A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Lithium is an effective treatment for Bipolar Disorder (BD) and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania.</p> <p>Results</p> <p>Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes.</p> <p>Conclusions</p> <p>We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel hypotheses for validation in future work, we prioritized SNPs near genes in the network based on functional annotation. We also developed a "concept signature" for the genes in the network and identified additional candidate genes that may influence the system because they are significantly associated with the signature.</p

Modeling complex genetic and environmental influences on comorbid bipolar disorder with tobacco use disorder

Abstract Background Comorbidity of psychiatric and substance use disorders represents a significant complication in the clinical course of both disorders. Bipolar Disorder (BD) is a psychiatric disorder characterized by severe mood swings, ranging from mania to depression, and up to a 70% rate of comorbid Tobacco Use Disorder (TUD). We found epidemiological evidence consistent with a common underlying etiology for BD and TUD, as well as evidence of both genetic and environmental influences on BD and TUD. Therefore, we hypothesized a common underlying genetic etiology, interacting with nicotine exposure, influencing susceptibility to both BD and TUD. Methods Using meta-analysis, we compared TUD rates for BD patients and the general population. We identified candidate genes showing statistically significant, replicated, evidence of association with both BD and TUD. We assessed commonality among these candidate genes and hypothesized broader, multi-gene network influences on the comorbidity. Using Fisher Exact tests we tested our hypothesized genetic networks for association with the comorbidity, then compared the inferences drawn with those derived from the commonality assessment. Finally, we prioritized candidate SNPs for validation. Results We estimate risk for TUD among BD patients at 2.4 times that of the general population. We found three candidate genes associated with both BD and TUD (COMT, SLC6A3, and SLC6A4) and commonality analysis suggests that these genes interact in predisposing psychiatric and substance use disorders. We identified a 69 gene network that influences neurotransmitter signaling and shows significant over-representation of genes associated with BD and TUD, as well as genes differentially expressed with exposure to tobacco smoke. Twenty four of these genes are known drug targets. Conclusions This work highlights novel bioinformatics resources and demonstrates the effectiveness of using an integrated bioinformatics approach to improve our understanding of complex disease etiology. We illustrate the development and testing of hypotheses for a comorbidity predisposed by both genetic and environmental influences. Consistent with our hypothesis, the selected network models multiple interacting genetic influences on comorbid BD with TUD, as well as the environmental influence of nicotine. This network nominates candidate genes for validation and drug testing, and we offer a panel of SNPs prioritized for follow-up.http://deepblue.lib.umich.edu/bitstream/2027.42/112449/1/12881_2009_Article_575.pd

CLOCK is suggested to associate with comorbid alcohol use and depressive disorders

<p>Abstract</p> <p>Background</p> <p>Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol.</p> <p>Methods</p> <p>32 SNPs in 19 circadian clockwork related genes were analyzed using DNA from 76 individuals with comorbid depression and AUD, 446 individuals with AUD and 517 healthy controls with no psychiatric diagnosis. The individuals participated in a nationwide health examination study, representative of the general population aged 30 and over in Finland.</p> <p>Results</p> <p>The <it>CLOCK </it>haplotype TTGC formed by SNPs rs3805151, rs2412648, rs11240 and rs2412646, was associated with increased risk for comorbidity (OR = 1.65, 95% CI = 1.14-2.28, P = 0.0077). The SNPs of importance for this suggestive association were rs2412646 and rs11240 indicating location of the functional variation in the block downstream rs2412648. There was no indication for association between <it>CLOCK </it>and AUD.</p> <p>Conclusion</p> <p>Our findings suggest an association between the <it>CLOCK </it>gene and the comorbid condition of alcohol use and depressive disorders. Together with previous reports it indicates that the <it>CLOCK </it>variations we found here may be a vulnerability factor to depression given the exposure to alcohol in individuals having AUD.</p

Genome-Wide Association Analysis of Major Depressive Disorder and Its Related Phenotypes.

