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Motivation Polygenic scores (PGS) aim to genetically predict complex traits at an individual level. PGS are typically trained on genome-wide association summary statistics and require an independent test dataset to tune parameters. More recent methods allow parameters to be tuned on the training data, removing the need for independent test data, but approaches are computationally intensive. Based on fine-mapping principles, we present RápidoPGS, a flexible and fast method to compute PGS requiring summary-level Genome-wide association studies (GWAS) datasets only, with little computational requirements and no test data required for parameter tuning. Results We show that RápidoPGS performs slightly less well than two out of three other widely used PGS methods (LDpred2, PRScs and SBayesR) for case–control datasets, with median r2 difference: -0.0092, -0.0042 and 0.0064, respectively, but up to 17 000-fold faster with reduced computational requirements. RápidoPGS is implemented in R and can work with user-supplied summary statistics or download them from the GWAS catalog. Availability and implementation Our method is available with a GPL license as an R package from CRAN and GitHub. Supplementary information Supplementary data are available at Bioinformatics online.

Gene-environment interactions (GxE) play a central role in the theoretical relationship between genetic factors and complex traits. While genome wide GxE studies of human behaviors remain underutilized, in part due to methodological limitations, existing GxE research in model organisms emphasizes the importance of interpreting genetic associations within environmental contexts. In this paper, we present a framework for conducting an analysis of GxE using raw data from genome wide association studies (GWAS) and applying the techniques to analyze gene-by-age interactions for alcohol use frequency. To illustrate the effectiveness of this procedure, we calculate genetic marginal effects from a GxE GWAS analysis for an ordinal measure of alcohol use frequency from the UK Biobank dataset, treating the respondent's age as the continuous moderating environment. The genetic marginal effects clarify the interpretation of the GxE associations and provide a direct and clear understanding of how the genetic associations vary across age (the environment). To highlight the advantages of our proposed methods for presenting GxE GWAS results, we compare the interpretation of marginal genetic effects with an interpretation that focuses narrowly on the significance of the interaction coefficients. The results imply that the genetic associations with alcohol use frequency vary considerably across ages, a conclusion that may not be obvious from the raw regression or interaction coefficients. GxE GWAS is less powerful than the standard "main effect" GWAS approach, and therefore require larger samples to detect significant moderated associations. Fortunately, the necessary sample sizes for a successful application of GxE GWAS can rely on the existing and on-going development of consortia and large-scale population-based studies.

Informative and accurate survival prediction with individualized dynamic risk profiles over time is critical for personalized disease prevention and clinical management. The massive genetic data, such as SNPs from genome-wide association studies (GWAS), together with well-characterized time-to-event phenotypes provide unprecedented opportunities for developing effective survival prediction models. Recent advances in deep learning have made extraordinary achievements in establishing powerful prediction models in the biomedical field. However, the applications of deep learning approaches in survival prediction are limited, especially with utilizing the wealthy GWAS data. Motivated by developing powerful prediction models for the progression of an eye disease, age-related macular degeneration (AMD), we develop and implement a multilayer deep neural network (DNN) survival model to effectively extract features and make accurate and interpretable predictions. Various simulation studies are performed to compare the prediction performance of the DNN survival model with several other machine learning-based survival models. Finally, using the GWAS data from two large-scale randomized clinical trials in AMD with over 7800 observations, we show that the DNN survival model not only outperforms several existing survival prediction models in terms of prediction accuracy (eg, c-index =0.76), but also successfully detects clinically meaningful risk subgroups by effectively learning the complex structures among genetic variants. Moreover, we obtain a subject-specific importance measure for each predictor from the DNN survival model, which provides valuable insights into the personalized early prevention and clinical management for this disease.

