Browsing by Subject "Genetic overlap"

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    Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder
    (Cambridge University Press, 2023) Johnson, Emma C.; Kapoor, Manav; Hatoum, Alexander S.; Zhou, Hang; Polimanti, Renato; Wendt, Frank R.; Walters, Raymond K.; Lai, Dongbing; Kember, Rachel L.; Hartz, Sarah; Meyers, Jacquelyn L.; Peterson, Roseann E.; Ripke, Stephan; Bigdeli, Tim B.; Fanous, Ayman H.; Pato, Carlos N.; Pato, Michele T.; Goate, Alison M.; Kranzler, Henry R.; O’Donovan, Michael C.; Walters, James T. R.; Gelernter, Joel; Edenberg, Howard J.; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Background: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.
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    The Landscape of Shared and Divergent Genetic Influences across 14 Psychiatric Disorders
    (medRxiv, 2025-01-15) Grotzinger, Andrew D.; Werme, Josefin; Peyrot, Wouter J.; Frei, Oleksandr; de Leeuw, Christiaan; Bicks, Lucy K.; Guo, Qiuyu; Margolis, Michael P.; Coombes, Brandon J.; Batzler, Anthony; Pazdernik, Vanessa; Biernacka, Joanna M.; Andreassen, Ole A.; Anttila, Verneri; Børglum, Anders D.; Cai, Na; Demontis, Ditte; Edenberg, Howard J.; Faraone, Stephen V.; Franke, Barbara; Gandal, Michael J.; Gelernter, Joel; Hettema, John M.; Jonas, Katherine G.; Knowles, James A.; Koenen, Karestan C.; Maihofer, Adam X.; Mallard, Travis T.; Mattheisen, Manuel; Mitchell, Karen S.; Neale, Benjamin M.; Nievergelt, Caroline M.; Nurnberger, John I.; O'Connell, Kevin S.; Robinson, Elise B.; Sanchez-Roige, Sandra S.; Santangelo, Susan L.; Stefansson, Hreinn; Stefansson, Kari; Stein, Murray B.; Strom, Nora I.; Thornton, Laura M.; Tucker-Drob, Elliot M.; Verhulst, Brad; Waldman, Irwin D.; Walters, G. Bragi; Wray, Naomi R.; Anxiety Disorders Working Group; Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group; Autism Spectrum Disorders Working Group; Bipolar Disorder Working Group; Eating Disorders Working Group; Major Depressive Disorder Working Group; Nicotine Dependence GenOmics (iNDiGO) Consortium; Obsessive-Compulsive Disorder Working Group; Post-Traumatic Stress Disorder Working Group; Schizophrenia Working Group; Substance Use Disorders Working Group; Tourette Syndrome Working Group; Lee, Phil H.; Kendler, Kenneth S.; Smoller, Jordan W.; Biochemistry and Molecular Biology, School of Medicine
    Psychiatric disorders display high levels of comorbidity and genetic overlap 1,2. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct 3, the majority of genetic signal is shared 4. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders 5. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors 6 that explain the majority of the genetic variance of the individual disorders (~66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap 7 and local genetic correlation 8 and very few disorder-specific loci 9 for two factors defined by: (i) schizophrenia and bipolar disorder ("SB factor"), and by (ii) major depression, PTSD, and anxiety ("internalizing factor"). At the functional level, we applied multiple methods 10-12 which demonstrated that the shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalizing factor was associated with oligodendrocyte biology. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations.