Vladimir Vladimirov

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Journals/Publications

• Gedik, H., Peterson, R., Chatzinakos, C., Dozmorov, M. G., Vladimirov, V., Riley, B. P., & Bacanu, S. A. (2024). A novel multi-omics mendelian randomization method for gene set enrichment and its application to psychiatric disorders. medRxiv : the preprint server for health sciences.
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  Genome-wide association studies (GWAS) of psychiatric disorders (PD) yield numerous loci with significant signals, but often do not implicate specific genes. Because GWAS risk loci are enriched in expression/protein/methylation quantitative loci (e/p/mQTL, hereafter xQTL), transcriptome/proteome/methylome-wide association studies (T/P/MWAS, hereafter XWAS) that integrate xQTL and GWAS information, can link GWAS signals to effects on specific genes. To further increase detection power, gene signals are aggregated within relevant gene sets (GS) by performing gene set enrichment (GSE) analyses. Often GSE methods test for enrichment of "signal" genes in curated GS while overlooking their linkage disequilibrium (LD) structure, allowing for the possibility of increased false positive rates. Moreover, no GSE tool uses xQTL information to perform mendelian randomization (MR) analysis. To make causal inference on association between PD and GS, we develop a novel MR GSE (MR-GSE) procedure. First, we generate a "synthetic" GWAS for each MSigDB GS by aggregating summary statistics for x-level (mRNA, protein or DNA methylation (DNAm) levels) from the largest xQTL studies available) of genes in a GS. Second, we use synthetic GS GWAS as exposure in a generalized summary-data-based-MR analysis of complex trait outcomes. We applied MR-GSE to GWAS of nine important PD. When applied to the underpowered opioid use disorder GWAS, none of the four analyses yielded any signals, which suggests a good control of false positive rates. For other PD, MR-GSE greatly increased the detection of GO terms signals (2,594) when compared to the commonly used (non-MR) GSE method (286). Some of the findings might be easier to adapt for treatment, e.g., our analyses suggest modest positive effects for supplementation with certain vitamins and/or omega-3 for schizophrenia, bipolar and major depression disorder patients. Similar to other MR methods, when applying MR-GSE researchers should be mindful of the confounding effects of horizontal pleiotropy on statistical inference.
• Luo, M., Trindade Pons, V., Thomas, N. S., Drake, J., Su, M. H., Vladimirov, V., van Loo, H. M., & Gillespie, N. A. (2024). The Mechanisms Underlying the Intergenerational Transmission of Substance Use and Misuse: An Integrated Research Approach. Twin research and human genetics : the official journal of the International Society for Twin Studies, 1-12.
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  Substance use and substance use disorders run in families. While it has long been recognized that the etiology of substance use behaviors and disorders involves a combination of genetic and environmental factors, two key questions remain largely unanswered: (1) the intergenerational transmission through which these genetic predispositions are passed from parents to children, and (2) the molecular mechanisms linking genetic variants to substance use behaviors and disorders. This article aims to provide a comprehensive conceptual framework and methodological approach for investigating the intergenerational transmission of substance use behaviors and disorders, by integrating genetic nurture analysis, gene expression imputation, and weighted gene co-expression network analysis. We also additionally describe two longitudinal cohorts - the Brisbane Longitudinal Twin Study in Australia and the Lifelines Cohort Study in the Netherlands. By applying the methodological framework to these two unique datasets, our future research will explore the complex interplay between genetic factors, gene expression, and environmental influences on substance use behaviors and disorders across different life stages and populations.
• Bekhbat, M., Drake, J., Reed, E. C., Lauten, T. H., Natour, T., Vladimirov, V. I., & Case, A. J. (2023). Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen. Brain, behavior, & immunity - health, 34, 100690.
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  Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p 
• Gedik, H., Nguyen, T. H., Peterson, R. E., Chatzinakos, C., Vladimirov, V. I., Riley, B. P., & Bacanu, S. A. (2023). Identifying potential risk genes and pathways for neuropsychiatric and substance use disorders using intermediate molecular mediator information. Frontiers in genetics, 14, 1191264.
