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1. BrainGENIE: The Brain Gene Expression and Network Imputation Engine

Author

Jonathan L. Hess, Thomas P. Quinn, Chunling Zhang, Gentry C. Hearn, Samuel Chen, Neuropsychiatric Consortium for Analysis and Sharing of Transcriptomes, Sek Won Kong, Murray Cairns, Ming T. Tsuang, Stephen V. Faraone, and Stephen J. Glatt

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood–brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947–11,816 genes (false-discovery rate-adjusted p

Published
2023
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2. Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

Author

Jiahui Hou, Jonathan L. Hess, Nicola Armstrong, Joshua C. Bis, Benjamin Grenier-Boley, Ida K. Karlsson, Ganna Leonenko, Katya Numbers, Eleanor K. O’Brien, Alexey Shadrin, Anbupalam Thalamuthu, Qiong Yang, Ole A. Andreassen, Henry Brodaty, Margaret Gatz, Nicole A. Kochan, Jean-Charles Lambert, Simon M. Laws, Colin L. Masters, Karen A. Mather, Nancy L. Pedersen, Danielle Posthuma, Perminder S. Sachdev, Julie Williams, the Alzheimer’s Disease Neuroimaging Initiative, Chun Chieh Fan, Stephen V. Faraone, Christine Fennema-Notestine, Shu-Ju Lin, Valentina Escott-Price, Peter Holmans, Sudha Seshadri, Ming T. Tsuang, William S. Kremen, and Stephen J. Glatt

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Published
2022
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3. The impact of early factors on persistent negative symptoms in youth at clinical high risk for psychosis

Author

Daniel J. Devoe, Lu Lui, Tyrone D. Cannon, Kristin Suzanne Cadenhead, Barbara A. Cornblatt, Matcheri Keshavan, Tom H. McGlashan, Diana. O. Perkins, Larry J. Seidman, William S. Stone, Ming T. Tsuang, Scott W. Woods, Elaine F. Walker, Daniel H. Mathalon, Carrie E. Bearden, and Jean Addington

Subjects
persistent negative symptoms, clinical high risk, premorbid functioning, psychosis, trauma, life events, Psychiatry, RC435-571
Abstract

IntroductionPersistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS.MethodCHR participants (N = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS (n = 67) versus those without PNS (n = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables.ResultsThere was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events.ConclusionIn terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence.

Published
2023
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4. Neurobehavioral risk factors influence prevalence and severity of hazardous substance use in youth at genetic and clinical high risk for psychosis

Author

Carolyn M. Amir, Simon Kapler, Gil D. Hoftman, Leila Kushan, Jamie Zinberg, Kristin S. Cadenhead, Leda Kennedy, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Diana O. Perkins, William Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, Jean Addington, and Carrie E. Bearden

Subjects
22q11.2 deletion syndrome, clinical high risk for psychosis (CHR), psychosis, substance use, cannabis, Psychiatry, RC435-571
Abstract

BackgroundElevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts.MethodsData on substance use frequency and severity, clinical symptoms, and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage = 19.26 ± 7.84 years) and 1,288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage = 18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed effects models.ResultsControlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use in CHR-P individuals was associated with increased psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social functioning, social anhedonia, and IQ compared to 22qDel carriers, and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at 1 year follow-up.ConclusionIndividuals at genetic and CHR-P have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals.

Published
2023
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5. Depression Predicts Global Functional Outcomes in Individuals at Clinical High Risk for Psychosis

Author

Wisteria Deng, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, Ming T. Tsuang, Scott W. Woods, Elaine F. Walker, Jutta Joormann, and Tyrone Cannon

Subjects
Psychiatry, RC435-571
Abstract

Objectives While co‐morbid depression is associated with poor functional outcome among patients with schizophrenia, whether depression similarly predicts poorer outcomes in individuals at clinical high‐risk for psychosis (CHR‐P) is not clear. The present study aimed to examine depressive symptoms in relation to long‐term global functional outcomes in the North American Prodrome Longitudinal Study cohort (NAPLS2). Methods CHR individuals were evaluated clinically at baseline and at 12‐ and 24‐month follow‐ups for depressive and prodromal symptom severity as well as general functioning. Regression models were built to investigate whether baseline positive and depressive symptom scores predicted longitudinal improvement in global functioning. Results A total of 406 CHR individuals completed the 12‐month follow‐up assessment and 259 CHR individuals completed the 24‐month assessment. Baseline depressive symptoms in the CHR‐P population were found to predict better global functional outcomes at 2 years. Furthermore, the degree of recovery of depressive symptoms in the first year following baseline completely mediated the association between depressive symptoms at baseline and functional improvement at 2 years. Conclusions Presence of affective symptoms within the CHR‐P population has different implications for prognosis compared with patients with schizophrenia. The present findings support the view that among those at risk for psychosis, depressive symptoms at baseline predict a more favorable course of functional recovery, and highlight the potential importance of treating co‐occurring depressive symptoms at an early stage of psychosis risk.

Published
2021
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6. Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD

Author

Loes M. Olde Loohuis, Eva Mennigen, Anil P. S. Ori, Diana Perkins, Elise Robinson, Jean Addington, Kristin S. Cadenhead, Barbara A. Cornblatt, Daniel H. Mathalon, Thomas H. McGlashan, Larry J. Seidman, Matcheri S. Keshavan, William S. Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, Ruben C. Gur, Raquel E. Gur, Carrie E. Bearden, and Roel A. Ophoff

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8–22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10−7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

Published
2021
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7. Discriminatory experiences predict neuroanatomical changes and anxiety among healthy individuals and those at clinical high risk for psychosis

Author

Meghan A. Collins, Yoonho Chung, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, and Tyrone D. Cannon

Subjects
Discrimination, Social adversity, Cortical thickness, Neurodevelopmental trajectory, Clinical high risk for psychosis, Anxiety, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.

Published
2021
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8. Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization

Author

Hengyi Cao, Oliver Y. Chén, Yoonho Chung, Jennifer K. Forsyth, Sarah C. McEwen, Dylan G. Gee, Carrie E. Bearden, Jean Addington, Bradley Goodyear, Kristin S. Cadenhead, Heline Mirzakhanian, Barbara A. Cornblatt, Ricardo E. Carrión, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Aysenil Belger, Larry J. Seidman, Heidi Thermenos, Ming T. Tsuang, Theo G. M. van Erp, Elaine F. Walker, Stephan Hamann, Alan Anticevic, Scott W. Woods, and Tyrone D. Cannon

Subjects
Science
Abstract

Brain function alterations in schizophrenia and other psychotic disorders remain poorly understood. Here, the authors discover that increased neural connectivity in the cerebello-thalamo-cortical circuitry predicts psychosis in those at high risk, and is present in people with schizophrenia.

Published
2018
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9. Genetic loci associated with an earlier age at onset in multiplex schizophrenia

Author

Annemarie L. Woolston, Po-Chang Hsiao, Po-Hsiu Kuo, Shi-Heng Wang, Yin-Ju Lien, Chih-Min Liu, Hai-Gwo Hwu, Tzu-Pin Lu, Eric Y. Chuang, Li-Ching Chang, Chien-Hsiun Chen, Jer-Yuarn Wu, Ming T. Tsuang, and Wei J. Chen

Subjects
Medicine, Science
Abstract

Abstract An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO. The 14-SNP GRS could distinguish the co-affected siblings (n = 90) of the earliest probands from those (n = 91) of the latest probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP GRS was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. The overall effect of the 14 SNPs on an AAO in schizophrenia was verified using co-affected siblings of the GWAS probands and trend effect across unrelated patients. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene intensively reported in Parkinson’s disease and schizophrenia research.

