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Gerring, Z.

Publications and source records attributed to Gerring, Z..

3 recordsLinked to original sources
bioRxiv2018

Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

BackgroundDespite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood.\n\nMethodsThis study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls; AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from \"daily or almost daily\" to \"never\", 438,308 individuals; AC-Quantity: total units of alcohol per week, 307,098 individuals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits.\n\nOutcomesPositive genetic correlation was observed between MD and AD (rgMD-AD=+0.47, P=6.6x10-10). AC-Quantity showed positive genetic correlation with both AD (rgAD-AC-Quantity=+0.75, P=1.8x10-14) and MD (rgMD-AC-Quantity=+0.14, P=2.9x10-7), while there was negative correlation of AC-Frequency with MD (rgMD-AC-Frequency=-0.17, P=1.5x10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P=1.29x10-6) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD.\n\nInterpretationResults support a causal role for MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts.\n\nFundingNational Institute of Mental Health and National Institute on Drug Abuse.\n\nPutting data into contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms \"alcohol\" AND \"depression\" AND \"Mendelian Randomization\". No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase (ADH) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased sample sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-sample Mendelian randomization to investigate causal relationships between alcohol dependence and major depression.\n\nTwin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large sample sizes to be informative.\n\nAdded value of this studyIn this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of individuals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence.\n\nImplications of all the available evidenceGiven the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

genetics↗
bioRxiv2018

Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder

The major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics and genetically predicted expression levels in different tissues, using our online tool Drug Targetor (drugtargetor.com). We also investigated drug-target relationships and drug effects on gene expression that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 25 druggable genes were significantly associated with MDD after multiple testing correction, and 19 were suggestively significant. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new - and better - treatment options.

genomics↗
bioRxiv2018

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2-4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.

genetics↗