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  Neuropsychiatric and substance use disorders (NPSUDs) have a complex etiology that includes environmental and polygenic risk factors with significant cross-trait genetic correlations. Genome-wide association studies (GWAS) of NPSUDs yield numerous association signals. However, for most of these regions, we do not yet have a firm understanding of either the specific risk variants or the effects of these variants. Post-GWAS methods allow researchers to use GWAS summary statistics and molecular mediators (transcript, protein, and methylation abundances) infer the effect of these mediators on risk for disorders. One group of post-GWAS approaches is commonly referred to as transcriptome/proteome/methylome-wide association studies, which are abbreviated as T/P/MWAS (or collectively as XWAS). Since these approaches use biological mediators, the multiple testing burden is reduced to the number of genes (∼20,000) instead of millions of GWAS SNPs, which leads to increased signal detection. In this work, our aim is to uncover likely risk genes for NPSUDs by performing XWAS analyses in two tissues-blood and brain. First, to identify putative causal risk genes, we performed an XWAS using the Summary-data-based Mendelian randomization, which uses GWAS summary statistics, reference xQTL data, and a reference LD panel. Second, given the large comorbidities among NPSUDs and the shared cis-xQTLs between blood and the brain, we improved XWAS signal detection for underpowered analyses by performing joint concordance analyses between XWAS results i) across the two tissues and ii) across NPSUDs. All XWAS signals i) were adjusted for heterogeneity in dependent instruments (HEIDI) (non-causality) -values and ii) used to test for pathway enrichment. The results suggest that there were widely shared gene/protein signals within the major histocompatibility complex region on chromosome 6 ( and ) and elsewhere in the genome ( and ). The identification of putative molecular genes and pathways underlying risk may offer new targets for therapeutic development. Our study revealed an enrichment of XWAS signals in vitamin D and omega-3 gene sets. So, including vitamin D and omega-3 in treatment plans may have a modest but beneficial effect on patients with bipolar disorder.
• Gedik, H., Peterson, R. E., Riley, B. P., Vladimirov, V. I., & Bacanu, S. A. (2023). Integrative Post-Genome-Wide Association Study Analyses Relevant to Psychiatric Disorders: Imputing Transcriptome and Proteome Signals. Complex psychiatry, 9(1-4), 130-144.
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  The genome-wide association study (GWAS) is a common tool to identify genetic variants associated with complex traits, including psychiatric disorders (PDs). However, post-GWAS analyses are needed to extend the statistical inference to biologically relevant entities, e.g., genes, proteins, and pathways. To achieve this goal, researchers developed methods that incorporate biologically relevant intermediate molecular phenotypes, such as gene expression and protein abundance, which are posited to mediate the variant-trait association. Transcriptome-wide association study (TWAS) and proteome-wide association study (PWAS) are commonly used methods to test the association between these molecular mediators and the trait.
• Moshfegh, C. M., Elkhatib, S. K., Watson, G. F., Drake, J., Taylor, Z. N., Reed, E. C., Lauten, T. H., Clopp, A. J., Vladimirov, V. I., & Case, A. J. (2023). S100a9 Protects Against the Effects of Repeated Social Defeat Stress. Biological psychiatry global open science, 3(4), 919-929.
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  Posttraumatic stress disorder, a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. We previously found that S100a8 and S100a9 messenger RNA, genes that encode the protein calprotectin, were significantly upregulated in T lymphocytes and positively correlated with inflammatory gene expression and the mitochondrial redox environment in these cells. Therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after psychological trauma.
• Denham, A. N., Drake, J., Gavrilov, M., Taylor, Z. N., Bacanu, S. A., & Vladimirov, V. I. (2022). Long Non-Coding RNAs: The New Frontier into Understanding the Etiology of Alcohol Use Disorder. Non-coding RNA, 8(4).
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  Alcohol use disorder (AUD) is a complex, chronic, debilitating condition impacting millions worldwide. Genetic, environmental, and epigenetic factors are known to contribute to the development of AUD. Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs, commonly referred to as the "dark matter" of the genome, with little to no protein-coding potential. LncRNAs have been implicated in numerous processes critical for cell survival, suggesting that they play important functional roles in regulating different cell processes. LncRNAs were also shown to display higher tissue specificity than protein-coding genes and have a higher abundance in the brain and central nervous system, demonstrating a possible role in the etiology of psychiatric disorders. Indeed, genetic (e.g., genome-wide association studies (GWAS)), molecular (e.g., expression quantitative trait loci (eQTL)) and epigenetic studies from postmortem brain tissues have identified a growing list of lncRNAs associated with neuropsychiatric and substance use disorders. Given that the expression patterns of lncRNAs have been associated with widespread changes in the transcriptome, including methylation, chromatin architecture, and activation or suppression of translational activity, the regulatory nature of lncRNAs may be ubiquitous and an innate component of gene regulation. In this review, we present a synopsis of the functional impact that lncRNAs may play in the etiology of AUD. We also discuss the classifications of lncRNAs, their known functional roles, and therapeutic advancements in the field of lncRNAs to further clarify the functional relationship between lncRNAs and AUD.
