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3. Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author

Barr, Cathy L., Batterson, James R., Berlin, Cheston, Budman, Cathy L., Coppola, Giovanni, Cox, Nancy J., Darrow, Sabrina, Dion, Yves, Freimer, Nelson B., Grados, Marco A., Greenberg, Erica, Hirschtritt, Matthew E., Huang, Alden Y., Illmann, Cornelia, King, Robert A., Kurlan, Roger, Leckman, James F., Lyon, Gholson J., Malaty, Irene A., McMahon, William M., Neale, Benjamin M., Okun, Michael S., Osiecki, Lisa, Robertson, Mary M., Rouleau, Guy A., Sandor, Paul, Singer, Harvey S., Smit, Jan H., Sul, Jae Hoon, Androutsos, Christos, Basha, Entela, Farkas, Luca, Fichna, Jakub, Janik, Piotr, Kapisyzi, Mira, Karagiannidis, Iordanis, Koumoula, Anastasia, Nagy, Peter, Puchala, Joanna, Szejko, Natalia, Szymanska, Urszula, Tsironi, Vaia, Apter, Alan, Ball, Juliane, Bodmer, Benjamin, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Garcia-Delgar, Blanca, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Drineas, Petros, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nawaz, Muhammad S., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J.W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Fernandez, Thomas V., Gilbert, Donald L., Hong, Hyun Ju, Ibanez-Gomez, Laura, Kim, Eun-Joo, Kim, Young Key, Kim, Young-Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett L., Maras, Athanasios, Murphy, Tara L., Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, State, Matthew W., Visscher, Frank, Wang, Sheng, Zinner, Samuel H., Tsetsos, Fotis, Topaloudi, Apostolia, Jain, Pritesh, Yang, Zhiyu, Yu, Dongmei, Kolovos, Petros, Tumer, Zeynep, Rizzo, Renata, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Müller-Vahl, Kirsten R., Cath, Danielle C., Boomsma, Dorret I., Wolanczyk, Tomasz, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Padmanabhuni, Shanmukha S., Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Yannaki, Evangelia, Stamatoyannopoulos, John A., Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Mir, Pablo, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Roessner, Veit, Walitza, Susanne, Schrag, Anette, Martino, Davide, Tischfield, Jay A., Heiman, Gary A., Willsey, A. Jeremy, Dietrich, Andrea, Davis, Lea K., Crowley, James J., Mathews, Carol A., Scharf, Jeremiah M., Georgitsi, Marianthi, Hoekstra, Pieter J., and Paschou, Peristera

Published
2024
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14. The Kaiser Permanente Northern California Adult Alcohol Registry, an Electronic Health Records-Based Registry of Patients With Alcohol Problems: Development and Implementation

Author

Palzes, Vanessa A, Weisner, Constance, Chi, Felicia W, Kline-Simon, Andrea H, Satre, Derek D, Hirschtritt, Matthew E, Ghadiali, Murtuza, and Sterling, Stacy

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

BackgroundElectronic health record (EHR)–based disease registries have aided health care professionals and researchers in increasing their understanding of chronic illnesses, including identifying patients with (or at risk of developing) conditions and tracking treatment progress and recovery. Despite excessive alcohol use being a major contributor to the global burden of disease and disability, no registries of alcohol problems exist. EHR-based data in Kaiser Permanente Northern California (KPNC), an integrated health system that conducts systematic alcohol screening, which provides specialty addiction medicine treatment internally and has a membership of over 4 million members that are highly representative of the US population with access to care, provide a unique opportunity to develop such a registry. ObjectiveOur objectives were to describe the development and implementation of a protocol for assembling the KPNC Adult Alcohol Registry, which may be useful to other researchers and health systems, and to characterize the registry cohort descriptively, including underlying health conditions. MethodsInclusion criteria were adult members with unhealthy alcohol use (using National Institute on Alcohol Abuse and Alcoholism guidelines), an alcohol use disorder (AUD) diagnosis, or an alcohol-related health problem between June 1, 2013, and May 31, 2019. We extracted patients’ longitudinal, multidimensional EHR data from 1 year before their date of eligibility through May 31, 2019, and conducted descriptive analyses. ResultsWe identified 723,604 adult patients who met the registry inclusion criteria at any time during the study period: 631,780 with unhealthy alcohol use, 143,690 with an AUD diagnosis, and 18,985 with an alcohol-related health problem. We identified 65,064 patients who met two or more criteria. Of the 4,973,195 adult patients with at least one encounter with the health system during the study period, the prevalence of unhealthy alcohol use was 13% (631,780/4,973,195), the prevalence of AUD diagnoses was 3% (143,690/4,973,195), and the prevalence of alcohol-related health problems was 0.4% (18,985/4,973,195). The registry cohort was 60% male (n=432,847) and 41% non-White (n=295,998) and had a median age of 41 years (IQR=27). About 48% (n=346,408) had a chronic medical condition, 18% (n=130,031) had a mental health condition, and 4% (n=30,429) had a drug use disorder diagnosis. ConclusionsWe demonstrated that EHR-based data collected during clinical care within an integrated health system could be leveraged to develop a registry of patients with alcohol problems that is flexible and can be easily updated. The registry’s comprehensive patient-level data over multiyear periods provides a strong foundation for robust research addressing critical public health questions related to the full course and spectrum of alcohol problems, including recovery, which would complement other methods used in alcohol research (eg, population-based surveys, clinical trials).