The ‘discovery’ stage of genome-wide association studies required amassing large, homogeneous cohorts. In order to attain clinically useful insights, we must now consider the presentation of disease within our clinics and, by extension, within our medical records. Large-scale use of electronic health record (EHR) data can help to understand phenotypes in a scalable manner, incorporating lifelong and whole-phenome context. However, extending analyses to incorporate EHR and biobank-based analyses will require careful consideration of phenotype definition. Judgements and clinical decisions that occur ‘outside’ the system inevitably contain some degree of bias and become encoded in EHR data. Any algorithmic approach to phenotypic characterization that assumes non-biased variables will generate compounded biased conclusions. Here, we discuss and illustrate potential biases inherent within EHR analyses, how these may be compounded across time and suggest frameworks for large-scale phenotypic analysis to minimize and uncover encoded bias.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss. publishedVersion

SummaryIdentifying genomic features responsible for genome-wide association study (GWAS) signals has proven to be a difficult challenge; many researchers have turned to colocalization analysis of GWAS signals with expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) to connect GWAS signals to candidate causal genes. The ColocQuiaL pipeline provides a framework to perform these colocalization analyses at scale across the genome and returns summary files and locus visualization plots to allow for detailed review of the results. As an example, we used ColocQuiaL to perform colocalization between the latest type 2 diabetes GWAS data and Genotype-Tissue Expression (GTEx) v8 single-tissue eQTL and sQTL data.Availability and ImplementationColocQuiaL is primarily written in R and is freely available at github: https://github.com/bychen9/eQTL_colocalizer.Contactbvoight@pennmedicine.upenn.edu

With the increasing accessibility of individual-level data from genome wide association studies, it is now common for researchers to have individual-level data of some traits in one specific population. For some traits, we can only access public released summary-level data due to privacy and safety concerns. The current methods to estimate genetic correlation can only be applied when the input data type of the two traits of interest is either both individual-level or both summary-level. When researchers have access to individual-level data for one trait and summary-level data for the other, they have to transform the individual-level data to summary-level data first and then apply summary data-based methods to estimate the genetic correlation. This procedure is computationally and statistically inefficient and introduces information loss. We introduce GENJI (Genetic correlation EstimatioN Jointly using Individual-level and summary data), a method that can estimate within-population or transethnic genetic correlation based on individual-level data for one trait and summary-level data for another trait. Through extensive simulations and analyses of real data on within-population and transethnic genetic correlation estimation, we show that GENJI produces more reliable and efficient estimation than summary data-based methods. Besides, when individual-level data are available for both traits, GENJI can achieve comparable performance than individual-level data-based methods. Downstream applications of genetic correlation can benefit from more accurate estimates. In particular, we show that more accurate genetic correlation estimation facilitates the predictability of cross-population polygenic risk scores.

Summary This protocol describes the application of the “omnigenic” model of the genetic architecture of complex traits to identify novel “core” genes influencing a disease-associated phenotype. Core genes are hypothesized to directly regulate disease and may serve as therapeutic targets. This protocol leverages GWAS data, a co-expression network, and publicly available data, including the GTEx database and the International Mouse Phenotyping Consortium Database, to identify modules enriched for genes with “core-like” characteristics. For complete details on the use and execution of this protocol, please refer to Sabik et al. (2020)., Graphical abstract, Highlights • A protocol to identify core modules by integrating gene expression data and GWAS data • Core modules serve as the basis for identifying genes influencing complex traits • Disease gene identification by module integration with publicly available databases, This protocol describes the application of the “omnigenic” model of the genetic architecture of complex traits to identify novel “core” genes influencing a disease-associated phenotype. Core genes are hypothesized to directly regulate disease and may serve as therapeutic targets. This protocol leverages GWAS data, a co-expression network, and publicly available data, including the GTEx database and the International Mouse Phenotyping Consortium Database, to identify modules enriched for genes with “core-like” characteristics.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P, GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

The current paradigm of personalized medicine envisages the use of genomic data to provide predictive information on the health course of an individual with the aim of prevention and individualized care. However, substantial efforts are required to realize the concept: enhanced genetic discoveries, translation into intervention strategies, and a systematic implementation in healthcare. Here we review how further genetic discoveries are improving personalized prediction and advance functional insights into the link between genetics and disease. In the second part we give our perspective on the way these advances in genomic research will transform the future of personalized prevention and medicine using Estonia as a primer.

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, a global genetic network mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discover significant interactions in Parkinson’s disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data., Genetic interactions may contribute to phenotypic traits but are challenging to decipher. Here, the authors develop BridGE, a computational approach for identifying pathways connected by genetic interactions from GWAS data.