• Felip, E., Moreno, V., Morgensztern, D., Curigliano, G., Rutkowski, P., Trigo, J. M., Calvo, A., Kowalski, D., Cortinovis, D., Plummer, R., Maio, M., Ascierto, P. A., Vladimirov, V. I., Cervantes, A., Zudaire, E., Hazra, A., T'jollyn, H., Bandyopadhyay, N., Greger, J. G., , Attiyeh, E., et al. (2022). First-in-human, open-label, phase 1/2 study of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced cancers. Cancer chemotherapy and pharmacology, 89(4), 499-514.
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  To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study.
• Lancaster, E. E., Vladimirov, V. I., Riley, B. P., Landry, J. W., Roberson-Nay, R., & York, T. P. (2022). Large-scale integration of DNA methylation and gene expression array platforms identifies both and relationships. Epigenetics, 17(12), 1753-1773.
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  Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.
• Bountress, K. E., Vladimirov, V., McMichael, G., Taylor, Z. N., Hardiman, G., Chung, D., Adams, Z. W., Danielson, C. K., & Amstadter, A. B. (2021). Gene Expression Differences Between Young Adults Based on Trauma History and Post-traumatic Stress Disorder. Frontiers in psychiatry, 12, 581093.
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  The purpose of this study was to identify gene expression differences associated with post-traumatic stress disorder (PTSD) and trauma exposure (TE) in a three-group study design comprised of those with and without trauma exposure and PTSD. We conducted gene expression and gene network analyses in a sample ( = 45) composed of female subjects of European Ancestry (EA) with PTSD, TE without PTSD, and controls. We identified 283 genes differentially expressed between PTSD-TE groups. In an independent sample of Veterans ( = 78) a small minority of these genes were also differentially expressed. We identified 7 gene network modules significantly associated with PTSD and TE (Bonferroni corrected ≤ 0.05), which at a false discovery rate (FDR) of ≤ 0.2, were significantly enriched for biological pathways involved in focal adhesion, neuroactive ligand receptor interaction, and immune related processes among others. This study uses gene network analyses to identify significant gene modules associated with PTSD, TE, and controls. On an individual gene level, we identified a large number of differentially expressed genes between PTSD-TE groups, a minority of which were also differentially expressed in the independent sample. We also demonstrate a lack of network module preservation between PTSD and TE, suggesting that the molecular signature of PTSD and trauma are likely independent of each other. Our results provide a basis for the identification of likely disease pathways and biomarkers involved in the etiology of PTSD.
• Chatzinakos, C., Lee, D., Cai, N., Vladimirov, V. I., Webb, B. T., Riley, B. P., Flint, J., Kendler, K. S., Ressler, K. J., Daskalakis, N. P., & Bacanu, S. A. (2021). Increasing the resolution and precision of psychiatric genome-wide association studies by re-imputing summary statistics using a large, diverse reference panel. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 186(1), 16-27.
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  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.
• Nguyen, T. H., He, X., Brown, R. C., Webb, B. T., Kendler, K. S., Vladimirov, V. I., Riley, B. P., & Bacanu, S. A. (2021). DECO: a framework for jointly analyzing de novo and rare case/control variants, and biological pathways. Briefings in bioinformatics, 22(5).
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  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.
• Vornholt, E., Drake, J., Mamdani, M., McMichael, G., Taylor, Z. N., Bacanu, S. A., Miles, M. F., & Vladimirov, V. I. (2021). Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges. Addiction biology, 26(6), e13071.
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  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.
• Chatzinakos, C., Georgiadis, F., Lee, D., Cai, N., Vladimirov, V. I., Docherty, A., Webb, B. T., Riley, B. P., Flint, J., Kendler, K. S., Daskalakis, N. P., & Bacanu, S. A. (2020). TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 183(8), 454-463.
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  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.