Published
2020
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15. Autism Spectrum Symptoms in a Tourette’s Disorder Sample

Author

Darrow, Sabrina M., Grados, Marco, Sandor, Paul, Hirschtritt, Matthew E., Illmann, Cornelia, Osiecki, Lisa, Dion, Yves, King, Robert, Pauls, David, Budman, Cathy L., Cath, Danielle C., Greenberg, Erica, Lyon, Gholson J., McMahon, William M., Lee, Paul C., Delucchi, Kevin L., Scharf, Jeremiah M., and Mathews, Carol A.

Published
2017
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16. Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome

Author

Greenberg, Erica, Tung, Esther S., Gauvin, Caitlin, Osiecki, Lisa, Yang, Kelly G., Curley, Erin, Essa, Angela, Illmann, Cornelia, Sandor, Paul, Dion, Yves, Lyon, Gholson J., King, Robert A., Darrow, Sabrina, Hirschtritt, Matthew E., Budman, Cathy L., Grados, Marco, Pauls, David L., Keuthen, Nancy J., Mathews, Carol A., Scharf, Jeremiah M., and The Tourette Association of America International Consortium for Genetics

Published
2018
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17. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Author

Jain, Pritesh, Miller-Fleming, Tyne, Topaloudi, Apostolia, Yu, Dongmei, Drineas, Petros, Georgitsi, Marianthi, Yang, Zhiyu, Rizzo, Renata, Müller-Vahl, Kirsten R., Tumer, Zeynep, Mol Debes, Nanette, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Mir, Pablo, Cath, Danielle C., Boomsma, Dorret I., Roessner, Veit, Wolanczyk, Tomasz, Janik, Piotr, Szejko, Natalia, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Walitza, Susanne, Schrag, Anette, Martino, Davide, Dietrich, Andrea, Mathews, Carol A., Scharf, Jeremiah M., Hoekstra, Pieter J., Davis, Lea K., Paschou, Peristera, Als, Thomas D., Aschauer, Harald, Atzmon, Gil, Bækvad-Hansen, Matie, Barr, Cathy L., Barzilai, Nir, Batterson, James R., Batterson, Robert, Benarroch, Fortu, Berlin, Cheston, Boberg, Julia, Bodmer, Benjamin, Bohnenpoll, Julia, Børglum, Anders D., Brown, Lawrence W., Bruun, Ruth, Budman, Cathy L., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cheon, Keun-Ah, Chouinard, Sylvain, Coffey, Barbara J., Coppola, Giovanni, Crowley, James J., Dahl, Niklas, Darrow, Sabrina M., Daly, Mark J., De Rubeis, Silvia, Dion, Yves, Djurfeldt, Diana R., Domenech-Salgado, Laura, Eapen, Valsamma, Elzerman, Lonneke, Fernandez, Thomas V., Freimer Carolin Fremer, Nelson B., Garcia-Delgar, Blanca, Garrido, Marcos, Gilbert, Donald L., Giusti-Rodriguez, Paola, Grados, Marco, Greenberg, Erica, Grove, Jakob, Hagstrom, Julie, Halvorsen, Matt, Hansen, Bjarne, Haavik, Jan, Hebebrand, Johannes, Heiman, Gary A., Herrera, Luis, Hinney, Anke, Hirschtritt, Matthew E., Sul, Jae Hoon, Hong, Hyun Ju, Hougaard, David M., Huang, Alden Y., Ibanez-Gomez, Laura, Ivankovic, Franjo, Jankovic, Joseph, Karlsson, Elinor K., Kaprio, Jakko A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Knowles, James A., Koh, Yun-Joo, Kook, Sodham, Khalifa, Najah, Konstantinidis, Anastasios, Kuperman, Samuel, Kurlan, Roger, Kvale, Gerd, Leckman, James, Lee, Paul C., Leventhal, Bennett, Lichtenstein, Paul, Lindbald-Toh, Kerstin, Lowe, Thomas, Ludolph, Andrea, da Silva, Claudia Luhrs, Luðvigsson, Pétur, Luykx, Jurjen, Lyon, Gholson J., Mahjani, Behrang, Maras, Athanasios, Mataix-Cols, David, Mattheisen, Manuel, Malaty, Irene A., McMahon, William M., McQuillin, Andrew, Meier, Sandra M., Moessner, Rainald, Mortensen, Preben B., Mors, Ole, Mudgal, Poorva, Nagy, Peter, Naarden, Allan, Neale, Benjamin M., Nawaz, Muhammad S., Nissen, Judith Becker, Nöthen Merete Nordentoft, Markus M., Nordsletten, Ashley E., Okun, Michael S., Ophoff, Roel, Osiecki, Lisa, Palotie, Aarno, Palviainen, Teemu P., Pato Michele T. Pato, Carlos N., Pittenger, Christopher, Pollak, Yehuda, Posthuma, Danielle, Ramos, Eliana, Reichert, Jennifer, Robertson, Mary M., Roffman, Joshua L., Rouleau, Guy, Rück, Christian, Sæmundsen, Evald, Samuels, Jack, Sandin, Sven, Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey S., Smit, Jan, Smoller, Jordan W., State, Matthew, Solem, Stian, Song, Dong-Ho, Song, Jungeun, Stamenkovic, Mara, Stefansson, Kári, Strom, Nora, Stuhrmann, Manfred, Szatkiewicz, Jin, Szymanska, Urszula, Tischfield, Jay A., Tsetsos, Fotis, Thorarensen, Ólafur, Tubing, Jennifer, Visscher, Frank, Wagner, Michael, Wanderer, Sina, Wang, Sheng, Werge, Thomas, Willsey, Jeremy A., Wolancyk, Tomasz, Woods, Douglas W., Woods, Martin, Zelaya, Ivette, Zinner, Samuel H., Apter, Alan, Ball, Juliane, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J. W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Dynamic Earth and Resources, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Medizin, Autism Spectrum Disorder/genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Risk Factors, Diabetes Mellitus, Tourette Syndrome/genetics, Humans, Female, Attention Deficit Disorder with Hyperactivity/genetics, Type 2, Biological Psychiatry
Abstract

