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1. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

Author

Stephen J. Guter, Laurie A. Demmer, Jasmine Lf Fung, Gerarda Cappuccio, Naomichi Matsumoto, Nicola Brunetti-Pierri, Catherine Sarret, Hamish S. Scott, Lynn Pais, Alison Yeung, Ken Saida, Christopher P. Barnett, Felix Boschann, Andre Heinen, Noriko Miyake, Jenny C. Taylor, Jonathan Gadian, Cyril Mignot, Boris Keren, Sandra Whalen, Hagar Mor-Shaked, Matteo P. Ferla, John Christodoulou, Raffaele Iorio, Alistair T. Pagnamenta, Tiong Yang Tan, Brian Hy Chung, Marcus Cy Chan, Susan M. White, Ruth Sheffer, Dana Mittag, Edwin H. Cook, Jens Schallner, Alicia B. Byrne, Rachel Stapleton, Natalie B Tan, Alison Kraus, Fabiola Di Dato, Tan, Natalie B, Pagnamenta, Alistair T, Ferla, Matteo P, Gadian, Jonathan, Byrne, Alicia B, White, Sue, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Tan, N. B., Pagnamenta, A. T., Ferla, M. P., Gadian, J., Chung, B. H. Y., Chan, M. C. Y., Fung, J. L. F., Cook, E., Guter, S., Boschann, F., Heinen, A., Schallner, J., Mignot, C., Keren, B., Whalen, S., Sarret, C., Mittag, D., Demmer, L., Stapleton, R., Saida, K., Matsumoto, N., Miyake, N., Sheffer, R., Mor-Shaked, H., Barnett, C. P., Byrne, A. B., Scott, H. S., Kraus, A., Cappuccio, G., Brunetti Pierri, N., Iorio, R., Di Dato, F., Pais, L. S., Yeung, A., Tan, T. Y., Taylor, J. C., Christodoulou, J., and White, S.

Subjects
medicine.medical_specialty, Genomics, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, GNB2, Intellectual disability, Genetics, medicine, Missense mutation, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, G-beta protein, medicine.disease, developmental delay, intellectual disability, Medical genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human genome, 030217 neurology & neurosurgery
Abstract

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Published
2021

3. Properties of beta oscillations in Dup15q syndrome

Author

Damla Şentürk, Joel Frohlich, Shafali S. Jeste, Lawrence T. Reiter, Vidya Saravanapandian, Carly Hyde, Edwin H. Cook, Joerg F. Hipp, Peyman Golshani, and Aaron Scheffler

Subjects
medicine.medical_specialty, Neurology, Cognitive Neuroscience, Dup15q syndrome, Autism, Audiology, Dup15q, Electroencephalography, Pathology and Forensic Medicine, lcsh:RC321-571, 03 medical and health sciences, Epilepsy, GABA, 0302 clinical medicine, Intellectual Disability, medicine, Humans, 0501 psychology and cognitive sciences, EEG, Child, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, medicine.diagnostic_test, business.industry, Research, 05 social sciences, Neurodevelopmental disorders, UBE3A, Neuropsychology, Infant, Reproducibility of Results, medicine.disease, Vineland Adaptive Behavior Scale, Child, Preschool, Pediatrics, Perinatology and Child Health, Biomarker (medicine), Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers, 050104 developmental & child psychology, Follow-Up Studies
Abstract

