Browsing by Author "Murray, Robin M."

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    Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users
    (Oxford University Press, 2023) Johnson, Emma C.; Colbert, Sarah M. C.; Jeffries, Paul W.; Tillman, Rebecca; Bigdeli, Tim B.; Karcher, Nicole R.; Chan, Grace; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I.; Plawecki, Martin H.; Degenhardt, Louisa; Martin, Nicholas G.; Kamarajan, Chella; Schuckit, Marc A.; Murray, Robin M.; Dick, Danielle M.; Edenberg, Howard J.; D'Souza, Deepak Cyril; Di Forti, Marta; Porjesz, Bernice; Nelson, Elliot C.; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Background and hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study design: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study results: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.
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    Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders
    (Elsevier, 2022) Blokland, Gabriëlla A. M.; Grove, Jakob; Chen, Chia-Yen; Cotsapas, Chris; Tobet, Stuart; Handa, Robert; Schizophrenia Working Group of the Psychiatric Genomics Consortium; St. Clair, David; Lencz, Todd; Mowry, Bryan J.; Periyasamy, Sathish; Cairns, Murray J.; Tooney, Paul A.; Wu, Jing Qin; Kelly, Brian; Kirov, George; Sullivan, Patrick F.; Corvin, Aiden; Riley, Brien P.; Esko, Tõnu; Milani, Lili; Jönsson, Erik G.; Palotie, Aarno; Ehrenreich, Hannelore; Begemann, Martin; Steixner-Kumar, Agnes; Sham, Pak C.; Iwata, Nakao; Weinberger, Daniel R.; Gejman, Pablo V.; Sanders, Alan R.; Buxbaum, Joseph D.; Rujescu, Dan; Giegling, Ina; Konte, Bettina; Hartmann, Annette M.; Bramon, Elvira; Murray, Robin M.; Pato, Michele T.; Lee, Jimmy; Melle, Ingrid; Molden, Espen; Ophoff, Roel A.; McQuillin, Andrew; Bass, Nicholas J.; Adolfsson, Rolf; Malhotra, Anil K.; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Martin, Nicholas G.; Fullerton, Janice M.; Mitchell, Philip B.; Schofield, Peter R.; Forstner, Andreas J.; Degenhardt, Franziska; Schaupp, Sabrina; Comes, Ashley L.; Kogevinas, Manolis; Guzman-Parra, José; Reif, Andreas; Streit, Fabian; Sirignano, Lea; Cichon, Sven; Grigoroiu-Serbanescu, Maria; Hauser, Joanna; Lissowska, Jolanta; Mayoral, Fermin; Müller-Myhsok, Bertram; Świątkowska, Beata; Schulze, Thomas G.; Nöthen, Markus M.; Rietschel, Marcella; Kelsoe, John; Leboyer, Marion; Jamain, Stéphane; Etain, Bruno; Bellivier, Frank; Vincent, John B.; Alda, Martin; O'Donovan, Claire; Cervantes, Pablo; Biernacka, Joanna M.; Frye, Mark; McElroy, Susan L.; Scott, Laura J.; Stahl, Eli A.; Landén, Mikael; Hamshere, Marian L.; Smeland, Olav B.; Djurovic, Srdjan; Vaaler, Arne E.; Andreassen, Ole A.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Baune, Bernhard T.; Air, Tracy; Preisig, Martin; Uher, Rudolf; Levinson, Douglas F.; Weissman, Myrna M.; Potash, James B.; Shi, Jianxin; Knowles, James A.; Perlis, Roy H.; Lucae, Susanne; Boomsma, Dorret I.; Penninx, Brenda W. J. H.; Hottenga, Jouke-Jan; de Geus, Eco J. C.; Willemsen, Gonneke; Milaneschi, Yuri; Tiemeier, Henning; Grabe, Hans J.; Teumer, Alexander; Van der Auwera, Sandra; Völker, Uwe; Hamilton, Steven P.; Magnusson, Patrik K. E.; Viktorin, Alexander; Mehta, Divya; Mullins, Niamh; Adams, Mark J.; Breen, Gerome; McIntosh, Andrew M.; Lewis, Cathryn M.; Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium; iPSYCH; Hougaard, David M.; Nordentoft, Merete; Mors, Ole; Mortensen, Preben B.; Werge, Thomas; Als, Thomas D.; Børglum, Anders D.; Petryshen, Tracey L.; Smoller, Jordan W.; Goldstein, Jill M.; Psychiatry, School of Medicine
    Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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    The relationship between cannabis and schizophrenia: a genetically informed perspective
    (Wiley, 2021) Johnson, Emma C.; Hatoum, Alexander S.; Deak, Joseph D.; Polimanti, Renato; Murray, Robin M.; Edenberg, Howard J.; Gelernter, Joel; Di Forti, Marta; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Background and aims: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. Design: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. Setting: Genome-wide association studies were published previously as part of international consortia. Participants: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. Measurements: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. Findings: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). Conclusions: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.