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Published
2023

20. Burnout Among Psychiatry Residents and One Program’s Approach to Creating a Culture of Wellness.

Author

Brown, Kathryn H., Bal, Berneen, Plauche, Jessica L., Sung, Dawn, and Hirschtritt, Matthew E.

Subjects
MENTAL health services, PSYCHIATRY, PSYCHOLOGICAL burnout, SECONDARY traumatic stress, VIOLENCE in the workplace
Abstract

Psychiatry residency training includes unique characteristics that can predispose trainees to burnout, including vicarious traumatization, prevalence of patient suicide and violence in the workplace, and social stigma surrounding mental health. For the purposes of this article, the authors examine these contributing factors and address how psychiatry residency training programs, specifically the Kaiser Permanente Oakland program, are responding to these unique challenges with wellness initiatives. Initiatives to promote wellness at Kaiser Permanente Oakland include a resident and faculty–led wellness committee, work-hour limits, reasonable call schedules, a robust mentorship program, funded social and networking events programs, and comprehensive mental health services. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Patient and Visit Characteristics Associated With Physical Restraint Use in the Emergency Department.

Author

Walia, Harbir, Tucker, Lue-Yen S., Manickam, Raj N., Kene, Mamata V., Sharp, Adam L., Berdahl, Carl T., and Hirschtritt, Matthew E.

Subjects
RESTRAINT of patients, HOSPITAL emergency services, ELECTRONIC health records
Abstract

OBJECTIVE: Physical restraints are used in emergency departments (EDs) to address behavioral emergencies in situations in which less restrictive methods have failed. The objective of this study was to evaluate for associations between patient/visit characteristics and physical restraint use. STUDY DESIGN: This study was designed as a cross-sectional, retrospective study of all encounters at Kaiser Permanente Northern California EDs from January 1, 2016, to December 31, 2019, to evaluate differences in patient and visit characteristics between visits involving physical restraint use and those without. METHODS: Using electronic health record data, this study identified physical restraint use among ED encounters and extracted demographic, clinical, and facility characteristics. The authors calculated odds ratios for physical restraint placement, adjusting for patient and visit characteristics and accounting for within-patient clustering. RESULTS: Among 4,410,816 encounters (representing 1,791,673 patients), 6369 encounters (0.1%) involved physical restraint use among 5,554 patients (0.3%). Variables associated with the lowest odds of physical restraint included female sex, presentation to the ED in more recent years, and presence of intentional self-harm/suicidal ideation. Variables associated with the highest odds of physical restraint included higher visit acuity and weekend presentations to the ED. DISCUSSION: This study, which leveraged a large, diverse patient sample generalizable to the Northern California population, found several patient and visit characteristics associated with physical restraint use in the ED. CONCLUSION: Results of this study may help identify patient groups and situational factors that are most likely to lead to physical restraint use and structural factors contributing to disparities in care, thereby informing interventions to reduce physical restraint use when possible. [ABSTRACT FROM AUTHOR]

Published
2023
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27. Fulfilling the Goals of 988 Through Crisis Stabilization Care.