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism, intellectual disability, hypotonia, and epilepsy. The 15q region harbors genes critical for brain development, particularlyUBE3Aand a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We recently described an electrophysiological biomarker of the syndrome, characterized by excessive beta oscillations (12–30 Hz), resembling electroencephalogram (EEG) changes induced by allosteric modulation of GABAARs. In this follow-up study, we tested a larger cohort of children with Dup15q syndrome to comprehensively examine properties of this EEG biomarker that would inform its use in future clinical trials, specifically, its (1) relation to basic clinical features, such as age, duplication type, and epilepsy; (2) relation to behavioral characteristics, such as cognition and adaptive function; (3) stability over time; and (4) reproducibility of the signal in clinical EEG recordings.MethodsWe computed EEG power and beta peak frequency (BPF) in a cohort of children with Dup15q syndrome (N= 41, age range 9–189 months). To relate EEG parameters to clinical (study 1) and behavioral features (study 2), we examined age, duplication type, epilepsy, cognition, and daily living skills (DLS) as predictors of beta power and BPF. To evaluate stability over time (study 3), we derived the intraclass correlation coefficients (ICC) from beta power and BPF computed from children with multiple EEG recordings (N= 10, age range 18–161 months). To evaluate reproducibility in a clinical setting (study 4), we derived ICCs from beta power computed from children (N= 8, age range 19–96 months), who had undergone both research EEG and clinical EEG.ResultsThe most promising relationships between EEG and clinical traits were found using BPF. BPF was predicted both by epilepsy status (R2= 0.11,p= 0.038) and the DLS component of the Vineland Adaptive Behavior Scale (R2= 0.17,p= 0.01). Beta power and peak frequency showed high stability across repeated visits (beta power ICC = 0.93, BPF ICC = 0.92). A reproducibility analysis revealed that beta power estimates are comparable between research and clinical EEG (ICC = 0.94).ConclusionsIn this era of precision health, with pharmacological and neuromodulatory therapies being developed and tested for specific genetic etiologies of neurodevelopmental disorders, quantification and examination of mechanistic biomarkers can greatly improve clinical trials. To this end, the robust beta oscillations evident in Dup15q syndrome are clinically reproducible and stable over time. With future preclinical and computational studies that will help disentangle the underlying mechanism, it is possible that this biomarker could serve as a robust measure of drug target engagement or a proximal outcome measure in future disease modifying intervention trials.

Published
2020

4. Comparing Clinician Consensus Recommendations to Patient-reported Opioid Use Across Multiple Hospital Systems

Author

Larry A. Nathanson, Elizabeth B. Habermann, Charles H. Cook, Aaron Fleishman, Sean M. Stokes, Lyen C. Huang, Gabriel A. Brat, Cornelius A. Thiels, Kortney A. Robinson, Mario Feranil, and Sarah Duncan

Subjects
medicine.medical_specialty, Percentile, Consensus, Sentinel lymph node, MEDLINE, Drug Prescriptions, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Pain, Postoperative, business.industry, Opioid use, medicine.disease, Drug Utilization, Hospitals, United States, Analgesics, Opioid, Inguinal hernia, Surgical Procedures, Operative, 030220 oncology & carcinogenesis, Pill, Practice Guidelines as Topic, Emergency medicine, 030211 gastroenterology & hepatology, Surgery, Observational study, business, Oxycodone, medicine.drug
Abstract

Objective: We compare consensus recommendations for 5 surgical procedures to prospectively collected patient consumption data. To address local variation, we combined data from multiple hospitals across the country. Summary of background data One approach to address the opioid epidemic has been to create prescribing consensus reports for common surgical procedures. However, it is unclear how these guidelines compare to patient-reported data from multiple hospital systems. Methods Prospective observational studies of surgery patients were completed between 3/2017 and 12/2018. Data were collected utilizing post-discharge surveys and chart reviews from 5 hospitals (representing 3 hospital systems) in 5 states across the USA. Prescribing recommendations for 5 common surgical procedures identified in 2 recent consensus reports were compared to the prospectively collected aggregated data. Surgeries included: laparoscopic cholecystectomy, open inguinal hernia repair, laparoscopic inguinal hernia repair, partial mastectomy without sentinel lymph node biopsy, and partial mastectomy with sentinel lymph node biopsy. Results Eight hundred forty-seven opioid-naive patients who underwent 1 of the 5 studied procedures reported counts of unused opioid pills after discharge. Forty-one percent did not take any opioid medications, and across all surgeries, the median consumption was 3 5 mg oxycodone pills or less. Generally, consensus reports recommended opioid quantities that were greater than the 75th percentile of consumption, and for 2 procedures, recommendations exceeded the 90th percentile of consumption. Conclusions Although consensus recommendations were an important first step to address opioid prescribing, our data suggests that following these recommendations would result in 47%-56% of pills prescribed remaining unused. Future multi-institutional efforts should be directed toward refining and personalizing prescribing recommendations.