This study investigated genetic correlations of longissimus muscle fatty acid composition with 32 traits related to growth, carcass, fat deposition and meat quality in 2448 pigs from six populations using genome wide SNP data. Most of significant loci for saturated (C14:0, C16:0 and C18:0) and mono-saturated fatty acids (C18:1n9 and C16:1n7) identified in GWAS, including those near ELOVL6, SCD and FASN genes, displayed negligible or weak effects on all the 32 traits. Fat deposition traits were the most relevant traits for fatty acid composition in genetic correlations. Backfat thickness and intramuscular fat content consistently showed strong negative genetic correlations with C18:2n6, and positive genetic correlations with C18:1n9 at least five populations. Intramuscular fat content consistently has positive correlations with saturated fatty acids (SFA) in six populations. This study provided insights into shared genetic control of fatty acid composition and the other economic traits, which is helpful in design of breeding strategies to genetically improve fatty acid composition in pork.

Genetic, environmental and pharmacological interventions into the aging process can confer resistance to a multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that mechanisms of aging might contribute to patterns of multimorbidity in humans, and hence could be targeted to prevent multiple conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation, and found strong, non-random associations between age-related diseases and aging mechanisms, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signalling pathway and activity of the ERK1/2 pathway played a significant role across multiple aging mechanisms and multiple, diverse age-related diseases. Mechanisms of aging therefore contribute to multiple age-related diseases and to patterns of human age-related multimorbidity, and could potentially be targeted to prevent more than one age-related condition in the same patient.

SummaryIn earlier work, we have developed and evaluated an alternative approach to the analysis of GWAS data, based on a statistic called the PPLD. More recently, motivated by a GWAS for genetic modifiers of the X-linked Mendelian disorder Duchenne Muscular Dystrophy (DMD), we adapted the PPLD for application to time-to-event (TE) phenotypes. Because DMD itself is relatively rare, this is a setting in which the very large sample sizes generally assembled for GWAS are simply not attainable. For this reason, statistical methods specially adapted for use in small data sets are required. Here we explore the behavior of the TE-PPLD via simulations, comparing the TE-PPLD with Cox Proportional Hazards analysis in the context of small to moderate sample sizes. Our results will help to inform our approach to the DMD study going forward, and they illustrate several respects in which the TE-PPLD, and by extension the original PPLD, offer advantages over regression-based approaches to GWAS in this context.

The current paradigm of personalized medicine envisages the use of genomic data to provide predictive information on the health course of an individual with the aim of prevention and individualized care. However, substantial efforts are required to realize the concept: enhanced genetic discoveries, translation into intervention strategies, and a systematic implementation in healthcare. Here we review how further genetic discoveries are improving personalized prediction and advance functional insights into the link between genetics and disease. In the second part we give our perspective on the way these advances in genomic research will transform the future of personalized prevention and medicine using Estonia as a primer.

A key question in human evolutionary genetics is whether and how natural selection has shaped the human genome. A new study by Song and colleagues uses GWAS data to examine evidence for the effects of polygenic adaptation in complex traits at different time scales.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytic to describe taxane-associated CIPN risk.MethodsWe analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher’s ratio. We then ranked ordered those SNPs which discriminated CIPN-positive from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross validation (LOOCV).ResultsUsing GWAS aggregate data, we identified a 267 SNP cluster which was associated with a CIPN+ phenotype with an accuracy of 96.1%. ConclusionsIdentification of a 267 SNP cluster could accurately predict CIPN risk. Validation using an independent patient cohort should be performed.