• Drake, J., McMichael, G. O., Vornholt, E. S., Cresswell, K., Williamson, V., Chatzinakos, C., Mamdani, M., Hariharan, S., Kendler, K. S., Kalsi, G., Riley, B. P., Dozmorov, M., Miles, M. F., Bacanu, S. A., & Vladimirov, V. I. (2020). Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence. Alcoholism, clinical and experimental research, 44(12), 2468-2480.
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  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.
• Vornholt, E., Drake, J., Mamdani, M., McMichael, G., Taylor, Z. N., Bacanu, S. A., Miles, M. F., & Vladimirov, V. I. (2020). Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC. PloS one, 15(12), e0243857.
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  Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique and shared biological processes dysregulated in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We further investigated potential mRNA/miRNA interactions at the network and individual gene expression levels to identify the neurobiological mechanisms underlying AD in the brain. By using genotyped and imputed SNP data, we identified expression quantitative trait loci (eQTL) uncovering potential genetic regulatory elements for gene networks associated with AD. At a Bonferroni corrected p≤0.05, we identified significant mRNA (NAc = 6; PFC = 3) and miRNA (NAc = 3; PFC = 2) AD modules. The gene-set enrichment analyses revealed modules preserved between PFC and NAc to be enriched for immune response processes, whereas genes involved in cellular morphogenesis/localization and cilia-based cell projection were enriched in NAc modules only. At a Bonferroni corrected p≤0.05, we identified significant mRNA/miRNA network module correlations (NAc = 6; PFC = 4), which at an individual transcript level implicated miR-449a/b as potential regulators for cellular morphogenesis/localization in NAc. Finally, we identified eQTLs (NAc: mRNA = 37, miRNA = 9; PFC: mRNA = 17, miRNA = 16) which potentially mediate alcohol's effect in a brain region-specific manner. Our study highlights the neurotoxic effects of chronic alcohol abuse as well as brain region specific molecular changes that may impact the development of alcohol addiction.
• Sheerin, C. M., Vladimirov, V., Williamson, V., Bountress, K., K Danielson, C., Ruggiero, K., & Amstadter, A. B. (2019). A preliminary investigation of rare variants associated with genetic risk for PTSD in a natural disaster-exposed adolescent sample. European journal of psychotraumatology, 10(1), 1688935.
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  : Posttraumatic stress disorder (PTSD) involves a complex interaction of biological, psychological, and social factors. Numerous studies have demonstrated genetic variation associated with the development of PTSD, primarily in adults. However, the contribution of low frequency and rare genetic variants to PTSD is unknown to date. Moreover, there is limited work on genetic risk for PTSD in child and adolescent populations. : This preliminary study aimed to identify the low frequency and rare genetic variation that contributes to PTSD using an exome array. : This post-disaster, adolescent sample (n = 707, 51% females, = 14.54) was assessed for PTSD diagnosis and symptom count following tornado exposure. : Gene-based models, covarying for ancestry principal components, age, sex, tornado severity, and previous trauma identified variants in four genes associated with diagnosis and 276 genes associated with symptom count (at < .001). Functional class analyses suggested an association with variants in the nonsense class (nonsynonymous variant that results in truncation of, and usually non-functional, protein) with both outcomes. An exploratory gene network pathway analysis showed a great number of significant genes involved in brain and immune function, illustrating the usefulness of downstream examination of gene-based findings that may point to relevant biological processes. : While further investigation in larger samples is warranted, findings align with extant PTSD literature that has identified variants associated with biological conditions such as immune function.
• Vornholt, E., Luo, D., Qiu, W., McMichael, G. O., Liu, Y., Gillespie, N., Ma, C., & Vladimirov, V. I. (2019). Postmortem brain tissue as an underutilized resource to study the molecular pathology of neuropsychiatric disorders across different ethnic populations. Neuroscience and biobehavioral reviews, 102, 195-207.
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  In recent years, large scale meta-analysis of genome-wide association studies (GWAS) have reliably identified genetic polymorphisms associated with neuropsychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). However, the majority of disease-associated single nucleotide polymorphisms (SNPs) appear within functionally ambiguous non-coding genomic regions. Recently, increased emphasis has been placed on identifying the functional relevance of disease-associated variants via correlating risk polymorphisms with gene expression levels in etiologically relevant tissues. For neuropsychiatric disorders, the etiologically relevant tissue is brain, which requires robust postmortem sample sizes from varying genetic backgrounds. While small sample sizes are of decreasing concern, postmortem brain databases are composed almost exclusively of Caucasian samples, which significantly limits study design and result interpretation. In this review, we highlight the importance of gene expression and expression quantitative loci (eQTL) studies in clinically relevant postmortem tissue while addressing the current limitations of existing postmortem brain databases. Finally, we introduce future collaborations to develop postmortem brain databases for neuropsychiatric disorders from Chinese and Asian subpopulations.