Published
2017
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10. Theory of mind, emotion recognition and social perception in individuals at clinical high risk for psychosis: Findings from the NAPLS-2 cohort

Author

Mariapaola Barbato, Lu Liu, Kristin S. Cadenhead, Tyrone D. Cannon, Barbara A. Cornblatt, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Carrie E. Bearden, Daniel H. Mathalon, Robert Heinssen, and Jean Addington

Subjects
Social cognition, Clinical high risk, Psychosis, Schizophrenia, Neurology. Diseases of the nervous system, RC346-429
Abstract

Social cognition, the mental operations that underlie social interactions, is a major construct to investigate in schizophrenia. Impairments in social cognition are present before the onset of psychosis, and even in unaffected first-degree relatives, suggesting that social cognition may be a trait marker of the illness. In a large cohort of individuals at clinical high risk for psychosis (CHR) and healthy controls, three domains of social cognition (theory of mind, facial emotion recognition and social perception) were assessed to clarify which domains are impaired in this population. Six-hundred and seventy-five CHR individuals and 264 controls, who were part of the multi-site North American Prodromal Longitudinal Study, completed The Awareness of Social Inference Test, the Penn Emotion Recognition task, the Penn Emotion Differentiation task, and the Relationship Across Domains, measures of theory of mind, facial emotion recognition, and social perception, respectively. Social cognition was not related to positive and negative symptom severity, but was associated with age and IQ. CHR individuals demonstrated poorer performance on all measures of social cognition. However, after controlling for age and IQ, the group differences remained significant for measures of theory of mind and social perception, but not for facial emotion recognition. Theory of mind and social perception are impaired in individuals at CHR for psychosis. Age and IQ seem to play an important role in the arising of deficits in facial affect recognition. Future studies should examine the stability of social cognition deficits over time and their role, if any, in the development of psychosis.

Published
2015
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11. Sampling from different populations: Sociodemographic, clinical, and functional differences between samples of first episode psychosis individuals and clinical high-risk individuals who progressed to psychosis

Author

Matthew A. Hagler, Maria Ferrara, Laura A. Yoviene Sykes, Fangyong Li, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Barbara A. Cornblatt, Diana O. Perkins, Daniel H. Mathalon, Larry J. Seidman, Ming T. Tsuang, Elaine F. Walker, Albert R. Powers, Adrienne R. Allen, Vinod H. Srihari, and Scott W. Woods

Subjects
Psychiatry and Mental health, Biological Psychiatry
Published
2023

12. Ethnoracial discrimination and the development of suspiciousness symptoms in individuals at clinical high-risk for psychosis

Author

Timothy I. Michaels, Ricardo E. Carrión, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, William S. Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, and Barbara A. Cornblatt

Subjects
Psychiatry and Mental health, Biological Psychiatry
Published
2023

13. Migrant status, clinical symptoms and functional outcome in youth at clinical high risk for psychosis: findings from the NAPLS-3 study

Author

Mariapaola Barbato, Lu Liu, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, William Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, and Jean Addington

Subjects
Psychiatry and Mental health, Health (social science), Social Psychology, Epidemiology
Published
2022

14. Sensitivity of Schizophrenia Endophenotype Biomarkers to Anticholinergic Medication Burden

Author

Yash B. Joshi, Juan L. Molina, David L. Braff, Michael F. Green, Ruben C. Gur, Raquel E. Gur, Keith H. Nuechterlein, William S. Stone, Tiffany A. Greenwood, Laura C. Lazzeroni, Allen D. Radant, Jeremy M. Silverman, Joyce Sprock, Catherine A. Sugar, Debby W. Tsuang, Ming T. Tsuang, Bruce I. Turetsky, Neal R. Swerdlow, and Gregory A. Light

Subjects
Psychiatry and Mental health
Published
2023

15. The associations between area-level residential instability and gray matter volumes from the North American Prodrome Longitudinal Study (NAPLS) consortium

Author

Benson S. Ku, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Michael T. Compton, Barbara A. Cornblatt, Benjamin G. Druss, Matcheri Keshavan, Daniel H. Mathalon, Diana O. Perkins, William S. Stone, Ming T. Tsuang, Scott W. Woods, and Elaine F. Walker

Subjects
Adult, Adolescent, Medical and Health Sciences, Article, Young Adult, Residential instability, Clinical high risk for psychosis, Behavioral and Social Science, Humans, Rostral anterior cingulate cortex, Longitudinal Studies, Gray Matter, Child, Biological Psychiatry, Psychiatry, Cerebral Cortex, Caudal middle frontal gyrus, Prevention, Psychology and Cognitive Sciences, Neurosciences, Serious Mental Illness, Magnetic Resonance Imaging, Brain Disorders, Caudal middle frontal gyms, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, North America, Schizophrenia
Abstract

IntroductionArea-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with reduced gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC). We hypothesize that greater ARI will be associated with reduced right CMFG and rACC GMVs.MethodsData were collected at baseline as part of the North American Prodrome Longitudinal Study Phase 2. Counties where participants resided during childhood were geographically coded using the US Census to area-level factors. ARI was defined as the percentage of residents living in a different house 5years ago. Generalized linear mixed models tested associations between ARI and GMVs.ResultsThis study included 29 healthy controls (HC)s and 64 clinical high risk for psychosis (CHR-P) individuals who were aged 12 to 24years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG (adjusted β=-0.258; 95% CI=-0.502 to -0.015) and right rACC volumes (adjusted β=-0.318; 95% CI=-0.612 to -0.023). The interaction term (ARI-by-diagnostic group) in the prediction of both brain regions was not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.ConclusionsARI may adversely impact similar brain regions as urban upbringing. Further investigation into the potential mechanisms of the relationship between ARI and neurobiology, including social stress, is needed.

Published
2022

16. Bullying in clinical high risk for psychosis participants from the NAPLS-3 cohort

Author

Amy Braun, Lu Liu, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, William Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, and Jean Addington

Subjects
Psychiatry and Mental health, Health (social science), Social Psychology, Epidemiology
Published
2022

17. Life Event Stress and Reduced Cortical Thickness in Youth at Clinical High Risk for Psychosis and Healthy Control Subjects

Author

Jean Addington, Scott W. Woods, Kristin S. Cadenhead, Meghan A. Collins, Carrie E. Bearden, Daniel H. Mathalon, Thomas H. McGlashan, Elaine F. Walker, Ming T. Tsuang, Tyrone D. Cannon, Diana O. Perkins, Katrina Aberizk, and Barbara A. Cornblatt

Subjects
Male, Psychosis, medicine.medical_specialty, Longitudinal study, Adolescent, Cognitive Neuroscience, Prodromal Symptoms, Audiology, Article, 050105 experimental psychology, Prodrome, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cortex (anatomy), Stress (linguistics), Healthy control, otorhinolaryngologic diseases, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Longitudinal Studies, Risk factor, Biological Psychiatry, business.industry, 05 social sciences, Life events, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Psychotic Disorders, Female, Neurology (clinical), business, Stress, Psychological, 030217 neurology & neurosurgery
Abstract

Background A decline in cortical thickness during early life appears to be a normal neuromaturational process. Accelerated cortical thinning has been linked with conversion to psychosis among individuals at clinical high risk for psychosis (CHR-P). Previous research indicates that exposure to life event stress (LES) is associated with exaggerated cortical thinning in both healthy and clinical populations, and LES is also linked with conversion to psychosis in CHR-P. To date, there are no reports on the relationship of LES with cortical thickness in CHR-P. This study examines this relationship and whether LES is linked with cortical thinning to a greater degree in individuals at CHR-P who convert to psychosis compared with individuals at CHR-P who do not convert and healthy control subjects. Methods Controlling for age and gender (364 male, 262 female), this study examined associations between LES and baseline cortical thickness in 436 individuals at CHR-P (375 nonconverters and 61 converters) and 190 comparison subjects in the North American Prodrome Longitudinal Study. Results Findings indicate that prebaseline cumulative LES is associated with reduced baseline cortical thickness in several regions among the CHR-P and control groups. Evidence suggests that LES is a risk factor for thinner cortex to the same extent across diagnostic groups, while CHR-P status is linked with thinner cortex in select regions after accounting for LES. Conclusions This research provides additional evidence to support the role of LES in cortical thinning in both healthy youth and those at CHR-P. Potential underlying mechanisms of the findings and implications for future research are discussed.