Background Genomic studies increasingly integrate expression quantitative trait loci (eQTL) information into their analysis pipelines, but few tools exist for the visualization of colocalization between eQTL and GWAS results. Those tools that do exist are limited in their analysis options, and do not integrate eQTL and GWAS information into a single figure panel, making the visualization of colocalization difficult. Results To address this issue, we developed the intuitive and user-friendly R package eQTpLot. eQTpLot takes as input standard GWAS and cis-eQTL summary statistics, and optional pairwise LD information, to generate a series of plots visualizing colocalization, correlation, and enrichment between eQTL and GWAS signals for a given gene-trait pair. With eQTpLot, investigators can easily generate a series of customizable plots clearly illustrating, for a given gene-trait pair: 1) colocalization between GWAS and eQTL signals, 2) correlation between GWAS and eQTL p-values, 3) enrichment of eQTLs among trait-significant variants, 4) the LD landscape of the locus in question, and 5) the relationship between the direction of effect of eQTL signals and the direction of effect of colocalizing GWAS peaks. These clear and comprehensive plots provide a unique view of eQTL-GWAS colocalization, allowing for a more complete understanding of the interaction between gene expression and trait associations. Conclusions eQTpLot provides a unique, user-friendly, and intuitive means of visualizing eQTL and GWAS signal colocalization, incorporating novel features not found in other eQTL visualization software. We believe eQTpLot will prove a useful tool for investigators seeking a convenient and customizable visualization of eQTL and GWAS data colocalization. Availability and implementation the eQTpLot R package and tutorial are available at https://github.com/RitchieLab/eQTpLot

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, an archetypal inflammatory marker, as a potential mediator for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated significant reciprocal relationships between lifetime smoking and both depression (ORSmk-Dep = 2.01, 95% CI 1.71-2.37, p < 0.001; O RDep-Smk = 1.09, 95% CI 1.06-1.13, p < 0.001) and CRP levels (ORSmk-CRP = 1.40, 95% CI 1.21-1.55, p < 0.001; ORCRP-Smk = 1.03, 95% CI 1.02-1.05, p < 0.001). These significant and positive associations were also supported by the majority of the robust MR methods performed. The reciprocal relationships between CRP levels (using >500 genetic instruments for CRP) and depression were not significant (ORCRP-Dep = 1.01, 95% CI 0.99-1.04; ORDep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to inflammation or when we adjusted the analysis by CRP-levels in multivariable analysis. Our study supports potential causal associations between lifetime smoking and depression, as well as between lifetime smoking and CRP levels, but not between CRP and depression. No evidence was found that CRP mediates the relationship between smoking and depression.

Genome-wide association studies (GWAS) are observational studies of a large set of genetic variants in an individual's sample in order to find if any of these variants are linked to a particular trait. In the last two decades, GWAS have contributed to several new discoveries in the field of genetics. This research presents a novel methodology to which GWAS can be applied to. It is mainly based on two machine learning methodologies, genetic algorithms and support vector machines. The database employed for the study consisted of information about 370,750 single-nucleotide polymorphisms belonging to 1076 cases of colorectal cancer and 973 controls. Ten pathways with different degrees of relationship with the trait under study were tested. The results obtained showed how the proposed methodology is able to detect relevant pathways for a certain trait: in this case, colorectal cancer. Keywords: machine learning; support vector machines; genetic algorithms; genome-wide association studies; single nucleotide polymorphism; pathways analysis

Genomic studies increasingly integrate expression quantitative trait loci (eQTL) information into their analysis pipelines, but few tools exist for the visualization of colocalization between eQTL and GWAS results. Those tools that do exist are limited in their analysis options, and do not integrate eQTL and GWAS information into a single figure panel, making the visualization of colocalization difficult.To address this issue, we developed the intuitive and user-friendly R package eQTpLot. eQTpLot takes as input standard GWAS and eQTL summary statistics, and optional pairwise LD information, to generate a series of plots visualizing colocalization, correlation, and enrichment between eQTL and GWAS signals for a given gene-trait pair. With eQTpLot, investigators can easily generate a series of customizable plots clearly illustrating, for a given gene-trait pair: 1) colocalization between GWAS and eQTL signals, 2) correlation between GWAS and eQTL p-values, 3) enrichment of eQTLs among trait-significant variants, 4) the LD landscape of the locus in question, and 5) the relationship between the direction of effect of eQTL signals and the direction of effect of colocalizing GWAS peaks. These clear and comprehensive plots provide a unique view of eQTL-GWAS colocalization, allowing for a more complete understanding of the interaction between gene expression and trait associations.In summary, eQTpLot provides a unique, user-friendly, and intuitive means of visualizing eQTL and GWAS signal colocalization, incorporating novel features not found in other eQTL visualization software. We believe eQTpLot will prove a useful tool for investigators seeking a convenient and customizable visualization of eQTL and GWAS data colocalization.Availability and Implementationthe eQTpLot R package and tutorial are available at https://github.com/RitchieLab/eQTpLot

