GAUSS: a summary-statistics-based R package for accurate estimation of linkage disequilibrium for variants, Gaussian imputation, and TWAS analysis of cosmopolitan cohorts.

MOTIVATION: As the availability of larger and more ethnically diverse reference panels grows, there is an increase in demand for ancestry-informed imputation of genome-wide association studies (GWAS), and other downstream analyses, e.g. fine-mapping. Performing such analyses at the genotype level is computationally challenging and necessitates, at best, a laborious process to access individual-level genotype and phenotype data. Summary-statistics-based tools, not requiring individual-level data, provide an efficient alternative that streamlines computational requirements and promotes open science by simplifying the re-analysis and downstream analysis of existing GWAS summary data. However, existing tools perform only disparate parts of needed analysis, have only command-line interfaces, and are difficult to extend/link by applied researchers. RESULTS: To address these challenges, we present Genome Analysis Using Summary Statistics (GAUSS)-a comprehensive and user-friendly R package designed to facilitate the re-analysis/downstream analysis of GWAS summary statistics. GAUSS offers an integrated toolkit for a range of functionalities, including (i) estimating ancestry proportion of study cohorts, (ii) calculating ancestry-informed linkage disequilibrium, (iii) imputing summary statistics of unobserved variants, (iv) conducting transcriptome-wide association studies, and (v) correcting for "Winner's Curse" biases. Notably, GAUSS utilizes an expansive, multi-ethnic reference panel consisting of 32 953 genomes from 29 ethnic groups. This panel enhances the range and accuracy of imputable variants, including the ability to impute summary statistics of rarer variants. As a result, GAUSS elevates the quality and applicability of existing GWAS analyses without requiring access to subject-level genotypic and phenotypic information. AVAILABILITY AND IMPLEMENTATION: The GAUSS R package, complete with its source code, is readily accessible to the public via our GitHub repository at https://github.com/statsleelab/gauss. To further assist users, we provided illustrative use-case scenarios that are conveniently found at https://statsleelab.github.io/gauss/, along with a comprehensive user guide detailed in Supplementary Text S1.

DECO: a framework for jointly analyzing de novo and rare case/control variants, and biological pathways.

MOTIVATION: Rare variant-based analyses are beginning to identify risk genes for neuropsychiatric disorders and other diseases. However, the identified genes only account for a fraction of predicted causal genes. Recent studies have shown that rare damaging variants are significantly enriched in specific gene-sets. Methods which are able to jointly model rare variants and gene-sets to identify enriched gene-sets and use these enriched gene-sets to prioritize additional risk genes could improve understanding of the genetic architecture of diseases. RESULTS: We propose DECO (Integrated analysis of de novo mutations, rare case/control variants and omics information via gene-sets), an integrated method for rare-variant and gene-set analysis. The method can (i) test the enrichment of gene-sets directly within the statistical model, and (ii) use enriched gene-sets to rank existing genes and prioritize additional risk genes for tested disorders. In simulations, DECO performs better than a homologous method that uses only variant data. To demonstrate the application of the proposed protocol, we have applied this approach to rare-variant datasets of schizophrenia. Compared with a method which only uses variant information, DECO is able to prioritize additional risk genes. AVAILABILITY: DECO can be used to analyze rare-variants and biological pathways or cell types for any disease. The package is available on Github https://github.com/hoangtn/DECO.

Relationship between polygenic risk scores and symptom dimensions of schizophrenia and schizotypy in multiplex families with schizophrenia.

BACKGROUND: Psychotic disorders and schizotypal traits aggregate in the relatives of probands with schizophrenia. It is currently unclear how variability in symptom dimensions in schizophrenia probands and their relatives is associated with polygenic liability to psychiatric disorders. AIMS: To investigate whether polygenic risk scores (PRSs) can predict symptom dimensions in members of multiplex families with schizophrenia. METHOD: The largest genome-wide data-sets for schizophrenia, bipolar disorder and major depressive disorder were used to construct PRSs in 861 participants from the Irish Study of High-Density Multiplex Schizophrenia Families. Symptom dimensions were derived using the Operational Criteria Checklist for Psychotic Disorders in participants with a history of a psychotic episode, and the Structured Interview for Schizotypy in participants without a history of a psychotic episode. Mixed-effects linear regression models were used to assess the relationship between PRS and symptom dimensions across the psychosis spectrum. RESULTS: Schizophrenia PRS is significantly associated with the negative/disorganised symptom dimension in participants with a history of a psychotic episode (P = 2.31 × 10-4) and negative dimension in participants without a history of a psychotic episode (P = 1.42 × 10-3). Bipolar disorder PRS is significantly associated with the manic symptom dimension in participants with a history of a psychotic episode (P = 3.70 × 10-4). No association with major depressive disorder PRS was observed. CONCLUSIONS: Polygenic liability to schizophrenia is associated with higher negative/disorganised symptoms in participants with a history of a psychotic episode and negative symptoms in participants without a history of a psychotic episode in multiplex families with schizophrenia. These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia.