• Chatzinakos, C., Lee, D., Webb, B. T., Vladimirov, V. I., Kendler, K. S., & Bacanu, S. A. (2018). JEPEGMIX2: improved gene-level joint analysis of eQTLs in cosmopolitan cohorts. Bioinformatics (Oxford, England), 34(2), 286-288.
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  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.
• Stansfield, J. C., Cresswell, K. G., Vladimirov, V. I., & Dozmorov, M. G. (2018). HiCcompare: an R-package for joint normalization and comparison of HI-C datasets. BMC bioinformatics, 19(1), 279.
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  Changes in spatial chromatin interactions are now emerging as a unifying mechanism orchestrating the regulation of gene expression. Hi-C sequencing technology allows insight into chromatin interactions on a genome-wide scale. However, Hi-C data contains many DNA sequence- and technology-driven biases. These biases prevent effective comparison of chromatin interactions aimed at identifying genomic regions differentially interacting between, e.g., disease-normal states or different cell types. Several methods have been developed for normalizing individual Hi-C datasets. However, they fail to account for biases between two or more Hi-C datasets, hindering comparative analysis of chromatin interactions.
• Adkins, A. E., Hack, L. M., Bigdeli, T. B., Williamson, V. S., McMichael, G. O., Mamdani, M., Edwards, A. C., Aliev, F., Chan, R. F., Bhandari, P., Raabe, R. C., Alaimo, J. T., Blackwell, G. G., Moscati, A., Poland, R. S., Rood, B., Patterson, D. G., Walsh, D., , C. S., , Whitfield, J. B., et al. (2017). Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcoholism, clinical and experimental research, 41(5), 911-928.
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  Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.
• Bigdeli, T. B., Lee, D., Webb, B. T., Riley, B. P., Vladimirov, V. I., Fanous, A. H., Kendler, K. S., & Bacanu, S. A. (2016). A simple yet accurate correction for winner's curse can predict signals discovered in much larger genome scans. Bioinformatics (Oxford, England), 32(17), 2598-603.
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  For genetic studies, statistically significant variants explain far less trait variance than 'sub-threshold' association signals. To dimension follow-up studies, researchers need to accurately estimate 'true' effect sizes at each SNP, e.g. the true mean of odds ratios (ORs)/regression coefficients (RRs) or Z-score noncentralities. Naïve estimates of effect sizes incur winner's curse biases, which are reduced only by laborious winner's curse adjustments (WCAs). Given that Z-scores estimates can be theoretically translated on other scales, we propose a simple method to compute WCA for Z-scores, i.e. their true means/noncentralities.
• Lee, D., Williamson, V. S., Bigdeli, T. B., Riley, B. P., Webb, B. T., Fanous, A. H., Kendler, K. S., Vladimirov, V. I., & Bacanu, S. A. (2016). JEPEGMIX: gene-level joint analysis of functional SNPs in cosmopolitan cohorts. Bioinformatics (Oxford, England), 32(2), 295-7.
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  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.
• van den Oord, E. J., Clark, S. L., Xie, L. Y., Shabalin, A. A., Dozmorov, M. G., Kumar, G., , S. S., Vladimirov, V. I., Magnusson, P. K., & Aberg, K. A. (2016). A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue. Schizophrenia bulletin, 42(4), 1018-26.
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  Mutated CpG sites (CpG-SNPs) are potential hotspots for human diseases because in addition to the sequence variation they may show individual differences in DNA methylation. We performed methylome-wide association studies (MWAS) to test whether methylation differences at those sites were associated with schizophrenia. We assayed all common CpG-SNPs with methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) using DNA extracted from 1408 blood samples and 66 postmortem brain samples (BA10) of schizophrenia cases and controls. Seven CpG-SNPs passed our FDR threshold of 0.1 in the blood MWAS. Of the CpG-SNPs methylated in brain, 94% were also methylated in blood. This significantly exceeded the 46.2% overlap expected by chance (P-value < 1.0×10(-8)) and justified replicating findings from blood in brain tissue. CpG-SNP rs3796293 in IL1RAP replicated (P-value = .003) with the same direction of effects. This site was further validated through targeted bisulfite pyrosequencing in 736 independent case-control blood samples (P-value < 9.5×10(-4)). Our top result in the brain MWAS (P-value = 8.8×10(-7)) was CpG-SNP rs16872141 located in the potential promoter of ENC1. Overall, our results suggested that CpG-SNP methylation may reflect effects of environmental insults and can provide biomarkers in blood that could potentially improve disease management.