Author

Hirschtritt, Matthew E., Howard, Caren A., and Simon, Gregory E.

Subjects
PSYCHIATRIC hospitals, MENTAL health services, FORUMS, CRISES
Abstract

Recent implementation of the nationwide 988 Suicide and Crisis Lifeline has expanded telephone-based mental health crisis services and created a unified framework for crisis care in the United States. However, the infrastructure for the final step of the crisis continuum—an appropriate mental health service for persons in crisis to receive the care they need—is fragmented, unevenly distributed, underfunded, and understudied. Given the few options for individuals in crisis, most often inpatient psychiatric hospitals are the default option. In this Open Forum, the authors describe the scope of the problem and propose how clinicians, policy makers, and researchers can improve the availability of evidence-based disposition options for individuals in crisis. [ABSTRACT FROM AUTHOR]

Published
2023
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28. Cannabis Use Among Patients With Psychotic Disorders

Author

Hirschtritt, Matthew E, Young-Wolff, Kelly C, Mathalon, Daniel H, and Satre, Derek D

Subjects
Analgesics, Marijuana Abuse, Cannabinoid Research, General Medicine, Serious Mental Illness, Brain Disorders, Substance Misuse, Mental Health, Good Health and Well Being, Psychotic Disorders, Clinical Research, Commentary, Cannabidiol, Humans, Cannabis
Abstract

Amidst a rapidly changing legal landscape, cannabis use in the United States has become increasingly common in the past several years. There is strong evidence to suggest that chronic and early cannabis use increases the risk of developing a psychotic disorder, and there is at least moderate evidence that suggests ongoing cannabis use among individuals with a psychotic disorder worsens clinical outcomes (eg, decreased psychiatric medication adherence, more frequent psychiatric hospitalizations). In this Review Article, we provide a focused, clinically oriented overview of the epidemiology and characteristics of cannabis use among individuals with first-episode psychosis; evaluation of cannabis use; and treatment modalities, focusing on behavioral interventions suitable for outpatient primary care settings. We discuss the limited data supporting pharmacologic interventions for cannabis use disorder, specifically among individuals with first-episode psychosis, and the unique potential of cannabidiol to serve as a harm-reduction strategy for individuals who are not able or willing to achieve abstinence for cannabis.

Published
2021

30. Agreement between Youth Self-Report and Biospecimen-Confirmed Substance Use: A Systematic Review.

Author

Folk, Johanna B., Hirschtritt, Matthew E., McCrary, Quincy D., and Kalapatapu, Raj K.

Subjects
*ONLINE information services, *SUBSTANCE abuse, *BIOLOGICAL products, *MEDICAL information storage & retrieval systems, *SELF-evaluation, *SYSTEMATIC reviews, *AMPHETAMINES, *HAIR, *MEDLINE, *URINALYSIS, *METABOLITES
Abstract

Context Biospecimen analysis may enhance confidence in the accuracy of self-reported substance use among adolescents and transitional age youth (TAY). Associations between biospecimen types and self-reported use, however, are poorly characterized in the existing literature. Objective: We performed a systematic review of associations between biospecimen-confirmed and self-reported substance use. Data sources: PubMed, Embase, and Web of Science. Study selection: We included studies documenting associations between self-reported and biospecimen-confirmed substance use among adolescents (12–18 years) and TAY (19–26 years) published 1990–2020. Data extraction: Three authors extracted relevant data using a template and assessed bias risk using a modified JBI Critical Appraisal Tool. Results: We screened 1523 titles and abstracts, evaluated 73 full texts for eligibility, and included 28 studies. Most studies examined urine (71.4%) and hair (32.1%) samples. Self-report retrospective recall period varied from past 24 h to lifetime use. Agreement between self-report and biospecimen results were low to moderate and were higher with rapidly metabolized substances (e.g., amphetamines) and when shorter retrospective recall periods were applied. Frequently encountered sources of potential bias included use of non-validated self-report measures and failure to account for confounding factors in the association between self-reported and biospecimen-confirmed use. Limitations: Study heterogeneity prevented a quantitative meta-analysis. Studies varied in retrospective recall periods, biospecimen processing, and use of validated self-report measures. Conclusions: Associations between self-reported and biospecimen-confirmed substance use are low to moderate and are higher for shorter recall periods and for substances with rapid metabolism. Future studies should employ validated self-report measures and include demographically diverse samples. [ABSTRACT FROM AUTHOR]

Published
2022
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31. Walking the Benzodiazepine High Wire.