Genome-wide analysis of schizophrenia and multiple sclerosis identifies shared genomic loci with mixed direction of effects.

Common genetic variants identified in genome-wide association studies (GWAS) show varying degrees of genetic pleiotropy across complex human disorders. Clinical studies of schizophrenia (SCZ) suggest that in addition to neuropsychiatric symptoms, patients with SCZ also show variable immune dysregulation. Epidemiological studies of multiple sclerosis (MS), an autoimmune, neurodegenerative disorder of the central nervous system, suggest that in addition to the manifestation of neuroinflammatory complications, patients with MS may also show co-occurring neuropsychiatric symptoms with disease progression. In this study, we analyzed the largest available GWAS datasets for SCZ (N = 161,405) and MS (N = 41,505) using Gaussian causal mixture modeling (MiXeR) and conditional/conjunctional false discovery rate (condFDR) frameworks to explore and quantify the shared genetic architecture of these two complex disorders at common variant level. Despite detecting only a negligible genetic correlation (rG = 0.057), we observe polygenic overlap between SCZ and MS, and a substantial genetic enrichment in SCZ conditional on associations with MS, and vice versa. By leveraging this cross-disorder enrichment, we identified 36 loci jointly associated with SCZ and MS at conjunctional FDR < 0.05 with mixed direction of effects. Follow-up functional analysis of the shared loci implicates candidate genes and biological processes involved in immune response and B-cell receptor signaling pathways. In conclusion, this study demonstrates the presence of polygenic overlap between SCZ and MS in the absence of a genetic correlation and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

The impact on estimations of genetic correlations by the use of super-normal, unscreened, and family-history screened controls in genome wide case-control studies.

Traditionally, in normal case-control studies of disorder A, the controls are defined as those not developing the disorder. However, in genome wide association (GWA) studies, controls are sometimes (a) unscreened or (b) screened for both disorder A and disorder B, producing super-normal controls. Using simulations, we examine how the observed genetic correlations between two disorders (A and B) are influenced by the use of unscreened, normal, and super-normal controls. Normal controls produce unbiased estimates of the genetic correlation. However, unscreened and super-normal controls both bias upward the genetic correlations. The strength of the bias increases with increasing population prevalences for the two disorders. With super-normal controls, the absolute magnitude of bias is stronger when the true genetic correlation is low. The opposite is seen with the use of unscreened controls. Adding screening of first-degree relatives of controls substantially increases the bias in genetic correlations with super-normal controls but has minimal impact when controls are screened only for the relevant disease.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges.

Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA-miRNA-mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.

Increasing the resolution and precision of psychiatric genome-wide association studies by re-imputing summary statistics using a large, diverse reference panel.

Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large-scale genome-wide association studies (GWAS). Methods for direct imputation of GWAS summary-statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage-disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500-subject coming from the 1000 Genome-Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic-mixture based solely on Z-scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary-statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post-traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS-studies.

A method for estimating coherence of molecular mechanisms in major human disease and traits.

BACKGROUND: Phenotypes such as height and intelligence, are thought to be a product of the collective effects of multiple phenotype-associated genes and interactions among their protein products. High/low degree of interactions is suggestive of coherent/random molecular mechanisms, respectively. Comparing the degree of interactions may help to better understand the coherence of phenotype-specific molecular mechanisms and the potential for therapeutic intervention. However, direct comparison of the degree of interactions is difficult due to different sizes and configurations of phenotype-associated gene networks. METHODS: We introduce a metric for measuring coherence of molecular-interaction networks as a slope of internal versus external distributions of the degree of interactions. The internal degree distribution is defined by interaction counts within a phenotype-specific gene network, while the external degree distribution counts interactions with other genes in the whole protein-protein interaction (PPI) network. We present a novel method for normalizing the coherence estimates, making them directly comparable. RESULTS: Using STRING and BioGrid PPI databases, we compared the coherence of 116 phenotype-associated gene sets from GWAScatalog against size-matched KEGG pathways (the reference for high coherence) and random networks (the lower limit of coherence). We observed a range of coherence estimates for each category of phenotypes. Metabolic traits and diseases were the most coherent, while psychiatric disorders and intelligence-related traits were the least coherent. We demonstrate that coherence and modularity measures capture distinct network properties. CONCLUSIONS: We present a general-purpose method for estimating and comparing the coherence of molecular-interaction gene networks that accounts for the network size and shape differences. Our results highlight gaps in our current knowledge of genetics and molecular mechanisms of complex phenotypes and suggest priorities for future GWASs.

Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.

BACKGROUND: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets. METHODS: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status. RESULTS: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD. CONCLUSIONS: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.

Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence.

BACKGROUND: Long noncoding RNA (lncRNA) have been implicated in the etiology of alcohol use. Since lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step toward understanding lncRNA functions in alcohol use and addiction. Thus, we sought to profile lncRNA expression in the nucleus accumbens (NAc) in a large postmortem alcohol brain sample. METHODS: LncRNA and protein-coding gene (PCG) expressions in the NAc from 41 subjects with alcohol dependence (AD) and 41 controls were assessed via a regression model. Weighted gene coexpression network analysis was used to identify lncRNA and PCG networks (i.e., modules) significantly correlated with AD. Within the significant modules, key network genes (i.e., hubs) were also identified. The lncRNA and PCG hubs were correlated via Pearson correlations to elucidate the potential biological functions of lncRNA. The lncRNA and PCG hubs were further integrated with GWAS data to identify expression quantitative trait loci (eQTL). RESULTS: At Bonferroni adj. p-value ≤ 0.05, we identified 19 lncRNA and 5 PCG significant modules, which were enriched for neuronal and immune-related processes. In these modules, we further identified 86 and 315 PCG and lncRNA hubs, respectively. At false discovery rate (FDR) of 10%, the correlation analyses between the lncRNA and PCG hubs revealed 3,125 positive and 1,860 negative correlations. Integration of hubs with genotype data identified 243 eQTLs affecting the expression of 39 and 204 PCG and lncRNA hubs, respectively. CONCLUSIONS: Our study identified lncRNA and gene networks significantly associated with AD in the NAc, coordinated lncRNA and mRNA coexpression changes, highlighting potentially regulatory functions for the lncRNA, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Meta-Analysis of Associations Between Hypothalamic-Pituitary-Adrenal Axis Genes and Risk of Posttraumatic Stress Disorder.

The hypothalamic-pituitary-adrenal (HPA) axis has been of interest in attempts to identify genetic vulnerability for posttraumatic stress disorder (PTSD). Although numerous HPA-axis genes have been implicated in candidate gene studies, the findings are mixed and interpretation is limited by study design and methodological inconsistencies. To address these inconsistencies in the PTSD candidate gene literature, we conducted meta-analyses of HPA-related genes from both a traditional single nucleotide polymorphism (SNP)-level analysis and a gene-level analysis, using novel methods aggregating markers in the same gene. Database searches (PubMed and PsycINFO) identified 24 unique articles examining six HPA-axis genes in PTSD; analyses were conducted on four genes (ADCYAP1R1, CRHR1, FKBP5, NR3C1) that met study eligibility criteria (original research, human subjects, main effect association study of selected genes, PTSD as an outcome, trauma-exposed control group) and had sufficient data and number of studies for use in meta-analysis, within 20 unique articles. Findings from SNP-level analyses indicated that two variants (rs9296158 in FKBP5 and rs258747 in NR3C1) were nominally associated with PTSD, ps = .001 and .001, respectively, following multiple testing correction. At the gene level, significant relations between PTSD and both NR3C1 and FKBP5 were detected and robust to sensitivity analyses. Although study limitations exist (e.g., varied outcomes, inability to test moderators), taken together, these results provide support for FKBP5 and NR3C1 in risk for PTSD. Overall, this work highlights the utility of meta-analyses in resolving discrepancies in the literature and the value of adopting gene-level approaches to investigate the etiology of PTSD.

Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX diagnoses. We factor-analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta-analyzed across ancestries (NTotal = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta-analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome-wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10-11 ). Gene-based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.

TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders.

Genetic signal detection in genome-wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2-P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as-is to ethnically mixed-cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example, MAGMA, we applied JEPEGMIX2-P to summary statistics of most large meta-analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.

Method to estimate the approximate samples size that yield a certain number of significant GWAS signals in polygenic traits.

To argue for increased sample collection for disorders without significant findings, researchers resorted to plotting, for multiple traits, the number of significant findings as a function of the sample size. However, for polygenic traits, the prevalence of the disorder confounds the relationship between the number of significant findings and the sample size. To adjust the number of significant findings for prevalence, we develop a method that uses the expected noncentrality of the contrast between liabilities of cases and controls. We empirically find that, when compared to the sample size, this measure is a better predictor of number of significant findings. Even more, we show that the sample size effect on the number of signals is explained by the noncentrality measure. Finally, we provide an R script to estimate the required sample size (noncentrality) needed to yield a prespecified number of significant findings, along with the converse.

JEPEGMIX2: improved gene-level joint analysis of eQTLs in cosmopolitan cohorts.

