruments, such as weak instruments and horizontal pleiotropy, remain unsolved. In this paper, we propose a new method called the cis-Mendelian randomization bias correction estimating equation (cis-MRBEE), which mitigates weak instrument bias by leveraging a local sparse genetic architecture: most variants within a genomic region are associated with a trait through linkage disequilibrium with a few causal variants. Cis-MRBEE identifies causal variants or proxies of exposures via fine-mapping, re-estimates genetic associations using the identified variants, and applies a double-penalized minimization to estimate causal exposures and account for horizontal pleiotropic effects. Simulations showed that in the presence of weak instruments and horizontal pleiotropy, directly adapting standard MVMR methods to cis-MVMR was infeasible, and existing cis-MVMR methods failed to control type I errors. In contrast, cis-MRBEE exhibited robustness to these sources of bias. We applied cis-MRBEE to the ANGPTL3 locus and identified a credible set comprising APOA1, APOC1, and PCSK9 as likely causal proteins for LDL-C, HDL-C, and TG. The subsequent analysis revealed a complex protein regulation network that influenced lipid traits. Furthermore, we used cis-MRBEE to discover that the expressions of CR1 in the basal ganglia, hippocampus, and oligodendrocytes were potentially causal for Alzheimer's disease and its biomarkers, A$\beta $42 and pTau, in cerebrospinal fluid.

MOTIVATION: The overall association evidence of a genetic variant with multiple traits can be evaluated by cross-phenotype association analysis using summary statistics from genome-wide association studies. Further dissecting the association pathways from a variant to multiple traits is important to understand the biological causal relationships among complex traits. RESULTS: Here, we introduce a flexible and computationally efficient Iterative Mendelian Randomization and Pleiotropy (IMRP) approach to simultaneously search for horizontal pleiotropic variants and estimate causal effect. Extensive simulations and real data applications suggest that IMRP has similar or better performance than existing Mendelian Randomization methods for both causal effect estimation and pleiotropic variant detection. The developed pleiotropy test is further extended to detect colocalization for multiple variants at a locus. IMRP will greatly facilitate our understanding of causal relationships underlying complex traits, in particular, when a large number of genetic instrumental variables are used for evaluating multiple traits. AVAILABILITY AND IMPLEMENTATION: The software IMRP is available at https://github.com/XiaofengZhuCase/IMRP. The simulation codes can be downloaded at http://hal.case.edu/∼xxz10/zhu-web/ under the link: MR Simulations software. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Summary: Many genome-wide association studies and genome-wide screening for gene-environment (GxE) interactions have been performed to elucidate the underlying mechanisms of human traits and diseases. When the analyzed outcome is quantitative, the overall contribution of identified genetic variants to the outcome is often expressed as the percentage of phenotypic variance explained. This is commonly done using individual-level genotype data but it is challenging when results are derived through meta-analyses. Here, we present R package, 'VarExp', that allows for the estimation of the percentage of phenotypic variance explained using summary statistics only. It allows for a range of models to be evaluated, including marginal genetic effects, GxE interaction effects and both effects jointly. Its implementation integrates all recent methodological developments and does not need external data to be uploaded by users. Availability and implementation: The R package is available at https://gitlab.pasteur.fr/statistical-genetics/VarExp.git. Supplementary information: Supplementary data are available at Bioinformatics online.

Finding the densest subgraph in a single graph is a fundamental problem that has been extensively studied. In many emerging applications, there exist dual networks. For example, in genetics, it is important to use protein interactions to interpret genetic interactions. In this application, one network represents physical interactions among nodes, for example, protein--protein interactions, and another network represents conceptual interactions, for example, genetic interactions. Edges in the conceptual network are usually derived based on certain correlation measure or statistical test measuring the strength of the interaction. Two nodes with strong conceptual interaction may not have direct physical interaction. In this article, we propose the novel dual-network model and investigate the problem of finding the densest connected subgraph (DCS), which has the largest density in the conceptual network and is also connected in the physical network. Density in the conceptual network represents the average strength of the measured interacting signals among the set of nodes. Connectivity in the physical network shows how they interact physically. Such pattern cannot be identified using the existing algorithms for a single network. We show that even though finding the densest subgraph in a single network is polynomial time solvable, the DCS problem is NP-hard. We develop a two-step approach to solve the DCS problem. In the first step, we effectively prune the dual networks, while guarantee that the optimal solution is contained in the remaining networks. For the second step, we develop two efficient greedy methods based on different search strategies to find the DCS. Different variations of the DCS problem are also studied. We perform extensive experiments on a variety of real and synthetic dual networks to evaluate the effectiveness and efficiency of the developed methods.

Finding dense subgraphs is an important problem that has recently attracted a lot of interests. Most of the existing work focuses on a single graph (or network1). In many real-life applications, however, there exist dual networks, in which one network represents the physical world and another network represents the conceptual world. In this paper, we investigate the problem of finding the densest connected subgraph (DCS) which has the largest density in the conceptual network and is also connected in the physical network. Such pattern cannot be identified using the existing algorithms for a single network. We show that even though finding the densest subgraph in a single network is polynomial time solvable, the DCS problem is NP-hard. We develop a two-step approach to solve the DCS problem. In the first step, we effectively prune the dual networks while guarantee that the optimal solution is contained in the remaining networks. For the second step, we develop two efficient greedy methods based on different search strategies to find the DCS. Different variations of the DCS problem are also studied. We perform extensive experiments on a variety of real and synthetic dual networks to evaluate the effectiveness and efficiency of the developed methods.

MOTIVATION: Admixed populations offer a unique opportunity for mapping diseases that have large disease allele frequency differences between ancestral populations. However, association analysis in such populations is challenging because population stratification may lead to association with loci unlinked to the disease locus. METHODS AND RESULTS: We show that local ancestry at a test single nucleotide polymorphism (SNP) may confound with the association signal and ignoring it can lead to spurious association. We demonstrate theoretically that adjustment for local ancestry at the test SNP is sufficient to remove the spurious association regardless of the mechanism of population stratification, whether due to local or global ancestry differences among study subjects; however, global ancestry adjustment procedures may not be effective. We further develop two novel association tests that adjust for local ancestry. Our first test is based on a conditional likelihood framework which models the distribution of the test SNP given disease status and flanking marker genotypes. A key advantage of this test lies in its ability to incorporate different directions of association in the ancestral populations. Our second test, which is computationally simpler, is based on logistic regression, with adjustment for local ancestry proportion. We conducted extensive simulations and found that the Type I error rates of our tests are under control; however, the global adjustment procedures yielded inflated Type I error rates when stratification is due to local ancestry difference.

MOTIVATION: Adjustment for population structure is necessary to avoid bias in genetic association studies of susceptibility variants for complex diseases. Population structure may differ from one genomic region to another due to the variability of individual ancestry associated with migration, random genetic drift or natural selection. Current association methods for correcting population stratification usually involve adjustment of global ancestry between study subjects. RESULTS: We suggest interrogating local population structure for fine mapping to more accurately locate true casual genes by better adjusting the confounding effect due to local ancestry. By extensive simulations on genome-wide datasets, we show that adjusting global ancestry may lead to false positives when local population structure is an important confounding factor. In contrast, adjusting local ancestry can effectively prevent false positives due to local population structure and thus can improve fine mapping for disease gene localization. We applied the local and global adjustments to the analysis of datasets from three genome-wide association studies, including European Americans, African Americans and Nigerians. Both European Americans and African Americans demonstrate greater variability in local ancestry than Nigerians. Adjusting local ancestry successfully eliminated the known spurious association between SNPs in the LCT gene and height due to the population structure existed in European Americans. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.