Background Heterophils are refers to white blood cells with phagocytosis and killing functions in the avian immune system, These cells identify and kill pathogenic microorganisms through precise regulatory mechanisms. As a simple index, the heterophil/lymphocyte ratio (H/L) in the blood reflects the immune system status of chickens. H/L is a complex trait affected by multiple genetic loci, but single nucleotide polymorphisms (SNPs) significantly associated with traits can usually explain only part of the phenotypic variation. Combining a genome-wide association study (GWAS) with pathway analysis can improve understanding of the biological pathways affecting traits. Our objective was to conduct a SNP- and pathway-based analysis to identify possible biological mechanisms involved in H/L traits. Methods GWAS for H/L was performed in 1,317 Cobb broilers to identify significant single nucleotide polymorphisms (SNPs) associated with H/L. Eight SNPs (P< 1/8,068) reached a significant level of association. The following results were obtained through a series of analyses, including pathway-based association analysis and analysis of the proportion of phenotypic variance explained by SNPs. Results On the basis of GWAS analysis results, one associated SNP (5% genome-wide significance (6.80E-6,0.05/8,068)) on GGA 1(chicken chromosome 1) and seven suggestively associated SNPs with a trend toward significance(1.24E-4, 1/8,068) on GGAs 1, 7, 13 and 19 were detected. The significant SNP on GGA 19 was in Complement C1q Binding Protein (C1QBP). The wild-type and mutant individuals showed significant differences in H/L at five loci (P< 0.05). According to the results of pathway-based analysis, nine associated pathways (P

Summary Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. However, for most traits it remains difficult to interpret what genes and biological processes are impacted by the top hits. Here, as a contrast, we describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—that are biologically simpler than most diseases, and for which we know a great deal in advance about the core genes and pathways. Unlike most GWAS of complex traits, for all three traits we find that most top hits are readily interpretable. We observe huge enrichment of significant signals near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of variation in each trait, including insights into differences in testosterone regulation between females and males. Meanwhile, in other respects the results are reminiscent of GWAS for more-complex traits. In particular, even these molecular traits are highly polygenic, with most of the variance coming not from core genes, but from thousands to tens of thousands of variants spread across most of the genome. Given that diseases are often impacted by many distinct biological processes, including these three, our results help to illustrate why so many variants can affect risk for any given disease.

Many variants with low frequencies or with low to modest effects likely remain unidentified in genome-wide association studies (GWAS) because of stringent genome-wide thresholds for detection. To improve the power of detection, variant prioritization based on their functional annotations and epigenetic landmarks has been used successfully. Here, we propose a novel method of prioritization of a GWAS by exploiting gene-level knowledge (e.g., annotations to pathways and ontologies) and show that it further improves power. Often, disease associated variants are found near genes that are coinvolved in specific biological pathways relevant to disease process. Utilization of this knowledge to conduct a prioritized scan increases the power to detect loci that map to genes clustered in a few specific pathways. We have developed a computationally scalable framework based on penalized logistic regression (termed GKnowMTest-Genomic Knowledge-guided Multiplte Testing) to enable a prioritized pathway-guided GWAS scan with a very large number of gene-level annotations. We demonstrate that the proposed strategy improves overall power and maintains the Type 1 error globally. Our method works on genome-wide summary level data and a user-specified list of pathways (e.g., those extracted from large pathway databases without reference to biology of a specific disease). It automatically reweights the input p values by incorporating the pathway enrichments as "adaptively learned" from the data using a cross-validation technique to avoid overfitting. We used whole-genome simulations and some publicly available GWAS data sets to illustrate the application of our method. The GKnowMTest framework has been implemented as a user-friendly open-source R package.