Published
2022

18. Risk of violent behaviour in young people at clinical high risk for psychosis from the North American Prodrome Longitudinal Studies consortium

Author

Lauren N. Tronick, Heline Mirzakhanian, Jean Addington, Carrie E. Bearden, Tyrone D. Cannon, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, William Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, and Kristin S. Cadenhead

Subjects
Psychiatry and Mental health, Pshychiatric Mental Health, Biological Psychiatry
Published
2023

19. Anticholinergic Medication Burden–Associated Cognitive Impairment in Schizophrenia

Author

Joyce Sprock, Debby W. Tsuang, Raquel E. Gur, Yash B. Joshi, Catherine A. Sugar, Laura C. Lazzeroni, Allen D. Radant, William S. Stone, Neal R. Swerdlow, Ming T. Tsuang, David L. Braff, Keith H. Nuechterlein, Bruce I. Turetsky, Michael F. Green, Juan L. Molina, Laura R MacDonald, Michael L. Thomas, Ruben C. Gur, Gregory A. Light, Tiffany A. Greenwood, Jeremy M. Silverman, and John Nungaray

Subjects
Adult, medicine.medical_specialty, Adolescent, medicine.drug_class, Neuropsychological Tests, Article, Cholinergic Antagonists, Cohort Studies, Young Adult, 03 medical and health sciences, Cognition, 0302 clinical medicine, mental disorders, medicine, Anticholinergic, Humans, Dementia, Cognitive Dysfunction, Psychiatry, Cognitive impairment, Aged, integumentary system, business.industry, Healthy subjects, food and beverages, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Cross-Sectional Studies, Schizophrenia, lipids (amino acids, peptides, and proteins), Psychopharmacology, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N = 1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia–2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes—including psychotropics used in usual care—should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

Published
2021

20. The Association Between Neighborhood Poverty and Hippocampal Volume Among Individuals at Clinical High-Risk for Psychosis: The Moderating Role of Social Engagement

Author

Benson S Ku, Katrina Aberizk, Jean Addington, Carrie E Bearden, Kristin S Cadenhead, Tyrone D Cannon, Ricardo E Carrión, Michael T Compton, Barbara A Cornblatt, Benjamin G Druss, Daniel H Mathalon, Diana O Perkins, Ming T Tsuang, Scott W Woods, and Elaine F Walker

Subjects
Adult, Male, Adolescent, brain imaging, hippocampal volume, Medical and Health Sciences, Hippocampus, Young Adult, Clinical Research, 2.3 Psychological, Residence Characteristics, Behavioral and Social Science, social determinants of mental health, Humans, Longitudinal Studies, Aetiology, Child, Psychiatry, neuroimaging, Prevention, Psychology and Cognitive Sciences, Social Participation, Magnetic Resonance Imaging, prodrome, Brain Disorders, schizophrenia, Psychiatry and Mental health, Mental Health, Cross-Sectional Studies, Psychotic Disorders, Female, social and economic factors, Regular Articles
Abstract

Reductions in hippocampal volume (HV) have been associated with both prolonged exposure to stress and psychotic illness. This study sought to determine whether higher levels of neighborhood poverty would be associated with reduced HV among individuals at clinical high-risk for psychosis (CHR-P), and whether social engagement would moderate this association. This cross-sectional study included a sample of participants (N = 174, age-range = 12–33 years, 35.1% female) recruited for the second phase of the North American Prodrome Longitudinal Study. Generalized linear mixed models tested the association between neighborhood poverty and bilateral HV, as well as the moderating role of social engagement on this association. Higher levels of neighborhood poverty were associated with reduced left (β = −0.180, P = .016) and right HV (β = −0.185, P = .016). Social engagement significantly moderated the relation between neighborhood poverty and bilateral HV. In participants with lower levels of social engagement (n = 77), neighborhood poverty was associated with reduced left (β = −0.266, P = .006) and right HV (β = −0.316, P = .002). Among participants with higher levels of social engagement (n = 97), neighborhood poverty was not significantly associated with left (β = −0.010, P = .932) or right HV (β = 0.087, P = .473). In this study, social engagement moderated the inverse relation between neighborhood poverty and HV. These findings demonstrate the importance of including broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at CHR-P.

Published
2022

21. Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis

Author

Holly K. Hamilton, Brian J. Roach, Peter M. Bachman, Aysenil Belger, Ricardo E. Carrión, Erica Duncan, Jason K. Johannesen, Gregory A. Light, Margaret A. Niznikiewicz, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Thomas H. McGlashan, Diana O. Perkins, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, and Daniel H. Mathalon

Subjects
Adult, Adolescent, Correction, Electroencephalography, Young Adult, Psychiatry and Mental health, Acoustic Stimulation, Psychotic Disorders, Evoked Potentials, Auditory, Schizophrenia, Humans, Female, Longitudinal Studies, Biomarkers, Antipsychotic Agents, Original Investigation
Abstract

IMPORTANCE: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). OBJECTIVE: To examine whether mismatch negativity (MMN) event–related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. DESIGN, SETTING, AND PARTICIPANTS: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. MAIN OUTCOMES AND MEASURES: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. RESULTS: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity. CONCLUSIONS AND RELEVANCE: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Published
2022

23. Social decline in the psychosis prodrome: Predictor potential and heterogeneity of outcome

Author

Andrea M. Auther, Carrie E. Bearden, Jean Addington, Matcheri S. Keshavan, John Torous, Daniel H. Mathalon, Ming T. Tsuang, Tyrone D. Cannon, Diana O. Perkins, Elaine F. Walker, Scott W. Woods, Ricardo E. Carrión, Danielle McLaughlin, Larry J. Seidman, Kristin S. Cadenhead, Thomas H. McGlashan, Barbara A. Cornblatt, and William S. Stone

Subjects
Longitudinal study, Psychosis, Adolescent, business.industry, Role functioning, Prodromal Symptoms, Long term disability, medicine.disease, 030227 psychiatry, Prodrome, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Psychotic Disorders, medicine, Humans, Longitudinal Studies, business, Social Adjustment, 030217 neurology & neurosurgery, Biological Psychiatry, Clinical psychology, Social functioning
Abstract

Background While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis. Methods 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40). Results Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups. Conclusions The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.

Published
2021

24. Incorporating cortisol into the NAPLS2 individualized risk calculator for prediction of psychosis

Author

Thomas H. McGlashan, Tyrone D. Cannon, Larry J. Seidman, Michelle A. Worthington, Ming T. Tsuang, Diana O. Perkins, Kristin S. Cadenhead, Barbara A. Cornblatt, Scott W. Woods, Jean Addington, Daniel H. Mathalon, Carrie E. Bearden, and Elaine F. Walker

Subjects
Hypothalamo-Hypophyseal System, Psychosis, Longitudinal study, Multivariate statistics, Hydrocortisone, Prodromal Symptoms, Clinical high-risk, Medical and Health Sciences, Article, Cortisol, law.invention, Prodrome, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, law, medicine, Humans, Longitudinal Studies, Biological Psychiatry, Survival analysis, Psychiatry, business.industry, Prevention, Psychology and Cognitive Sciences, Stressor, medicine.disease, Risk calculator, Brain Disorders, 030227 psychiatry, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, Calculator, Biomarker (medicine), Prediction, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundRisk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHRP) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator.MethodsParticipants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels.ResultsA total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index=0.59, HR=21.5, p-value=0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index=0.78, SE=0.028).ConclusionsSalivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals.

Published
2021

25. Concordance and factor structure of subthreshold positive symptoms in youth at clinical high risk for psychosis

Author

Tyrone D. Cannon, Diana O. Perkins, Scott W. Woods, Barbara A. Cornblatt, Larry J. Seidman, Thomas H. McGlashan, Ming T. Tsuang, Tyler M. Moore, Matcheri S. Keshavan, Jean Addington, Kristin S. Cadenhead, Carrie E. Bearden, William S. Stone, Monica E. Calkins, Daniel H. Mathalon, Lu Liu, and Elaine F. Walker

Subjects
Psychosis, Adolescent, Concordance, media_common.quotation_subject, Prodromal Symptoms, Factor structure, Delusions, 03 medical and health sciences, 0302 clinical medicine, Perception, Clinical heterogeneity, Humans, Medicine, Biological Psychiatry, media_common, Subthreshold conduction, business.industry, medicine.disease, Exploratory factor analysis, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Thought content, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden.