Motivation: To increase detection power, researchers use gene level analysis methods to aggregate weak marker signals. Due to gene expression controlling biological processes, researchers proposed aggregating signals for expression Quantitative Trait Loci (eQTL). Most gene-level eQTL methods make statistical inferences based on (i) summary statistics from genome-wide association studies (GWAS) and (ii) linkage disequilibrium patterns from a relevant reference panel. While most such tools assume homogeneous cohorts, our Gene-level Joint Analysis of functional SNPs in Cosmopolitan Cohorts (JEPEGMIX) method accommodates cosmopolitan cohorts by using heterogeneous panels. However, JEPGMIX relies on brain eQTLs from older gene expression studies and does not adjust for background enrichment in GWAS signals. Results: We propose JEPEGMIX2, an extension of JEPEGMIX. When compared to JPEGMIX, it uses (i) cis-eQTL SNPs from the latest expression studies and (ii) brains specific (sub)tissues and tissues other than brain. JEPEGMIX2 also (i) avoids accumulating averagely enriched polygenic information by adjusting for background enrichment and (ii) to avoid an increase in false positive rates for studies with numerous highly enriched (above the background) genes, it outputs gene q-values based on Holm adjustment of P-values. Availability and implementation: https://github.com/Chatzinakos/JEPEGMIX2. Supplementary information: Supplementary data are available at Bioinformatics online.

The Coherence Problem: Finding Meaning in GWAS Complexity.

Genome wide association studies (GWAS) for behavioral traits and psychiatric disorders have inspired both confident optimism and withering criticism. Although many recent findings from well powered GWAS have been replicated in independent data sets, the genes identified have pinned down few if any underlying causal mechanisms. Therefore, a key issue is whether or not the genes implicated by GWAS form a coherent story on their own and thus could in principle lead to insight into the biological mechanisms underlying the trait or disorder. We sketch here four scenarios for how genes may contribute to traits and disorders; genetic studies may help elucidate mechanisms under only two of our scenarios. We also describe here an approach to characterize, in an unbiased fashion, the molecular coherence of the gene sets implicated by GWAS of various behavioral and psychiatric phenotypes and we sketch how the four scenarios may be reflected in our molecular coherence measure.

Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

BACKGROUND: Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported. METHODS: We conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses. RESULTS: No individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of hSNP2  = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, hSNP2  = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed. CONCLUSIONS: Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings.

Replication of the Interaction of PRKG1 and Trauma Exposure on Alcohol Misuse in an Independent African American Sample.

In the present study, we sought to replicate recent findings of Polimanti et al. (2017), who conducted a genome-wide gene-by-environment interaction study (GEWIS) and identified a gene-by-trauma interaction that predicts alcohol misuse among African Americans.  Consistent with the findings published by Polimanti and colleagues, results of the current study demonstrated an interaction effect, b = 0.41, of trauma exposure and rs1729578 in the intron of PRKG1 on alcohol misuse in a subsample of ancestral African Americans. The minor allele (rs1729578*C) was positively associated with increased alcohol use disorder symptoms in trauma-exposed subjects and negatively associated in non-trauma-exposed subjects.  This effect, however, was only significant for one out of three alcohol outcome measures we investigated, suggesting the interaction may be most salient when predicting higher severity of alcohol misuse. Additionally, the effect did not remain significant after we accounted for testing the effect on three different outcome variables. Also in line with the original study, the gene-by-environment effect was not demonstrated among the ancestral European subsample.  The findings suggest this gene variant may increase an individual's susceptibility to environmental influences, both adverse and supportive.

JEPEGMIX: gene-level joint analysis of functional SNPs in cosmopolitan cohorts.

MOTIVATION: To increase detection power, gene level analysis methods are used to aggregate weak signals. To greatly increase computational efficiency, most methods use as input summary statistics from genome-wide association studies (GWAS). Subsequently, gene statistics are constructed using linkage disequilibrium (LD) patterns from a relevant reference panel. However, all methods, including our own Joint Effect on Phenotype of eQTL/functional single nucleotide polymorphisms (SNPs) associated with a Gene (JEPEG), assume homogeneous panels, e.g. European. However, this renders these tools unsuitable for the analysis of large cosmopolitan cohorts. RESULTS: We propose a JEPEG extension, JEPEGMIX, which similar to one of our software tools, Direct Imputation of summary STatistics of unmeasured SNPs from MIXed ethnicity cohorts, is capable of estimating accurate LD patterns for cosmopolitan cohorts. JEPEGMIX uses this accurate LD estimates to (i) impute the summary statistics at unmeasured functional variants and (ii) test for the joint effect of all measured and imputed functional variants which are associated with a gene. We illustrate the performance of our tool by analyzing the GWAS meta-analysis summary statistics from the multi-ethnic Psychiatric Genomics Consortium Schizophrenia stage 2 cohort. This practical application supports the immune system being one of the main drivers of the process leading to schizophrenia. AVAILABILITY AND IMPLEMENTATION: Software, annotation database and examples are available at http://dleelab.github.io/jepegmix/. CONTACT: donghyung.lee@vcuhealth.org SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online.