• Lee, D., Bigdeli, T. B., Williamson, V. S., Vladimirov, V. I., Riley, B. P., Fanous, A. H., & Bacanu, S. A. (2015). DISTMIX: direct imputation of summary statistics for unmeasured SNPs from mixed ethnicity cohorts. Bioinformatics (Oxford, England), 31(19), 3099-104.
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  To increase the signal resolution for large-scale meta-analyses of genome-wide association studies, genotypes at unmeasured single nucleotide polymorphisms (SNPs) are commonly imputed using large multi-ethnic reference panels. However, the ever increasing size and ethnic diversity of both reference panels and cohorts makes genotype imputation computationally challenging for moderately sized computer clusters. Moreover, genotype imputation requires subject-level genetic data, which unlike summary statistics provided by virtually all studies, is not publicly available. While there are much less demanding methods which avoid the genotype imputation step by directly imputing SNP statistics, e.g. Directly Imputing summary STatistics (DIST) proposed by our group, their implicit assumptions make them applicable only to ethnically homogeneous cohorts.
• Lee, D., Williamson, V. S., Bigdeli, T. B., Riley, B. P., Fanous, A. H., Vladimirov, V. I., & Bacanu, S. A. (2015). JEPEG: a summary statistics based tool for gene-level joint testing of functional variants. Bioinformatics (Oxford, England), 31(8), 1176-82.
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  Gene expression is influenced by variants commonly known as expression quantitative trait loci (eQTL). On the basis of this fact, researchers proposed to use eQTL/functional information univariately for prioritizing single nucleotide polymorphisms (SNPs) signals from genome-wide association studies (GWAS). However, most genes are influenced by multiple eQTLs which, thus, jointly affect any downstream phenotype. Therefore, when compared with the univariate prioritization approach, a joint modeling of eQTL action on phenotypes has the potential to substantially increase signal detection power. Nonetheless, a joint eQTL analysis is impeded by (i) not measuring all eQTLs in a gene and/or (ii) lack of access to individual genotypes.
• Mamdani, M., Williamson, V., McMichael, G. O., Blevins, T., Aliev, F., Adkins, A., Hack, L., Bigdeli, T., van der Vaart, A. D., Web, B. T., Bacanu, S. A., Kalsi, G., , C. C., Kendler, K. S., Miles, M. F., Dick, D., Riley, B. P., Dumur, C., & Vladimirov, V. I. (2015). Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence. PloS one, 10(9), e0137671.
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  Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
• Savage, J. E., McMichael, O., Gorlin, E. I., Beadel, J. R., Teachman, B., Vladimirov, V. I., Hettema, J. M., & Roberson-Nay, R. (2015). Validation of candidate anxiety disorder genes using a carbon dioxide challenge task. Biological psychology, 109, 61-6.
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  Few replicable genetic variants have been identified in the etiology of heritable anxiety disorders such as panic disorder. Endophenotypic measures that have reduced heterogeneity may provide more powerful targets for gene identification. We assessed hypersensitivity to carbon dioxide (a reliable endophenotype of panic and anxiety) in 174 Caucasian college students, who were genotyped on 26 polymorphic markers from 11 genes previously associated with panic/anxiety. Individual trajectories of respiratory and subjective anxiety response to carbon dioxide were measured and tested for association with these genetic markers. One marker in the acid-sensing ion channel 1 (ASIC1) gene, rs1108923, had a significant association with respiratory rate. No genes had a significant association with subjective anxiety response. Our findings support previously reported associations between ASIC1 and panic/anxiety, but not other genes previously associated with anxiety disorders. The use of endophenotypic markers is a promising avenue for gene identification in anxiety and other complex disorders.
• Mamdani, M., McMichael, G. O., Gadepalli, V., Williamson, V., Parker, E. K., Haroutunian, V., & Vladimirov, V. I. (2013). Differential regulation of schizophrenia-associated microRNA gene function by variable number tandem repeats (VNTR) polymorphism. Schizophrenia research, 151(1-3), 284-6.