Published
2020

5. Familiality of behavioral flexibility and response inhibition deficits in autism spectrum disorder (ASD)

Author

Stormi P. White, Lauren M. Schmitt, Michael E. Ragozzino, Erin K. Bojanek, Matthew W. Mosconi, Edwin H. Cook, and John A. Sweeney

Subjects
Adult, Male, Proband, Autism Spectrum Disorder, lcsh:RC346-429, 03 medical and health sciences, Cognition, 0302 clinical medicine, Developmental Neuroscience, Task Performance and Analysis, medicine, Humans, Learning, 0501 psychology and cognitive sciences, Child, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Subclinical infection, Analysis of Variance, Behavior, business.industry, Research, 05 social sciences, Neuropsychology, Flexibility (personality), medicine.disease, Inhibition, Psychological, Psychiatry and Mental health, Phenotype, Autism spectrum disorder, Autism, Female, Analysis of variance, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Developmental Biology, Clinical psychology
Abstract

Background Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD. Methods We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+). Results Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP− parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively. Conclusion Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits.

Published
2019

6. Impact of cytomegalovirus load on host response to sepsis

Author

Thomas F. Marandu, Charles H. Cook, and Michael F. Dombek

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Cytomegalovirus reactivation, 030106 microbiology, Immunology, Congenital cytomegalovirus infection, Cytomegalovirus, Virus, Sepsis, 03 medical and health sciences, Medical microbiology, Immunity, medicine, Immunology and Allergy, Host (biology), business.industry, General Medicine, Viral Load, medicine.disease, 030104 developmental biology, Cytomegalovirus Infections, Virus Activation, business, Viral load
Abstract

There is a decades old association between cytomegalovirus reactivation and sepsis in immune-competent hosts. Much has been learned about this relationship, which has been described as bidirectional, meaning that the virus incites and is incited by the host's inflammatory response. More recent work has suggested that chronic viral infection leaves the host with exaggerated immunity to bacterial infections. In this review, the relationship between CMV and host responses to sepsis are reviewed, with particular attention to the impact that tissue viral load contributes to this phenomenon.

Published
2019

7. Whole Blood Serotonin Levels and Platelet 5-HT2A Binding in Autism Spectrum Disorder

Author

George M. Anderson, Suma Jacob, Matthew W. Mosconi, Alicia K. Montgomery, Edwin H. Cook, Elizabeth Aaron, Xinguo Ren, Stephen J. Guter, Ghanshyam N. Pandey, Jeremy Veenstra-VanderWeele, and Ana Carneiro

Subjects
medicine.medical_specialty, genetic structures, 05 social sciences, medicine.disease, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Autism spectrum disorder, Internal medicine, mental disorders, Developmental and Educational Psychology, medicine, Biomarker (medicine), Autism, 0501 psychology and cognitive sciences, Platelet, Serotonin, Receptor, Psychology, 030217 neurology & neurosurgery, 5-HT receptor, 050104 developmental & child psychology, Whole blood
Abstract

Elevated whole blood serotonin (WB5-HT) is a well-replicated biomarker in autism spectrum disorder (ASD). Decreased platelet serotonin receptor 5-HT2A binding has been reported in ASD. WB5-HT levels and platelet 5-HT2A specific binding were obtained from 110 individuals with ASD and 18 controls. Individuals with ASD had significantly higher WB5-HT levels than controls. There was no difference in the platelet 5-HT2A specific binding between groups. Multiple regression analyses revealed that platelet 5-HT2A binding significantly predicted WB5-HT in the control sample but not in the ASD sample. These results indicate that the relationship between WB5-HT and platelet 5-HT2A binding differs depending on ASD diagnosis, suggesting differences in platelet 5-HT system regulation in ASD.