Major Depressive Disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. Thirteen to 14 million adults in the U.S. are believed to have MDD and an estimated 75% attempt suicide making MDD a major public health problem. Recently several genome-wide association (GWA) studies of MDD have been reported; however, few GWA studies focus on the analysis for MDD related phenotypes such as neuroticism and age at onset of MDD. The purpose of this study is to determine risk factors for MDD, identify genome-wide genetic variants affecting neuroticism and age at onset as quantitative traits, and detect gender differences influencing neuroticism. Bivariate and multiple logistic regression analyses were performed on 1,738 MDD cases and 1,618 non-MDD controls to determine phenotypic risk factors for MDD. Multiple linear regression analyses in PLINK software were used for GWA analyses for neuroticism and age at onset of MDD with 437,547 Single Nucleotide Polymorphisms (SNPs). Gender (OR: 1.43; 95% CI: 1.24 - 1.64) and a family history (OR: 2.88; 95% CI: 2.48 - 3.35) were significantly associated with an increased risk of MDD, which supports the findings of prior studies. Through GWA analysis 34 SNPs were identified to be associated with neuroticism (p \u3c 10-4). The best SNP was rs4806846 within the TMPRSS9 gene (p = 7.79 x10-6). Furthermore, 46 SNPs were found showing significant gene x gender interactions for neuroticism with p\u3c10-4. The best SNP showing gene x gender interaction was rs2430132 (p = 5.37x10-6) in HMCN1 gene. In addition, GWA analysis showed that several SNPs within 4 genes (GPR143, ASS1P4, MXRA5 and MAGEC1/2) were significantly associated with age at onset of MDD (p \u3c 5x10-7). This study confirmed previous findings that MDD is associated with an increased prevalence in women (about 43% more compared to men) and is highly heritable among first degree relatives. Several novel genetic loci were identified to be associated with neuroticism and age at onset. Gender differences were found in genetic influence of neuroticism. These findings offer the potential for new insights into the pathogenesis of MDD

Is the relationship between major depressive disorder and self-reported alcohol use disorder an artificial one ?

AIMS: Many studies have suggested a close relationship between alcohol use disorder (AUD) and major depressive disorder (MDD). This study aimed to test whether the relationship between self-reported AUD and MDD was artificially strengthened by the diagnosis of MDD. This association was tested comparing relationships between alcohol use and AUD for depressive people and non-depressive people. METHODS: As part of the Cohort Study on Substance Use Risk Factors, 4352 male Swiss alcohol users in their early twenties answered questions concerning their alcohol use, AUD and MDD at two time points. Generalized linear models for cross-sectional and longitudinal associations were calculated. RESULTS: For cross-sectional associations, depressive participants reported a higher number of AUD symptoms (β = 0.743, P &lt; 0.001) than non-depressive participants. Moreover, there was an interaction (β = -0.204, P = 0.001): the relationship between alcohol use and AUD was weaker for depressive participants rather than non-depressive participants. For longitudinal associations, there were almost no significant relationships between MDD at baseline and AUD at follow-up, but the interaction was still significant (β = -0.249, P &lt; 0.001). CONCLUSION: MDD thus appeared to be a confounding variable in the relationship between alcohol use and AUD, and self-reported measures of AUD seemed to be overestimated by depressive people. This result brings into question the accuracy of self-reported measures of substance use disorders. Furthermore, it adds to the emerging debate about the usefulness of substance use disorder as a concept, when heavy substance use itself appears to be a sensitive and reliable indicator

Genetic Insights into the Heterogeneity and Comorbidity of Substance Use Disorders