Published
2021

26. Progressive reconfiguration of resting-state brain networks as psychosis develops: Preliminary results from the North American Prodrome Longitudinal Study (NAPLS) consortium

Author

Doreen M. Olvet, Jean Addington, Tyrone D. Cannon, Sarah McEwen, Carrie E. Bearden, Alan Anticevic, Larry J. Seidman, Scott W. Woods, Heidi W. Thermenos, Kristin S. Cadenhead, Diana O. Perkins, Daniel H. Mathalon, Bradley G. Goodyear, Elaine F. Walker, Hengyi Cao, Thomas H. McGlashan, Aysenil Belger, Heline Mirzakhanian, Stephan Hamann, Yoonho Chung, Ming T. Tsuang, Theo G.M. van Erp, and Barbara A. Cornblatt

Subjects
Psychosis, medicine.medical_specialty, Network diversity, Longitudinal study, Medical and Health Sciences, Article, Prodrome, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Humans, Medicine, Longitudinal Studies, Resting state, Global efficiency, Biological Psychiatry, Psychiatry, Brain network, Resting state fMRI, business.industry, Psychology and Cognitive Sciences, Neurosciences, Brain, Clinical high risk, medicine.disease, Magnetic Resonance Imaging, United States, Brain Disorders, 030227 psychiatry, Graph theory, Psychiatry and Mental health, Mental Health, Psychotic Disorders, Neurological, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Mounting evidence has shown disrupted brain network architecture across the psychosis spectrum. However, whether these changes relate to the development of psychosis is unclear. Here, we used graph theoretical analysis to investigate longitudinal changes in resting-state brain networks in samples of 72 subjects at clinical high risk (including 8 cases who converted to full psychosis) and 48 healthy controls drawn from the North American Prodrome Longitudinal Study (NAPLS) consortium. We observed progressive reduction in global efficiency (P = 0.006) and increase in network diversity (P = 0.001) in converters compared with non-converters and controls. More refined analysis separating nodes into nine key brain networks demonstrated that these alterations were primarily driven by progressively diminished local efficiency in the default-mode network (P = 0.004) and progressively enhanced node diversity across all networks (P < 0.05). The change rates of network efficiency and network diversity were significantly correlated (P = 0.003), suggesting these changes may reflect shared underlying neural mechanisms. In addition, change rates of global efficiency and node diversity were significantly correlated with change rate of cortical thinning in the prefrontal cortex in converters (P < 0.03) and could be predicted by visuospatial memory scores at baseline (P < 0.04). These results provide preliminary evidence for longitudinal reconfiguration of resting-state brain networks during psychosis development and suggest that decreased network efficiency, reflecting an increase in path length between nodes, and increased network diversity, reflecting a decrease in the consistency of functional network organization, are implicated in the progression to full psychosis.

Published
2020

27. Rare coding variants in ten genes confer substantial risk for schizophrenia

Author

Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D. Barchas, Nicholas Bass, Tim B. Bigdeli, Gerome Breen, Evelyn J. Bromet, Peter F. Buckley, William E. Bunney, Jonas Bybjerg-Grauholm, William F. Byerley, Sinéad B. Chapman, Wei J. Chen, Claire Churchhouse, Nicholas Craddock, Caroline M. Cusick, Lynn DeLisi, Sheila Dodge, Michael A. Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V. Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B. Gabriel, Diane Gage, Sarah A. Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C. Glahn, Jakob Grove, Mei-Hua Hall, Eija Hämäläinen, Henrike O. Heyne, Matti Holi, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Hai-Gwo Hwu, René S. Kahn, Hyun Min Kang, Konrad J. Karczewski, George Kirov, James A. Knowles, Francis S. Lee, Douglas S. Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R. Marder, Steven A. McCarroll, Andrew M. McIntosh, Helena Medeiros, Lili Milani, Christopher P. Morley, Derek W. Morris, Preben Bo Mortensen, Richard M. Myers, Merete Nordentoft, Niamh L. O’Brien, Ana Maria Olivares, Dost Ongur, Willem H. Ouwehand, Duncan S. Palmer, Tiina Paunio, Digby Quested, Mark H. Rapaport, Elliott Rees, Brandi Rollins, F. Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura J. Scott, Sally I. Sharp, Pamela Sklar, Jordan W. Smoller, Janet L. Sobell, Matthew Solomonson, Eli A. Stahl, Christine R. Stevens, Jaana Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A. Watts, Douglas H. Blackwood, Anders D. Børglum, Bruce M. Cohen, Aiden P. Corvin, Tõnu Esko, Nelson B. Freimer, Stephen J. Glatt, Christina M. Hultman, Andrew McQuillin, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Ann E. Pulver, David St. Clair, Ming T. Tsuang, Marquis P. Vawter, James T. Walters, Thomas M. Werge, Roel A. Ophoff, Patrick F. Sullivan, Michael J. Owen, Michael Boehnke, Michael C. O’Donovan, Benjamin M. Neale, Mark J. Daly, Psychiatry, HUS Psychiatry, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Department of Psychiatry, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, and Aarno Palotie / Principal Investigator

Subjects
Multidisciplinary, Schizophrenia/genetics, MUTATIONS, Receptors, N-Methyl-D-Aspartate/genetics, Genetic Predisposition to Disease/genetics, 3112 Neurosciences, ASSOCIATION, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate, INDIVIDUALS, Neurodevelopmental Disorders, Case-Control Studies, Mutation, Schizophrenia, Humans, Genetic Predisposition to Disease, Exome, 3111 Biomedicine, BURDEN
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of 1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Published
2022

28. Inflammation in Mental Disorders: Is the Microbiota the Missing Link?

Author

Sophie Ouabbou, Ming T. Tsuang, Keith Butler, and Ying He

Subjects
0301 basic medicine, medicine.medical_specialty, Neurology, Physiology, Review, Gut flora, Bioinformatics, Affect (psychology), digestive system, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Bipolar disorder, Microbiome, Irritable bowel syndrome, Inflammation, biology, Mood Disorders, business.industry, Mental Disorders, General Neuroscience, Brain, General Medicine, biology.organism_classification, medicine.disease, Gastrointestinal Microbiome, 030104 developmental biology, Psychotic Disorders, Mood disorders, business, 030217 neurology & neurosurgery
Abstract

Research suggests that inflammation is important in the pathophysiology of mental disorders. In addition, a growing body of evidence has led to the concept of the microbiota-gut-brain axis. To understand the potential interactions, we begin by exploring the liaison between the immune system and mental disorders, then we describe the evidence that the microbiota impact the immune response in the developing brain. Next, we review the literature that has documented microbiome alterations in major mental disorders. We end with a summary of therapeutic applications, ranging from psycho-biotics to immunomodulatory drugs that could affect the microbiota-gut-brain axis, and potential treatments to alleviate the adverse effects of antipsychotics. We conclude that there is promising evidence to support the position that the microbiota plays an important role in the immunological pathophysiology of mental disorders with an emphasis on psychotic disorders and mood disorders. However, more research is needed to elucidate the mechanisms. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00535-1) contains supplementary material, which is available to authorized users.

Published
2020

29. Polygenic Risk Score Contribution to Psychosis Prediction in a Target Population of Persons at Clinical High Risk

Author

Carrie E. Bearden, Scott W. Woods, Tyrone D. Cannon, Jean Addington, Jenna Barbee, Clark Jeffries, Barbara A. Cornblatt, Larry J. Seidman, Ming T. Tsuang, Daniel H. Mathalon, Kristin S. Cadenhead, Elaine F. Walker, Loes M. Olde Loohuis, John Ford, Diana O. Perkins, and Thomas H. McGlashan

Subjects
Male, Gerontology, Multifactorial Inheritance, Psychosis, NAPLS, Adolescent, High-risk, MEDLINE, Prodromal Symptoms, Genome-wide association study, Target population, Medical and Health Sciences, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Predictive Value of Tests, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, Young adult, Risk Calculator, Psychiatry, Polygenic Risk Score, business.industry, Prevention, Psychology and Cognitive Sciences, medicine.disease, Brain Disorders, 030227 psychiatry, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, Predictive value of tests, Schizophrenia, Female, Polygenic risk score, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

OBJECTIVE: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%–25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. METHODS: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. RESULTS: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R(2) (R(2) adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. CONCLUSIONS: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Published
2020

30. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations

Author

Cheryl A. Roe, Claire Churchhouse, Wei J. Chen, Felecia Cerrato, Sharon D. Chandler, Menachem Fromer, Ashley Dumont, Stephen V. Faraone, Stephen J. Glatt, Benjamin M. Neale, Hai-Gwo Hwu, Giulio Genovese, Mark J. Daly, Nan M. Laird, Samuel A. Rose, Shi-Heng Wang, Kaitlin E. Samocha, Kimberly Chambert, Jennifer L. Moran, Daniel P. Howrigan, Jack A. Kosmicki, Tarjinder Singh, Steven A. McCarroll, and Ming T. Tsuang

Subjects
Parents, Adult, Male, 0301 basic medicine, Proband, Population, Biology, medicine.disease_cause, Article, Whole Exome Sequencing, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Exome Sequencing, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Psychology, Genetic Predisposition to Disease, Family, Aetiology, Child, education, Gene, De novo mutations, Exome sequencing, Protein coding, education.field_of_study, Mutation, Neurology & Neurosurgery, General Neuroscience, Human Genome, Neurosciences, Serious Mental Illness, medicine.disease, Brain Disorders, Mental Health, 030104 developmental biology, Schizophrenia, Female, Cognitive Sciences, Neuroscience, 030217 neurology & neurosurgery, Biotechnology
Abstract

Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1-10 genes; permuted P = 3 × 10-5). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.

Published
2020

31. Characterizing sustained social anxiety in individuals at clinical high risk for psychosis: trajectory, risk factors, and functional outcomes

Author

Wisteria Deng, Jean Addington, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Daniel H. Mathalon, Diana O. Perkins, Larry J. Seidman, Ming T. Tsuang, Scott W. Woods, Elaine F. Walker, and Tyrone D. Cannon

Subjects
polygenic risk, Prodromal Symptoms, Comorbidity, Anxiety, Risk Factors, 2.3 Psychological, Behavioral and Social Science, Humans, Psychology, Longitudinal Studies, Aetiology, Applied Psychology, stress exposure, Psychiatry, outcome studies, Prevention, Neurosciences, Serious Mental Illness, covariant trajectories, Brain Disorders, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, Schizophrenia, Public Health and Health Services, social and economic factors
Abstract

Background While comorbidity of clinical high-risk for psychosis (CHR-P) status and social anxiety is well-established, it remains unclear how social anxiety and positive symptoms covary over time in this population. The present study aimed to determine whether there are more than one covariant trajectory of social anxiety and positive symptoms in the North American Prodrome Longitudinal Study cohort (NAPLS 2) and, if so, to test whether the different trajectory subgroups differ in terms of genetic and environmental risk factors for psychotic disorders and general functional outcome. Methods In total, 764 CHR individuals were evaluated at baseline for social anxiety and psychosis risk symptom severity and followed up every 6 months for 2 years. Application of group-based multi-trajectory modeling discerned three subgroups based on the covariant trajectories of social anxiety and positive symptoms over 2 years. Results One of the subgroups showed sustained social anxiety over time despite moderate recovery in positive symptoms, while the other two showed recovery of social anxiety below clinically significant thresholds, along with modest to moderate recovery in positive symptom severity. The trajectory group with sustained social anxiety had poorer long-term global functional outcomes than the other trajectory groups. In addition, compared with the other two trajectory groups, membership in the group with sustained social anxiety was predicted by higher levels of polygenic risk for schizophrenia and environmental stress exposures. Conclusions Together, these analyses indicate differential relevance of sustained v. remitting social anxiety symptoms in the CHR-P population, which in turn may carry implications for differential intervention strategies.

Published
2022

32. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. 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Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. 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F., Ehrlich, S., Escaramis, G., Espeseth, T., Estivill, X., Farmer, A., Favaro, A., Fischer, K., Floyd, J. A. B., Focker, M., Foretova, L., Forzan, M., Franklin, C. S., Gambaro, G., Giuranna, J., Giusti-Rodriquez, P., Gonidakis, F., Gordon, S., Mayora, M. G., Guillaume, S., Hanscombe, K. B., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Henders, A. K., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Horwood, L. J., Hubel, C., Petersen, L. V., Purves, K. L., Raevuori, A., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op 't Landt, M. C. T., Slopien, A., Soranzo, N., Sorbi, S., Southam, L., Steen, V. W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jordan, J., Julia, A., Kalsi, G., Kaminska, D., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, M. A., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Kirk, K. M., Klareskog, L., Knudsen, G. P. S., Larsen, J. T., Le Hellard, S., Leppa, V. M., Lichtenstein, P., Lin, B. D., Lundervold, A., Luykx, J., Maj, M., Mannik, K., Marsal, S., Stuber, G. D., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wade, T. D., Wagner, G., Walton, E., Whiteman, D. C., Wichmann, H. E., Widen, E., Yao, S., Zeggini, E., Zerwas, S., Zipfel, S., Jungkunz, M., Dietl, L., Schwarze, C. E., Dahmen, N., Schott, B. H., Mobascher, A., Crivelli, S., Dennis, M. F., Harvey, P. D., Carter, B. W., Huffman, J. E., Jacobson, D., Madduri, R., Olsen, M. K., Pestian, J., Gaziano, J. M., Muralidhar, S., Ramoni, R., Beckham, J., Chang, K. -M., O'Donnell, C. J., Tsao, P. S., Breeling, J., Huang, G., Romero, J. P. C., Moser, J., Whitbourne, S. B., Brewer, J. V., Aslan, M., Connor, T., Argyres, D. P., Stephens, B., Brophy, M. T., Humphries, D. E., Selva, L. E., Do, N., Shayan, S., Cho, K., Pyarajan, S., Hauser, E., Sun, Y., Zhao, H., Wilson, P., Mcardle, R., Dellitalia, L., Mattocks, K., Harley, J., Zablocki, C. J., Whittle, J., Jacono, F., Gutierrez, S., Gibson, G., Hammer, K., Kaminsky, L., Villareal, G., Kinlay, S., Xu, J., Hamner, M., Mathew, R., Bhushan, S., Iruvanti, P., Godschalk, M., Ballas, Z., Ivins, D., Mastorides, S., Moorman, J., Gappy, S., Klein, J., Ratcliffe, N., Florez, H., Okusaga, O., Murdoch, M., Sriram, P., Yeh, S. S., Tandon, N., Jhala, D., Aguayo, S., Cohen, D., Sharma, S., Liangpunsakul, S., Oursler, K. A., Whooley, M., Ahuja, S., Constans, J., Meyer, P., Greco, J., Rauchman, M., Servatius, R., Gaddy, M., Wallbom, A., Morgan, T., Stapley, T., Sherman, S., Ross, G., Tsao, P., Strollo, P., Boyko, E., Meyer, L., Gupta, S., Huq, M., Fayad, J., Hung, A., Lichy, J., Hurley, R., Robey, B., Striker, R., Erlangsen, A., Kessler, R. C., Porteous, D., Ursano, R. J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards A.C., Galfalvy H., Levey D.F., Lori A., Shabalin A., Starnawska A., Su M.-H., Watson H.J., Adams M., Awasthi S., Gandal M., Hafferty J.D., Hishimoto A., Kim M., Okazaki S., Otsuka I., Ripke S., Ware E.B., Bergen A.W., Berrettini W.H., Bohus M., Brandt H., Chang X., Chen W.J., Chen H.-C., Crawford S., Crow S., DiBlasi E., Duriez P., Fernandez-Aranda F., Fichter M.M., Gallinger S., Glatt S.J., Gorwood P., Guo Y., Hakonarson H., Halmi K.A., Hwu H.-G., Jain S., Jamain S., Jimenez-Murcia S., Johnson C., Kaplan A.S., Kaye W.H., Keel P.K., Kennedy J.L., Klump K.L., Li D., Liao S.-C., Lieb K., Lilenfeld L., Liu C.-M., Magistretti P.J., Marshall C.R., Mitchell J.E., Monson E.T., Myers R.M., Pinto D., Powers A., Ramoz N., Roepke S., Rozanov V., Scherer S.W., Schmahl C., Sokolowski M., Strober M., Thornton L.M., Treasure J., Tsuang M.T., Witt S.H., Woodside D.B., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Air T.M., Alda M., Alfredsson L., Andreassen O.A., Anjorin A., Appadurai V., Soler 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Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

33. Hippocampal Connectivity With the Default Mode Network Is Linked to Hippocampal Volume in the Clinical High Risk for Psychosis Syndrome and Healthy Individuals

Author

Katrina Aberizk, Esra Sefik, Jean Addington, Alan Anticevic, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Diana O. Perkins, William S. Stone, Ming T. Tsuang, Scott W. Woods, and Elaine F. Walker

Subjects
Clinical Psychology
Abstract

Reduced hippocampal volume is an established brain morphological feature of psychiatric conditions. Hippocampal volume is associated with brain connectivity in humans and nonhuman animals, and altered connectivity is associated with risk for psychiatric illness. Associations between hippocampal volume and connectivity are poorly characterized in humans, especially in phases of psychiatric illness that precede disease onset. This study examined associations between hippocampal volume and hippocampal functional connectivity during rest in 141 healthy control participants and 248 individuals at risk for psychosis. Significant inverse associations between hippocampal volume and hippocampal functional connectivity with the inferior parietal lobe (IPL) and thalamus were observed. Select associations between hippocampal functional connectivity and hippocampal volume were moderated by diagnostic group. Significant moderation results shifted from implicating the IPL to the temporal pole after we excluded participants on antipsychotic medication. Considered together, these findings imply that hippocampal functional connectivity with the temporoparietal junction, within a specialized subsystem of the default mode network, is sensitive to hippocampal volume.