Author

Kroenke, Kurt and Hirschtritt, Matthew E.

Subjects
DRUG prescribing, PSYCHOTHERAPY, TRANQUILIZING drugs, PATIENT education, DRUG overdose
Abstract

The number of benzodiazepine (BZD) prescriptions has substantially increased over the past decade, leading to a parallel rise in rates of misuse and overdose. These increases have prompted the U.S. Food and Drug Administration to update its "boxed warning" and have caused organizations to revisit prescribing guidelines. Concurrently, strong evidence from clinical trials supports the anxiolytic efficacy of BZDs. Although antidepressants and psychotherapy remain preferred treatments for chronic anxiety, BZDs remain helpful in treating acute or severe and persistent anxiety that does not respond to first-line therapy. Provider and patient education, coupled with prescribing surveillance, may be preferable to an overly stringent regulatory approach to guiding BZD use. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Benzodiazepine and Unhealthy Alcohol Use Among Adult Outpatients

Author

Hirschtritt, Matthew E, Palzes, Vanessa A, Kline-Simon, Andrea H, Kroenke, Kurt, Campbell, Cynthia I, and Sterling, Stacy A

Subjects
Adult, Male, Adolescent, Middle Aged, Lorazepam, Article, California, Substance Misuse, Alcohol Use and Health, Alcoholism, Benzodiazepines, Young Adult, Good Health and Well Being, Cross-Sectional Studies, Anti-Anxiety Agents, Clinical Research, Behavioral and Social Science, Outpatients, Public Health and Health Services, Health Policy & Services, Humans, Female, Aged, Retrospective Studies
Abstract

OBJECTIVES: Concomitant excessive alcohol consumption and benzodiazepine use is associated with adverse health outcomes. We examined associations of unhealthy alcohol use and other patient characteristics with benzodiazepine use. STUDY DESIGN: A cross-sectional analysis of 2,089,525 Kaiser Permanente of Northern California outpatients screened for unhealthy alcohol use in primary care between November 1, 2014, and December 31, 2016. METHODS: We fit multivariable generalized linear models to estimate the associations between unhealthy alcohol use and benzodiazepine dispensation and, among patients who were dispensed a benzodiazepine, mean doses (in mean lorazepam-equivalent daily doses [LEDDs]) and prescription durations. We controlled for patient sex, age, race/ethnicity, estimated household income, Charlson Comorbidity Index (CCI) score, anxiety disorder, alcohol use disorder, insomnia, musculoskeletal pain, and epilepsy. RESULTS: In the 12 months centered around (6 months before and 6 months after) the first alcohol-screening visit, 7.5% of patients used benzodiazepines. The following characteristics were independently associated with higher rates of benzodiazepine use, higher LEDD, and longer prescription duration: older age, white race/ethnicity, lower estimated household income, higher CCI score, and the presence of an anxiety disorder, insomnia, musculoskeletal pain, or epilepsy. Women and patients with an alcohol use disorder or unhealthy alcohol use, compared with men and patients with low-risk drinking or abstinence, were more likely to use a benzodiazepine; however, their LEDDs were lower and their prescription durations were shorter. CONCLUSIONS: Benzodiazepine use in primary care was associated with older age, female sex, white race/ethnicity, lower socioeconomic status, and unhealthy alcohol use. These findings may be applied to develop policies and interventions to promote judicious benzodiazepine use.

Published
2019

35. Analysis of shared heritability in common disorders of the brain

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository

Subjects
Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.