[eng] Substance use disorders (SUDs) are psychiatric disorders characterized by a recurring desire to continue taking a substance regardless of its destructive consequences. The etiology of SUDs is complex and multifactorial, where both genetic and environmental factors have an impact on the disease development. In addition, SUDs often co-occur at high prevalence with other psychiatric conditions, significantly impacting life expectancy, disease severity and societal burden. Over the past decade, genome-wide association studies (GWASs) have identified various risk loci for substance-specific SUD, as well as a shared genetic vulnerability for addiction. In addition, post-GWAS analyses have helped unravel the complex genetic architecture of SUDs, which can also involve an interplay of gene-environment interactions, and its relationship with comorbid mental health conditions. Current research in this field is making collective efforts to provide deeper and clearer knowledge into the genetic and environmental factors involved into the co-occurrence of SUDs and psychiatric disorders, which may be partially driving the high heterogeneity observed in SUDs, and the biological mechanisms driving these relationships. The present thesis comprises two studies that leverage in-house clinical cohorts, with both phenotypical and genetic data available, and state-of-the-art genomic techniques to investigate the shared genetic liability between SUDs and co-occurring traits, and to shed light into the genetic underpinnings of SUDs heterogeneity. The first study particularly focused on the relationship between SUDs and attention-deficit and hyperactivity disorder (ADHD). In this study, we tested whether the genetic liability to five SUD-related phenotypes share a common genetic background in both the general population and clinically diagnosed ADHD individuals, using an in-house sample of 989 subjects and polygenic scores (PGSs) analyses. We further explored the genetic overlap and the causal relationship between ADHD and SUDs using genetic correlation and Mendelian randomization analyses. Our results confirmed a significant genetic correlation between ADHD and SUDs and supported the current literature on the causal effect of the genetic liability to ADHD on the risk for SUDs. We provided novel findings on the effect of the genetic liability to lifetime cannabis use on an increased risk for ADHD and found evidence of a shared genetic background underlying SUDs between general population and ADHD, at least for lifetime cannabis use, alcohol dependence and smoking initiation. The second study aimed to disentangle SUDs heterogeneity using multidimensional data from a deeply phenotyped SUDs cohort of 1,427 individuals and PGSs for comorbid psychiatric disorders, behavioral and other related traits. We systematically explored the associations between the PGSs and 39 SUD-related phenotypes, and performed PGSs-environment interaction analyses using information on lifetime emotional, physical and/or sexual abuse. Our results revealed different patterns of associations between the genetic liability for mental health-related traits and SUD-related phenotypes, which may help explain part of the heterogeneity observed in SUDs. We also found evidence of a PGS-environment interaction showing that genetic liability for suicide attempt worsened the psychiatric status in SUDs individuals with a history of emotional physical and/or sexual abuse. Overall, the results of the present thesis provide new insights into the genetic overlap and causal relationships between SUDs and ADHD and contribute to a better understanding of the role of the genetic liability for psychiatric disorders and related traits, as well as its interaction with adverse life experiences, in the complexity of SUD heterogeneity. Lastly, this thesis provides a general discussion of the findings, which offers an extensive interpretation of the results in the context of existing literature, discusses the main methodological implications and outlines prospective directions for advancing in this line of research.[cat] Els trastorns per l'ús de substàncies (TUS) són trastorns psiquiàtrics caracteritzats per un desig recurrent de continuar prenent una o diverses substàncies, independentment de les seves conseqüències destructives. L'etiologia dels TUS és complexa i multifactorial, on tant factors genètics com ambientals tenen un impacte en el desenvolupament de la malaltia. A més, els TUS sovint es presenten simultàniament amb altres trastorns psiquiàtrics, afectant significativament la severitat de la malaltia, l’esperança de vida i la càrrega en la societat. Durant l'última dècada, els estudis d'associació del genoma complet (GWASs) han identificat diverses variants genètiques de risc per a TUS de substàncies específiques, així com una vulnerabilitat genètica compartida per a l'addicció. A més, les anàlisis post-GWAS han ajudat a desxifrar l'arquitectura genètica complexa dels TUS, que també pot implicar la interacció entre gens i ambient, i la seva relació amb trastorns de salut mental comòrbids. La recerca actual en aquest camp està focalitzada en profunditzar en el coneixement sobre els factors genètics i ambientals involucrats en la coexistència del TUS i trastorns psiquiàtrics, el qual pot ser parcialment responsable de l’alta heterogeneïtat observada en el TUS, i els mecanismes biològics implicats. La present tesi està composta per dos estudis que utilitzen cohorts clíniques, amb dades fenotípiques i genètiques disponibles, i tècniques genòmiques actuals per explorar la carga genètica compartida entre els TUS i els trets comòrbids, i per investigar la heterogeneïtat dels TUS des del punt de vista genètic. El primer estudi es centra particularment en la relació entre els TUS i el trastorn per dèficit d’atenció i hiperactivitat (TDAH). En aquest estudi, vam testar si la càrrega genètica per a cinc fenotips de TUS comparteixen una base genètica comuna en la població general i en individus amb TDAH, fent servir un mostra interna de 989 individus i anàlisis de puntuacions poligèniques (PGSs). Seguidament, vam explorar el solapament genètic i la relació causal entre el TDAH i els TUS utilitzant anàlisis de correlació genètica i de randomització mendeliana. Els nostres resultats confirmen una base genètic comuna entre el TDAH i els TUS i donen suport a la literatura actual sobre l'efecte causal de la càrrega genètica pel TDAH en el risc de TUS. A més, descrivim per primera vegada l'efecte causal de la càrrega genètica per a l'ús de cànnabis en el risc de TDAH i trobem evidències d'un component genètic compartit subjacent als TUS en la població general i en els individus amb TDAH, almenys per a l'ús de cànnabis, la dependència a l'alcohol i l'inici del consum de tabac. El segon estudi té com a objectiu desxifrar la heterogeneïtat dels TUS utilitzant dades multidimensionals d'una cohort de TUS de 1,427 individus dels quals es disposa una àmplia informació fenotípica, i PGSs per a trastorns psiquiàtrics comòrbids, trets del comportament i altres trets relacionats. Vam explorar les associacions entre els PGSs i 39 fenotips de TUS, i vam portar a terme anàlisis d’interacció PGS-ambient utilitzant informació sobre abús emocional, físic i/o sexual al llarg de la vida. Els nostres resultats revelen diferents patrons d'associacions entre la càrrega genètica per a trets relacionats amb la salut mental i fenotips de TUS, el que pot ajudar a explicar part de la heterogeneïtat observada en els TUS. També trobem evidència d'una interacció PGS-ambient que mostra que la càrrega genètica per a intents de suïcidi empitjora l'estat psiquiàtric en individus amb TUS que han patit abús emocional, físic i/o sexual. En conjunt, els resultats de la present tesi aporten noves perspectives sobre el solapament genètic i les relacions causals entre els TUS i el TDAH i contribueixen a una millor comprensió del paper de la càrrega genètica pels trastorns psiquiàtrics i trets relacionats, així com la seva interacció amb experiències adverses al llarg de la vida, en la complexitat de la heterogeneïtat dels TUS. Finalment, aquesta tesi ofereix una discussió general, la qual proporciona una extensa interpretació dels resultats en el context de la literatura existent, discuteix les principals implicacions metodològiques i detalla les futures direccions per avançar en aquesta línia de investigació