Published
2023

34. Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk

Author

Meghan A. Collins, Jie Lisa Ji, Yoonho Chung, Cole A. Lympus, Yvette Afriyie-Agyemang, Jean M. Addington, Bradley G. Goodyear, Carrie E. Bearden, Kristin S. Cadenhead, Heline Mirzakhanian, Ming T. Tsuang, Barbara A. Cornblatt, Ricardo E. Carrión, Matcheri Keshavan, Wiliam S. Stone, Daniel H. Mathalon, Diana O. Perkins, Elaine F. Walker, Scott W. Woods, Albert R. Powers, Alan Anticevic, and Tyrone D. Cannon

Subjects
Male, Pediatric, Psychiatry, Adolescent, Prevention, Psychology and Cognitive Sciences, Neurosciences, Prodromal Symptoms, Cerebral Cortical Thinning, Biological Sciences, Serious Mental Illness, Medical and Health Sciences, Brain Disorders, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Mental Health, Psychotic Disorders, Clinical Research, Behavioral and Social Science, Ethnicity, Humans, Female, Longitudinal Studies, Molecular Biology, Minority Groups
Abstract

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Published
2021

36. Family history of psychosis in youth at clinical high risk: A replication study

Author

Olga Santesteban-Echarri, Danah Sandel, Lu Liu, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, William S. Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, and Jean Addington

Subjects
Risk, Psychiatry and Mental health, Adolescent, Psychotic Disorders, Humans, Prodromal Symptoms, Longitudinal Studies, Biological Psychiatry
Abstract

Having a first-degree relative with a psychotic disorder increases an individual's risk for developing psychosis to 10% compared to 1% in the general population. The impact of being at family high-risk for psychosis (FHR) has been examined in samples of youth who are at clinical high-risk for psychosis (CHR). The second North American Prodrome Longitudinal Study (NAPLS-2) identified very few clinical differences between CHR individuals with and without FHR. This paper aims to confirm these results in a new CHR sample, NAPLS-3. The NAPLS-3 sample consisted of 703 CHR participants, of whom 82 were at FHR (CHR+FHR), and 621 were not (CHR+FHRneg). The Family Interview for Genetic Studies was used to determine the presence of a first-degree relative with a psychotic disorder. The groups were compared on social and role functioning, positive and negative symptoms, IQ, cannabis use, and trauma. At baseline, the CHR+FHR group reported a statistically significant increased severity of positive and negative symptoms, lower IQ scores, and increased reports of trauma, psychological and physical abuse. There were no differences in transition rates between the two groups. This study supports some of the already reported differences in trauma, physical and psychological abuse between CHR individuals with and without FHR.

Published
2021

37. Longitudinal impact of trauma in the North American Prodrome Longitudinal Study-3

Author

Megan S. Farris, Amy Braun, Lu Liu, Carrie E. Bearden, Kristin S. Cadenhead, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, William S. Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, Tyrone D. Cannon, and Jean Addington

Subjects
Psychiatry and Mental health, Psychotic Disorders, North America, Humans, Prodromal Symptoms, Longitudinal Studies, Pshychiatric Mental Health, Biological Psychiatry
Abstract

Individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this article was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals.From the North American Prodrome Longitudinal Study-3 (NAPLS-3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015 and 2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis.From the 690 CHR participants and 96 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p .001). Emotional neglect (70.3%) was the most commonly reported type of trauma, followed by psychological abuse (57.4%). Among CHR participants, time to transition to psychosis was not associated with trauma. Baseline depression and suspiciousness/persecutory ideas were statistically significantly different between CHR individuals who did or did not experience trauma. However, when examining clinical and functional outcomes over 12-months of follow-up, there were no differences between those who experienced trauma and those who did not.Overall, trauma is a significantly prevalent among CHR individuals. The effects of trauma on transition and longitudinal clinical and functional outcomes were not significant.

Published
2021

38. Cannabis use and attenuated positive and negative symptoms in youth at clinical high risk for psychosis

Author

Olga Santesteban-Echarri, Lu Liu, Madeline Miller, Carrie E. Bearden, Kristin S. Cadenhead, Tyrone D. Cannon, Barbara A. Cornblatt, Matcheri Keshavan, Daniel H. Mathalon, Thomas H. McGlashan, Diana O. Perkins, Larry J. Seidman, William S. Stone, Ming T. Tsuang, Elaine F. Walker, Scott W. Woods, and Jean Addington

Subjects
Adult, Risk, Adolescent, Substance-Related Disorders, Prodromal Symptoms, Psychiatry and Mental health, Young Adult, Psychotic Disorders, Humans, Longitudinal Studies, Prospective Studies, Child, Biological Psychiatry, Cannabis
Abstract

Cannabis use is more prevalent among youth at clinical high-risk (CHR) for psychosis than healthy controls (HC). There is mixed evidence as to whether cannabis use is associated with increased severity of attenuated psychotic symptoms (APS) or whether current cannabis use is associated with the transition to psychosis. This study aims to assess cannabis use differences between CHR youth and HC and the impact of cannabis use on APS, clinical status, and transition to psychosis. Participants were from the North American Prodrome Longitudinal Study-3, a prospective longitudinal study including 710 individuals, age 12-30, meeting criteria for a psychosis risk syndrome based on the Structured Interview for Psychosis-Risk Syndromes, and 96 HC. Cannabis use, frequency, and severity of use were assessed with the Alcohol Use Scale/Drug Use Scale. Current and past cannabis use disorders were assessed with the Structured Clinical Interview for DSM-5. Compared to HC, CHR individuals reported significantly increased lifetime cannabis use, during the past six months, and at baseline; greater frequency and severity of cannabis use; and increased prevalence of cannabis use disorder. Relative to CHR youth without cannabis use, CHR cannabis users had significantly higher ratings on baseline grandiosity and lower 12-months social anhedonia. Severity of cannabis was unrelated to clinical status at 2-years, and it did not differentiate CHR individuals who transitioned to psychosis from those who did not. However, a major limitation was that the current number of CHR cannabis users was small, and survival analyses resulted in a smaller power than the 80 % recommended.

Published
2021

39. Individualized Prediction of Prodromal Symptom Remission for Youth at Clinical High Risk for Psychosis

Author

Carrie E. Bearden, Elaine F. Walker, Michelle A. Worthington, Kristin S. Cadenhead, William S. Stone, Daniel H. Mathalon, Jean Addington, Tyrone D. Cannon, Barbara A. Cornblatt, Diana O. Perkins, Scott W. Woods, Thomas H. McGlashan, Matcheri S. Keshavan, and Ming T. Tsuang

Subjects
Adult, Male, Psychosis, Longitudinal study, Adolescent, media_common.quotation_subject, clinical high risk, Prodromal Symptoms, Medical and Health Sciences, Risk Assessment, Prodrome, Machine Learning, risk prediction, remission, Clinical Research, medicine, Humans, Generalizability theory, psychosis, Longitudinal Studies, Child, media_common, First episode, Pediatric, Psychiatry, business.industry, Prevention, Psychology and Cognitive Sciences, Remission Induction, medicine.disease, Serious Mental Illness, Brain Disorders, schizophrenia, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, Schizophrenia, Predictive power, Disease Progression, Female, Psychological resilience, business, Clinical psychology, Regular Articles
Abstract

The clinical high-risk period before a first episode of psychosis (CHR-P) has been widely studied with the goal of understanding the development of psychosis; however, less attention has been paid to the 75%–80% of CHR-P individuals who do not transition to psychosis. It is an open question whether multivariable models could be developed to predict remission outcomes at the same level of performance and generalizability as those that predict conversion to psychosis. Participants were drawn from the North American Prodrome Longitudinal Study (NAPLS3). An empirically derived set of clinical and demographic predictor variables were selected with elastic net regularization and were included in a gradient boosting machine algorithm to predict prodromal symptom remission. The predictive model was tested in a comparably sized independent sample (NAPLS2). The classification algorithm developed in NAPLS3 achieved an area under the curve of 0.66 (0.60–0.72) with a sensitivity of 0.68 and specificity of 0.53 when tested in an independent external sample (NAPLS2). Overall, future remitters had lower baseline prodromal symptoms than nonremitters. This study is the first to use a data-driven machine-learning approach to assess clinical and demographic predictors of symptomatic remission in individuals who do not convert to psychosis. The predictive power of the models in this study suggest that remission represents a unique clinical phenomenon. Further study is warranted to best understand factors contributing to resilience and recovery from the CHR-P state.