Published
2018

36. Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies

Author

Yu, Dongmei, Sul, Jae Hoon, Tsetsos, Fotis, Nawaz, Muhammad S., Huang, Alden Y., Zelaya, Ivette, Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M., Hirschtritt, Matthew E., Greenberg, Erica, Muller-Vahl, Kirsten R., Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy, Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L., Grados, Marco, Singer, Harvey S., Nöthen, Markus M., Hebebrand, Johannes, Hinney, Anke, King, Robert A., Fernandez, Thomas V., Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Budman, Cathy L., Rizzo, Renata, Lyon, Gholson J., McMahon, William M., Batterson, James R., Cath, Danielle C., Malaty, Irene A., Okun, Michael S., Berlin, Cheston, Woods, Douglas W., Lee, Paul C., Jankovic, Joseph, Robertson, Mary M., Gilbert, Donald L., Brown, Lawrence W., Coffey, Barbara J., Dietrich, Andrea, Hoekstra, Pieter J., Kuperman, Samuel, Zinner, Samuel H., Luðvigsson, Pétur, Sæmundsen, Evald, Thorarensen, Ólafur, Atzmon, Gil, Barzilai, Nir, Wagner, Michael, Moessner, Rainald, Ophoff, Roel, Pato, Carlos N., Pato, Michele T., Knowles, James A., Roffman, Joshua L., Smoller, Jordan W., Buckner, Randy L., Jeremy Willsey, A., Tischfield, Jay A., Heiman, Gary A., Stefansson, Hreinn, Stefansson, Kári, Posthuma, Danielle, Cox, Nancy J., Pauls, David L., Freimer, Nelson B., Neale, Benjamin M., Davis, Lea K., Paschou, Peristera, Coppola, Giovanni, Mathews, Carol A., Scharf, Jeremiah M., Bruun, Ruth D., Chouinard, Sylvain, Grados, Marco A., Kurlan, Roger, Leckman, James F., Rouleau, Guy A., Smit, Jan, Wolanczyk, Tomasz, Complex Trait Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Plastic, Reconstructive and Hand Surgery, ANS - Cellular & Molecular Mechanisms, and Child Psychiatry

Subjects
medicine.medical_specialty, Multifactorial Inheritance, congenital, hereditary, and neonatal diseases and abnormalities, Tourette's syndrome, Medizin, Genome-wide association study, Biology, Tourette syndrome, Polymorphism, Single Nucleotide, Severity of Illness Index, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Risk Factors, mental disorders, Child and adolescent psychiatry, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Genetics, COPY NUMBER VARIANTS, RISK, medicine.disease, Genetic architecture, 030227 psychiatry, Psychiatry and Mental health, fms-Like Tyrosine Kinase 3, Case-Control Studies, Tic Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study, Tourette Syndrome
Abstract

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette'sassociated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Published
2019

39. Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

Author

Claudio‐Campos, Karla, Stevens, Daniel, Koo, Sang‐Wahn, Valko, Alexa, Bienvenu, Oscar Joseph, Budman, Cathy B., Cath, Danielle C., Darrow, Sabrina, Geller, Daniel, Goes, Fernando S., Grados, Marco A., Greenberg, Benjamin D., Greenberg, Erica, Hirschtritt, Matthew E., Illmann, Cornelia, Ivankovic, Franjo, King, Robert A., Knowles, James A., Krasnow, Janice, and Lee, Paul C.

Abstract

Background: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. Objective: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. Methods: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta‐analyses, incorporating data from previously published literature. Results: Rates of obsessive–compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta‐analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First‐degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. Conclusions: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2021
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40. Cannabis Use Among Patients With Psychotic Disorders.

Author

Hirschtritt, Matthew E., Young-Wolff, Kelly C., Mathalon, Daniel H., and Satre, Derek D.

Subjects
*PSYCHOSES, *MARIJUANA, *PRIMARY care, *TREATMENT effectiveness, *PATIENT compliance
Abstract

Amidst a rapidly changing legal landscape, cannabis use in the United States has become increasingly common in the past several years. There is strong evidence to suggest that chronic and early cannabis use increases the risk of developing a psychotic disorder, and there is at least moderate evidence that suggests ongoing cannabis use among individuals with a psychotic disorder worsens clinical outcomes (eg, decreased psychiatric medication adherence, more frequent psychiatric hospitalizations). In this Review Article, we provide a focused, clinically oriented overview of the epidemiology and characteristics of cannabis use among individuals with first-episode psychosis; evaluation of cannabis use; and treatment modalities, focusing on behavioral interventions suitable for outpatient primary care settings. We discuss the limited data supporting pharmacologic interventions for cannabis use disorder, specifically among individuals with first-episode psychosis, and the unique potential of cannabidiol to serve as a harm-reduction strategy for individuals who are not able or willing to achieve abstinence for cannabis. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Cannabis Use Among Court-Involved Minority Sexual Orientation and Gender Identity Adolescents.

Author

Hirschtritt, Matthew E., Folk, Johanna B., Marshall, Brandon D. L., Yu Li, and Tolou-Shams, Marina

Subjects
SEXUAL minorities, GENDER identity, MARIJUANA, TEENAGERS, SOCIAL norms
Abstract