Genetic analysis of bipolar disorder and alcohol use disorder

Includes bibliographical referencesBackground: Mental health disorders represent a major public health problem in most countries around the world. In South Africa, the lifetime prevalence of psychiatric disorders is 30.3%, with substance-use disorders and mood disorders being the second and third most prevalent classes of lifetime disorders, respectively. Bipolar disorder (BD) has a lifetime prevalence of 1.4% and alcohol use disorder (AUD) a lifetime prevalence of 30.3%, and they are frequently comorbid. Both of these disorders have a relatively high heritability, yet the exact genetic basis of each remains unknown. Genetic variants within the hypothalamic-pituitary-adrenal (HPA)-axis and glutamatergic pathways have previously been implicated in both phenotypes. The aim of this project was to investigate the aetiology of BD and AUD, using high-throughput genomic technologies, bioinformatics, brain-imaging and environmental measures. An additional aim was to assess the genetic aetiology of BD-AUD comorbidity. Methods: For the genetic analysis underlying BD, a South African 'Afrikaner' family was investigated. Whole-genome sequencing (WGS) and whole-genome linkage analysis was performed for individuals with BD Type I (BDI) and unaffected family members using the Illumina HiSeq2000 and Affymetrix Axiom TM Genome-wide CEU 1 Array, respectively. For the AUD analysis, two groups were investigated; a South African adolescent group comprising 80 individuals with AUD and 80 controls, and a group of 8123 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The South African group of adolescents were genotyped using the Illumina Infinium iSelect custom 6000 BeadChip, childhood trauma data was obtained and brain magnetic resonance images were collected for a subset of this group. Genotype data on HPA-axis genes were obtained from a previous study for the ALSPAC cohort. The fourth group of individuals investigated in this thesis comprised 233 individuals with BD-AUD comorbidity from the Systemic Treatment Enhancement Program for BD (STEP-BD). Genotype data for genes from the glutamatergic and HPA-axis pathways were obtained from a previous study conducted on these individuals. Results: The chromosomal regions 6p25, 10p14-10p15.1, 11q23-11q25, and 13q21-22 scored the highest LOD scores for BD and the most over-represented pathway in the affected family members was the T-cell receptor signalling pathway. In the South African adolescent group, circadian rhythm genes were associated with AUD and childhood trauma predicted alcohol use in adolescence. The gene-imaging analysis identified a SNP in the glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GRIN2B) gene as being associated with brain volume in the left orbitofrontal cortex and posterior cingulate. HPA-axis genes did not show an association with AUD and no significant gene x environment interactions were detected for AUD in the ALSPAC cohort. Single variants in the glutamatergic genes and HPA-axis were not associated with BD-AUD comorbidity. However, from the gene-based analysis, the glutamatergic gene PRKCI was associated with BD-AUD comorbidity. Conclusions: It appears that disruption in immune-related genes may contribute to the development of BD in an Afrikaner family. No significant gene x environment interactions were detected for adolescent AUD. The circadian pathway and childhood trauma may play a role in the development of adolescent AUD. Differential brain volume and BD-AUD comorbidity may be characterised by variation in the glutamatergic pathway. These pathways and the interactions between them should be further investigated in BD and AUD