Published
2021

40. Sleep Disturbance in Individuals at Clinical High Risk for Psychosis

Author

Jean Addington, William S. Stone, Carrie E. Bearden, Scott W. Woods, Eva Velthorst, Ming T. Tsuang, Tyrone D. Cannon, Muhammad A. Parvaz, Kristin S. Cadenhead, Daniel J. Buysse, Barbara A. Cornblatt, Thomas H. McGlashan, Diana O. Perkins, Nina Zaks, Jamie Zinberg, Daniel H. Mathalon, Tjasa Velikonja, Matcheri S. Keshavan, Monica Done, and Elaine F. Walker

Subjects
Adult, Male, Risk, Sleep Wake Disorders, Psychosis, Longitudinal study, Adolescent, Prodromal Symptoms, Pittsburgh Sleep Quality Index, Prodrome, Young Adult, Medicine, Humans, Longitudinal Studies, Depression (differential diagnoses), Sleep disorder, business.industry, medicine.disease, Prognosis, Sleep in non-human animals, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, North America, Disease Progression, Female, business, Clinical psychology, Regular Articles
Abstract

Introduction Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time. Methods Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations. Results Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar. Discussion The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.

Published
2021

41. BRAINGENIE: THE BRAIN GENE EXPRESSION AND NETWORK IMPUTATION ENGINE

Author

Stephen Glatt, Jonathan Hess, Thomas Quinn, Sek Won Kong, Murray Cairns, Ming T. Tsuang, and Stephen Faraone

Subjects
Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Biological Psychiatry
Published
2022

43. Bullying in clinical high risk for psychosis participants from the NAPLS-3 cohort

Author

Amy, Braun, Lu, Liu, Carrie E, Bearden, Kristin S, Cadenhead, Barbara A, Cornblatt, Matcheri, Keshavan, Daniel H, Mathalon, Thomas H, McGlashan, Diana O, Perkins, Larry J, Seidman, William, Stone, Ming T, Tsuang, Elaine F, Walker, Scott W, Woods, Tyrone D, Cannon, and Jean, Addington

Subjects
Cohort Studies, Psychotic Disorders, Risk Factors, Bullying, Humans, Prodromal Symptoms
Abstract

Bullying is associated with a heightened risk for poor outcomes, including psychosis. This study aimed to replicate previous findings on bullying prevalence in clinical high-risk (CHR) individuals, to assess the longitudinal course of clinical and functional variables between bullied and non-bullied CHR and the association of bullying with premorbid functioning, clinical outcome, transition to psychosis and risk of violence.The sample consisted of 691 CHR participants and 96 healthy controls. Participants reported whether they had experienced bullying and how long it had lasted. Assessments included DSM-5 diagnoses, attenuated psychotic symptoms, negative symptoms, social and role functioning, depression, stress, premorbid functioning, and risk of violence. The bullied and non-bullied CHR groups were compared at baseline and further longitudinally on clinical and functioning variables and transition to psychosis.Bullying was more prevalent among CHR individuals than healthy controls. Bullied CHR had a higher prevalence of PTSD and more severe depression and stress at baseline than non-bullied CHR. There was no impact of bullying on clinical and functional variables over time. Bullying was not related to final clinical status or transition to psychosis. However, bullied participants had poorer premorbid functioning and a greater risk of violence.While bullying may not impact the likelihood of CHR individuals to transition to psychosis, it may be a risk factor for development of the at-risk state and may be related to a greater risk of violence. Future studies should consider bullying perpetration among CHR individuals.

Published
2021

44. Depression Predicts Global Functional Outcomes in Individuals at Clinical High Risk for Psychosis

Author

Elaine F. Walker, Scott W. Woods, Diana O. Perkins, Wisteria Deng, Carrie E. Bearden, Larry J. Seidman, Barbara A. Cornblatt, Thomas H. McGlashan, Kristin S. Cadenhead, Jutta Joormann, Jean Addington, Ming T. Tsuang, Daniel H. Mathalon, and Tyrone D. Cannon

Subjects
Psychosis, medicine.medical_specialty, RC435-571, Clinical Research, mental disorders, 2.1 Biological and endogenous factors, Medicine, Aetiology, Psychiatry, Depression (differential diagnoses), screening and diagnosis, Depression, business.industry, Prevention, Rehabilitation, Serious Mental Illness, medicine.disease, Brain Disorders, Detection, Mental Health, Schizophrenia, business, General Economics, Econometrics and Finance, 4.2 Evaluation of markers and technologies
Abstract

ObjectivesWhile co-morbid depression is associated with poor functional outcome among patients with schizophrenia, whether depression similarly predicts poorer outcomes in individuals at clinical high-risk for psychosis (CHR-P) is not clear. The present study aimed to examine depressive symptoms in relation to long-term global functional outcomes in the North American Prodrome Longitudinal Study cohort (NAPLS2).MethodsCHR individuals were evaluated clinically at baseline and at 12- and 24-month follow-ups for depressive and prodromal symptom severity as well as general functioning. Regression models were built to investigate whether baseline positive and depressive symptom scores predicted longitudinal improvement in global functioning.ResultsA total of 406 CHR individuals completed the 12-month follow-up assessment and 259 CHR individuals completed the 24-month assessment. Baseline depressive symptoms in the CHR-P population were found to predict better global functional outcomes at 2years. Furthermore, the degree of recovery of depressive symptoms in the first year following baseline completely mediated the association between depressive symptoms at baseline and functional improvement at 2years.ConclusionsPresence of affective symptoms within the CHR-P population has different implications for prognosis compared with patients with schizophrenia. The present findings support the view that among those at risk for psychosis, depressive symptoms at baseline predict a more favorable course of functional recovery, and highlight the potential importance of treating co-occurring depressive symptoms at an early stage of psychosis risk.

Published
2021

45. Towards generalizable and transdiagnostic tools for psychosis prediction.: An independent validation and improvement of the NAPLS-2 risk calculator in the multi-site PRONIA cohort

Author

Peter Falkai, Lana Kambeitz-Ilankovic, Stephan Ruhrmann, Larry J. Seidman, Barbara A. Cornblatt, Dominic B. Dwyer, Rebekka Lencer, Alan Anticevic, Stephen J. Wood, Thomas H. McGlashan, Scott W. Woods, Diana O. Perkins, Eva Meisenzahl, Joseph Kambeitz, Michelle A. Worthington, Rachele Sanfelici, Rachel Upthegrove, Jean Addington, Philip McGuire, Marlene Rosen, Kristin S. Cadenhead, Paolo Fusar-Poli, Nikolaos Koutsouleris, Raquel E. Gur, Tyrone D. Cannon, Paolo Brambilla, Daniel H. Mathalon, Frauke Schultze-Lutter, Alessandro Bertolino, Carrie E. Bearden, Elaine F. Walker, Ming T. Tsuang, Stefan Borgwardt, Raimo K. R. Salokangas, and Jarmo Hietala

Subjects
Psychosis, Longitudinal study, medicine.medical_specialty, Population, Prodromal Symptoms, Logistic regression, Medical and Health Sciences, Article, Prodrome, Psychosis prediction, Risk Factors, Internal medicine, Machine learning, medicine, Humans, Longitudinal Studies, education, Biological Psychiatry, Depression (differential diagnoses), Psychiatry, education.field_of_study, business.industry, Prevention, Psychology and Cognitive Sciences, Biological Sciences, medicine.disease, Prognosis, First-episode depression, Brain Disorders, Clinical trial, Clinical high-risk states, Mental Health, Good Health and Well Being, Reciprocal external validation, Psychotic Disorders, Cohort, Risk calculators, sense organs, Patient Safety, business
Abstract

Background Transition to psychosis is among the most adverse outcomes of clinical high-risk (CHR) syndromes encompassing ultra-high risk (UHR) and basic symptom states. Clinical risk calculators may facilitate an early and individualized interception of psychosis, but their real-world implementation requires thorough validation across diverse risk populations, including young patients with depressive syndromes. Methods We validated the previously described NAPLS-2 (North American Prodrome Longitudinal Study 2) calculator in 334 patients (26 with transition to psychosis) with CHR or recent-onset depression (ROD) drawn from the multisite European PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Patients were categorized into three risk enrichment levels, ranging from UHR, over CHR, to a broad-risk population comprising patients with CHR or ROD (CHR|ROD). We assessed how risk enrichment and different predictive algorithms influenced prognostic performance using reciprocal external validation. Results After calibration, the NAPLS-2 model predicted psychosis with a balanced accuracy (BAC) (sensitivity, specificity) of 68% (73%, 63%) in the PRONIA-UHR cohort, 67% (74%, 60%) in the CHR cohort, and 70% (73%, 66%) in patients with CHR|ROD. Multiple model derivation in PRONIA–CHR|ROD and validation in NAPLS-2–UHR patients confirmed that broader risk definitions produced more accurate risk calculators (CHR|ROD-based vs. UHR-based performance: 67% [68%, 66%] vs. 58% [61%, 56%]). Support vector machines were superior in CHR|ROD (BAC = 71%), while ridge logistic regression and support vector machines performed similarly in CHR (BAC = 67%) and UHR cohorts (BAC = 65%). Attenuated psychotic symptoms predicted psychosis across risk levels, while younger age and reduced processing speed became increasingly relevant for broader risk cohorts. Conclusions Clinical-neurocognitive machine learning models operating in young patients with affective and CHR syndromes facilitate a more precise and generalizable prediction of psychosis. Future studies should investigate their therapeutic utility in large-scale clinical trials.