We examined the effects of family functioning and beliefs regarding peers' cannabis use among minority (n 5 112) and non-minority (n 5 275) sexual orientation and gender identity (SOGI), firsttime court-involved adolescents. We examined longitudinally the effects of baseline general family functioning and peer cannabis use beliefs on self-reported cannabis use and cannabis-related consequences after 12 months. At baseline, 39.2 percent of adolescents reported using cannabis. Minority SOGI adolescents reported worse family functioning (p 5 .017) and higher peer cannabis use beliefs (p = .047). Higher peer cannabis use beliefs at baseline predicted recent cannabis use at the 12-month assessment for both minority and non-minority SOGI adolescents. Better family functioning predicted a lower likelihood of recent cannabis use at 12 months for non-minority SOGI adolescents, but not for minority SOGI adolescents. Baseline peer cannabis use beliefs and family functioning predicted cannabis-related consequences for both cohorts at 12 months when accounting for intermediate (i.e., four-month and eight-month) data. Among all first-time court-involved adolescents, those who believed greater cannabis use among their peers reported more subsequent cannabis use themselves. Conversely, higher general family functioning may be less of a protective factor for minority SOGI adolescents. These results suggest the utility of feedback interventions to modify peer norm beliefs among first-time court-involved adolescents. [ABSTRACT FROM AUTHOR]

Published
2021
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42. Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Author

Tsetsos, Fotis, Yu, Dongmei, Sul, Jae Hoon, Huang, Alden Y., Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M., Hirschtritt, Matthew E., Greenberg, Erica, Muller-Vahl, Kirsten R., Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy A., Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L., Grados, Marco A., and Singer, Harvey S.

Published
2021
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43. Telepsychiatry, Hospitals, and the COVID-19 Pandemic.

Author

Morris, Nathaniel P. and Hirschtritt, Matthew E.

Subjects
COVID-19 pandemic, TELEPSYCHIATRY, SOCIAL distancing, HOSPITALS, PATIENT safety
Abstract

Calls for social distancing amid the COVID-19 pandemic have renewed attention on the utility of telepsychiatry. Although considerable evidence supports use of telepsychiatry in outpatient settings, telepsychiatry in hospitals is less studied and less developed. The COVID-19 pandemic may lead to rapid adoption of telepsychiatry by hospitals, and this column explores opportunities hospital-based telepsychiatry offers for staffing, patient and staff safety, social connection, and real-time responsiveness. Because hospital-based telepsychiatry brings unique challenges compared with outpatient telepsychiatry, this column also proposes a research agenda for studying and supporting adoption of these technologies in hospital settings. [ABSTRACT FROM AUTHOR]

Published
2020
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44. Addressing Problems With Alcohol and Other Substances Among Older Adults During the COVID-19 Pandemic.

Author

Satre, Derek D., Hirschtritt, Matthew E., Silverberg, Michael J., and Sterling, Stacy A.

Abstract

The article outlines clinical concerns for mental health providers, particularly in addressing psychiatric problems with alcohol and substances such as tobacco, cannabis, prescription opioids and benzodiazepines, among older adults during the COVID-19 pandemic.

Published
2020
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45. Mental Health Services in a U.S. Prison During the COVID-19 Pandemic.

Author

Burton, Paul R. S., Morris, Nathaniel P., and Hirschtritt, Matthew E.

Subjects
COVID-19 pandemic, MENTAL health services, PRISONERS, INFLUENZA pandemic, 1918-1919, SUBSTANCE abuse, CORRECTIONAL health nursing, FORUMS
Abstract

Pandemics pose unique risks to people in correctional facilities. Among other vulnerabilities, incarcerated populations often have high rates of mental disorders and substance use disorders, which may increase risks for morbidity and mortality during a pandemic. California's San Quentin State Prison (SQSP) experienced multiple outbreaks during the 1918 influenza pandemic, and, a century later, the prison faces a new pandemic. This Open Forum describes the modification of mental health services in SQSP during the early stages of the COVID-19 pandemic. The authors explore the challenges of reducing risks of viral contagion while maintaining high-quality mental health care in a correctional setting. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Lifetime Prevalence, Age of Risk, and Etiology of Comorbid Psychiatric Disorders in Tourette Syndrome

Author

Hirschtritt, Matthew E., Lee, Paul C., Pauls, David L., Dion, Yves, Grados, Marco A., Illmann, Cornelia, King, Robert A., Sandor, Paul, McMahon, William M., Lyon, Gholson J., Cath, Danielle C., Kurlan, Roger, Robertson, Mary M., Osiecki, Lisa, Scharf, Jeremiah M., and Mathews, Carol A.