SummaryWe present here an alternative method for genome-wide association study (GWAS) that is more powerful than traditional GWAS methods for locus detection. Single-variant GWAS methods incur a substantial multiple-testing burden because of the vast number of single nucleotide polymorphisms (SNPs) being tested simultaneously. Furthermore, these methods do not consider the functional genetic effect on the outcome because they ignore more complex joint effects of nearby SNPs within a region. By contrast, our method reduces the number of tests to be performed by screening the entire genome for associations using a sliding-window approach based on wavelets. In this context, a sequence of SNPs represents a genetic signal, and for each screened region, we transform the genetic signal into the wavelet space. The null and alternative hypotheses are modelled using the posterior distribution of the wavelet coefficients. We enhance our decision procedure by using additional information from the regression coefficients and by taking advantage of the pyramidal structure of wavelets. When faced with more complex signals than single-SNP associations, we show through simulations that Wavelet Screening provides a substantial gain in power compared to both the traditional GWAS modelling as well as another popular regional-based association test called ‘SNP-set (Sequence) Kernel Association Test’ (SKAT). To demonstrate feasibility, we re-analysed data from the large Norwegian HARVEST cohort.

Algorithms for active module identification (AMI) are central to analysis of omics data. Such algorithms receive a gene network and nodes’ activity scores as input and report sub-networks that show significant over-representation of accrued activity signal (‘active modules’), thus representing biological processes that presumably play key roles in the analyzed biological conditions. Although such methods exist for almost two decades, only a handful of studies attempted to compare the biological signals captured by different methods. Here, we systematically evaluated six popular AMI methods on gene expression (GE) and GWAS data. Notably, we observed that GO terms enriched in modules detected by these methods on the real data were often also enriched on modules found on randomly permuted input data. This indicated that AMI methods frequently report modules that are not specific to the biological context measured by the analyzed omics dataset. To tackle this bias, we designed a permutation-based method that evaluates the empirical significance of GO terms reported as enriched in modules. We used the method to fashion five novel performance criteria for evaluating AMI methods. Last, we developed DOMINO, a novel AMI algorithm, that outperformed the other six algorithms in extensive testing on GE and GWAS data. Software is available at https://github.com/Shamir-Lab.

Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.

Nonsyndromic clefts of the lip and palate are common birth defects resulting from gene-gene and gene-environment interactions. Mutations in human MSX1 have been linked to orofacial clefting and we show here that Msx1 deficiency causes a growth defect of the medial nasal process (Mnp) in mouse embryos. Although this defect alone does not disrupt lip formation, Msx1-deficient embryos develop a cleft lip when the mother is transiently exposed to reduced oxygen levels or to phenytoin, a drug known to cause embryonic hypoxia. In the absence of interacting environmental factors, the Mnp growth defect caused by Msx1 deficiency is modified by a Pax9-dependent 'morphogenetic regulation', which modulates Mnp shape, rescues lip formation and involves a localized abrogation of Bmp4-mediated repression of Pax9 Analyses of GWAS data revealed a genome-wide significant association of a Gene Ontology morphogenesis term (including assigned roles for MSX1, MSX2, PAX9, BMP4 and GREM1) specifically for nonsyndromic cleft lip with cleft palate. Our data indicate that MSX1 mutations could increase the risk for cleft lip formation by interacting with an impaired morphogenetic regulation that adjusts Mnp shape, or through interactions that inhibit Mnp growth.

Publisher's version (útgefin grein), An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09–0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms., This work is supported by the Swedish Research Council (grant number: 2018-00648, to D.L.), Karolinska Institutet Research Foundation (grant number: 2018-01585, to D.L.), Grant of Excellence, Icelandic Research Fund (grant number 163362-051, to U.A.V.), and ERC Consolidator Grant (StressGene, grant number:726413, to U.A.V.). We thank Dr. Agnar Helgason, Dr. Patrick Sulem, and Dr. Kári Stefánsson from deCODE Genetics, Iceland for helpful discussions on data analysis and interpretations. We also acknowledge the shared GWAS statistical summaries of schizophrenia from the Psychiatric Genetics Consortium and breast cancer from the Breast Cancer Association Consortium.