Published
2021

46. The association between migrant status and transition in an ultra-high risk for psychosis population

Author

Dorien H. Nieman, Monika Schlögelhofer, Connie Markulev, Stephen J. Wood, Scott W. Woods, Eric Y.H. Chen, Mark van der Gaag, Hok Pan Yuen, Lieuwe de Haan, Thomas H. McGlashan, Ian B. Hickie, Anita Riecher-Rössler, Hellen Geros, S. Smesny, Brian O'Donoghue, Jean Addington, Diana O. Perkins, Barbara A. Cornblatt, Barnaby Nelson, Patrick D. McGorry, Ashleigh Lin, Andrew Thompson, Ming T. Tsuang, Merete Nordentoft, Kristin S. Cadenhead, Gregor Berger, Jessica A. Hartmann, G. Paul Amminger, Helga K. Ising, Alison R. Yung, Tyrone D. Cannon, Carrie E. Beaden, Swapna Verma, Miriam R. Schäfer, Nilufar Mossaheb, Daniel H. Mathalon, Nathan G. Mifsud, Suzie Lavoie, Elaine F. Walker, Larry J. Seidman, Holly Sizer, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, ANS - Compulsivity, Impulsivity & Attention, and Clinical Psychology

Subjects
Adult, Psychosis, medicine.medical_specialty, Health (social science), Social Psychology, Adolescent, Epidemiology, Population, Migrants, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Ultra-high risk for psychosis, Risk Factors, Medicine, Humans, 030212 general & internal medicine, education, Proportional Hazards Models, Psychiatric Status Rating Scales, Transients and Migrants, education.field_of_study, business.industry, Proportional hazards model, Hazard ratio, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Cohort, business, Cohort study, Demography
Abstract

Purpose: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder.Methods: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model.Results: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147–756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62–1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70–1.51).Conclusions: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.

Published
2021

48. Impact of childhood adversity on corticolimbic volumes in youth at clinical high-risk for psychosis

Author

Larry J. Seidman, Carrie E. Bearden, Elaine F. Walker, Daniel H. Mathalon, Allison M. LoPilato, Scott W. Woods, Ming T. Tsuang, Jean Addington, Thomas H. McGlashan, Kristin S. Cadenhead, Barbara A. Cornblatt, Diana O. Perkins, Katrina Goines, and Tyrone D. Cannon

Subjects
Male, Risk, Psychosis, Longitudinal study, Adolescent, media_common.quotation_subject, Hippocampus, Cortical volume, Neglect, Young Adult, 03 medical and health sciences, Risk model, 0302 clinical medicine, Adverse Childhood Experiences, Limbic System, medicine, Humans, Child Abuse, Longitudinal Studies, Child, Mri scan, Poverty, Biological Psychiatry, media_common, Cerebral Cortex, Mechanism (biology), medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Hippocampal volume, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Childhood adversity is among the strongest risk factors for psychosis-spectrum disorders, though the nature and specificity of the biological mechanisms underlying this association remains unclear. Previous research reveals overlaps in the volumetric alterations observed in both adversity-exposed individuals and in psychosis-spectrum populations, highlighting the possibility that deviations in corticolimbic gray matter development may be one mechanism linking adversity and psychosis. Given that childhood adversity encompasses a wide range of adverse experiences, there is also a critical need to examine whether these different types of experiences have unique effects on corticolimbic regions. This study examined the association between childhood adversity and cortical, hippocampal, and amygdalar volume in a large sample of youth at clinical-high risk (CHR) for psychosis. We utilized a novel differentiated adversity approach that distinguishes exposures along dimensions of threat (e.g., abuse) and deprivation (e.g., poverty, neglect) to test for differential associations. Participants were drawn from the North American Prodromal Longitudinal Study (NAPLS) and completed an MRI scan and a retrospective assessment of childhood adversity at baseline. We found that deprivation exposure, but not threat, was uniquely associated with smaller cortical volume and smaller right hippocampal volume in CHR youth. These associations were masked in a generalized risk model that utilized a total adversity score. The findings suggest that deprivation exposures during childhood contribute to the subtle volumetric reductions observed in clinical high-risk samples and highlight the importance of disentangling different dimensions of adversity.

Published
2019

49. Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia

Author

Chen-Chung Liu, Yen-Tsung Huang, Benjamin M. Neale, Hai-Gwo Hwu, Ling-Ling Yeh, Yi-Ting Lin, Wei J. Chen, Tzung-Jeng Hwang, Yi-Ling Chien, Po-Chang Hsiao, Sharon D. Chandler, Chih-Min Liu, Chia-Yen Chen, Ming H. Hsieh, Shi-Heng Wang, Stephen V. Faraone, Stephen J. Glatt, and Ming T. Tsuang

Subjects
Adult, Male, 0301 basic medicine, Multifactorial Inheritance, medicine.risk_factor, Offspring, Genome-wide association study, Logistic regression, behavioral disciplines and activities, Paternal Age, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Paternal age effect, Biological Psychiatry, business.industry, Confounding, Odds ratio, medicine.disease, 030104 developmental biology, Schizophrenia, Female, Biological psychiatry, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography
Abstract

Background Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium. Methods Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents’ genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients’ early onset of schizophrenia (≤18 years old) on paternal age was conducted. Results Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients’ early onset of schizophrenia remained (odds ratio = 1.29, p = .04). Conclusions The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.

Published
2019

50. Neurocognitive profiles in the prodrome to psychosis in NAPLS-1

Author

Diana O. Perkins, Scott W. Woods, Kristin S. Cadenhead, Carrie E. Bearden, Eric C. Meyer, Elaine F. Walker, Larry J. Seidman, Anthony J. Giuliano, Thomas H. McGlashan, Eva Velthorst, Tyrone D. Cannon, Ming T. Tsuang, Jean Addington, and Barbara A. Cornblatt

Subjects
Clinical High Risk, Adult, Male, Risk, Longitudinal study, Psychosis, Adolescent, Prodromal Symptoms, Medical and Health Sciences, Article, Prodrome, Young Adult, 03 medical and health sciences, Cluster analysis, 0302 clinical medicine, Neuropsychology, Clinical Research, Humans, Medicine, Cognitive Dysfunction, Longitudinal Studies, Family history, Biological Psychiatry, Pediatric, Psychiatry, business.industry, Prevention, Psychology and Cognitive Sciences, Neurosciences, Mean age, Functional outcome, Serious Mental Illness, medicine.disease, Brain Disorders, 030227 psychiatry, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Psychotic Disorders, Convergent validity, Disease Progression, Schizophrenia, Female, Heterogeneity, business, Neurocognitive, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Background Most studies of neurocognitive functioning in Clinical High Risk (CHR) cohorts have examined group averages, likely concealing heterogeneous subgroups. We aimed to identify neurocognitive subgroups and to explore associated outcomes. Methods Data were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2 1/2 years. We applied Ward's method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules. Results Four neurocognitive clusters were identified: Significantly Impaired (n = 33); Mildly Impaired (n = 82); Normal (n = 145) and High (n = 64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity. Conclusion Neurocognitive profiles vary substantially in their severity and are associated with diagnostic and functional outcome, underscoring neurocognition as a predictor of illness outcomes. These findings, if replicated, are a first step toward personalized treatment for individuals at-risk for psychosis.

Published
2019

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