Subjects
Male, Canada, Adolescent, Mental Disorders, Age Factors, Comorbidity, Article, United Kingdom, United States, Young Adult, Age Distribution, Risk Factors, Child, Preschool, Prevalence, Humans, Female, Age of Onset, Child, Netherlands, Tourette Syndrome
Abstract

Tourette syndrome (TS) is characterized by high rates of psychiatric comorbidity; however, few studies have fully characterized these comorbidities. Furthermore, most studies have included relatively few participants (200), and none has examined the ages of highest risk for each TS-associated comorbidity or their etiologic relationship to TS.To characterize the lifetime prevalence, clinical associations, ages of highest risk, and etiology of psychiatric comorbidity among individuals with TS.Cross-sectional structured diagnostic interviews conducted between April 1, 1992, and December 31, 2008, of participants with TS (n = 1374) and TS-unaffected family members (n = 1142).Lifetime prevalence of comorbid DSM-IV-TR disorders, their heritabilities, ages of maximal risk, and associations with symptom severity, age at onset, and parental psychiatric history.The lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had 2 or more psychiatric disorders. The mean (SD) number of lifetime comorbid diagnoses was 2.1 (1.6); the mean number was 0.9 (1.3) when obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) were excluded, and 72.1% of the individuals met the criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15-19 years for both). Tourette syndrome was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95% CI, 1.0-1.9; P = .04) and decreased risk of substance use disorders (OR, 0.6; 95% CI, 0.3-0.9; P = .02) independent from comorbid OCD and ADHD; however, high rates of mood disorders among participants with TS (29.8%) may be accounted for by comorbid OCD (OR, 3.7; 95% CI, 2.9-4.8; P .001). Parental history of ADHD was associated with a higher burden of non-OCD, non-ADHD comorbid psychiatric disorders (OR, 1.86; 95% CI, 1.32-2.61; P .001). Genetic correlations between TS and mood (RhoG, 0.47), anxiety (RhoG, 0.35), and disruptive behavior disorders (RhoG, 0.48), may be accounted for by ADHD and, for mood disorders, by OCD.This study is, to our knowledge, the most comprehensive of its kind. It confirms the belief that psychiatric comorbidities are common among individuals with TS, demonstrates that most comorbidities begin early in life, and indicates that certain comorbidities may be mediated by the presence of comorbid OCD or ADHD. In addition, genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to TS.

Published
2015

48. Drug Formularies in Correctional Settings.

Author

Morris, Nathaniel P., Hirschtritt, Matthew E., and Tamburello, Anthony C.

Subjects
DRUG formularies, MENTAL health services, MEDICAL care, OPIOID abuse, MENTAL health personnel
Abstract

An editorial discussing the National Commission on Correctional Health Care (NCCHC) defines a formulary as a written list of prescription and nonprescription medications that are ordinarily available to authorized prescribers, including consultants, working for the facility, including drug formularies in correctional settings can disrupt psychiatric care during a patient's transition from the community into a prison or jail.

Published
2020
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49. Realizing E-Prescribing's Potential to Reduce Outpatient Psychiatric Medication Errors.

Author

Hirschtritt, Matthew E., Chan, Steven, and Ly, Wilson O.

Subjects
INTERNET pharmacies, MEDICATION error prevention, DRUG prescribing, PSYCHIATRIC drugs, OUTPATIENT medical care, TECHNOLOGICAL literacy, INTERNETWORKING
Abstract

Preliminary evidence from observational and cohort studies suggests that replacement of paper- and phone-based medication prescriptions with electronic prescribing systems in ambulatory settings is associated with decreased medication errors. However, problems from traditional prescribing also occur with e-prescribing (such as incorrect medication dose and instructions or wrong patient), as do some new problems (a confusing user interface leading to prescribing the wrong medication). The authors present four steps for reducing medication errors in outpatient psychiatric settings: continuing to implement e-prescribing, streamlining user interfaces, improving interoperability among various e-prescribing and retail pharmacy systems, and using education and advocacy to achieve these goals. [ABSTRACT FROM AUTHOR]

Published
2018
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50. Risk Assessment of Online Child Sexual Exploitation Offenders.

Author

Hirschtritt, Matthew E., Tucker, Douglas, and Binder, Renée L.

Subjects
SEX crimes, SEX offenders, MENTAL health personnel, RISK assessment, INTERNET access, PARAPHILIAS
Abstract

Over the past two decades in the United States, a dramatic increase in access to the Internet has facilitated an increase in the production, viewing, and distribution of child pornography. In this context, forensic mental health professionals may be called on to estimate the risk of future violence, especially of contact sexual offenses, among individuals charged with online sexual offenses. We summarize demographic and clinical characteristics that differentiate online from contact and "mixed" offenders (those who commit both online and contact offenses), offending histories of these three groups, and the current state of knowledge regarding risk of progression from online-only to contact offending. Multiple studies suggest that online, contact, and mixed offenders demonstrate distinct profiles, and wide variations exist in the offense histories of online-offending groups. Longitudinal studies of individuals charged with online offenses are few in number and are mostly limited to detection of formal charges. Nevertheless, available studies suggest that most individuals who are charged with online offenses and who do not have histories of contact offenses are unlikely to engage in future contact offenses. Within the limitations of the current literature, we suggest guidance for the evaluation and treatment of online offenders. [ABSTRACT FROM AUTHOR]

Published
2019
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