Published
2019

8. Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis

Author

Michał Nowicki, Hong Zhang, Franz Ricklefs, Michael Gutknecht, Charles Cobbs, Arun K. Rooj, Prajna Behera, Carmela Passaro, Hirotaka Ito, Sean E. Lawler, Rachel Zane, Lai Ding, Marion Griessl, E. Antonio Chiocca, C. David James, Mykola Zdioruk, Magdalena Skubal, Harald Krenzlin, Sharon Peled, Charles H. Cook, Korneel Grauwet, and Viola Lorenz

Subjects
0301 basic medicine, medicine.drug_class, Angiogenesis, viruses, Congenital cytomegalovirus infection, Cytomegalovirus, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, stomatognathic system, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Platelet-Derived Growth Factor, Lymphokines, Neovascularization, Pathologic, biology, virus diseases, Neoplasms, Experimental, General Medicine, medicine.disease, Neoplasm Proteins, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cytomegalovirus Infections, NIH 3T3 Cells, Cancer research, biology.protein, Pericyte, Antiviral drug, Glioblastoma, Pericytes, Platelet-derived growth factor receptor, Research Article, Cidofovir
Abstract

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV(+) mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV(+) mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV(+) mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV(+) mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.

Published
2019

9. Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts

Author

Marion Griessl, Peter D. Zimmerman, Sara A. Mansfield, Haytham Elgharably, Charles H. Cook, Varun Dwivedi, and Ajit P. Limaye

Subjects
biology, business.industry, Congenital cytomegalovirus infection, medicine.disease, Cytomegalovirus immunoglobulin, Virology, Immunoglobulin G, 03 medical and health sciences, Titer, 0302 clinical medicine, Infectious Diseases, Immune system, Critical illness, medicine, biology.protein, 030211 gastroenterology & hepatology, 030212 general & internal medicine, Dna viral, business, Viral load
Abstract

Cytomegalovirus (CMV) reactivation occurs in roughly one-third of immunocompetent patients during critical illness, and is associated with worse outcomes. These outcomes have prompted consideration of early antiviral prophylaxis, but two-third of patients would receive unnecessary treatment. Tissue viral load has been associated with risk of reactivation in murine models, and recent work has suggested a relationship between immune responses to CMV and underlying viral load. We, therefore, sought to confirm the hypothesis that serum CMV-specific immunoglobulin G (IgG) correlates with tissue viral load, and might be used to predict the risk of reactivation during critical illness. We confirm that there is a good correlation between tissue viral load and serum CMV-specific IgG after laboratory infection of inbred mice. Further, we show that naturally infected outbred hosts have variable tissue viral DNA loads that do not correlate well with serum IgG. Perhaps as a consequence, CMV-specific IgG was not predictive of reactivation events in immunocompetent humans. When reactivation did occur, those with the lowest IgG levels had longer durations of reactivation, but IgG quartiles were not associated with differing peak DNAemia. Together our data suggest that CMV-specific IgG titers diverge from tissue viral loads in outbred immunocompetent hosts, and their importance for the control of reactivation events remains unclear.

Published
2019

10. Case Study: Fatal Exertional Rhabdomyolysis Possibly Related to Drastic Weight Cutting

Author

Akiva Leibowitz, Todd Sarge, Somnath Bose, Kadhiresan R. Murugappan, Shahzad Shaefi, Sara E. Neves, Michael N. Cocchi, and Charles H. Cook

Subjects
0301 basic medicine, medicine.medical_specialty, Strenuous exercise, Population, Medicine (miscellaneous), 03 medical and health sciences, 0302 clinical medicine, medicine, Orthopedics and Sports Medicine, education, Intensive care medicine, education.field_of_study, Sickle cell trait, 030109 nutrition & dietetics, Nutrition and Dietetics, biology, business.industry, Rapid weight loss, Athletes, 030229 sport sciences, General Medicine, medicine.disease, biology.organism_classification, Exertional rhabdomyolysis, business, Rhabdomyolysis, Medical literature
Abstract

Rapid weight loss or “weight cutting” is a dangerous practice that is ubiquitous in modern combat sports yet underrepresented in the medical literature. We present a case of exertional rhabdomyolysis in a mixed martial artist with sickle cell trait to illustrate the hazards of weight cutting and ensuing critical illness. Sickle cell trait is known to predispose patients to exertional rhabdomyolysis, and multiple fatal cases have been reported in the setting of strenuous exercise. Dehydration and consequent electrolyte abnormalities make combat sport athletes with sickle cell trait particularly vulnerable to this entity. This case suggests a potential role for sickle cell trait screening in this population and underscores the need for safer weight-control practices and monitoring among all combat sport athletes.

Published
2019

11. Gallbladder volvulus in a patient with chronic lymphocytic leukemia treated with laparoscopic cholecystectomy

Author

Lisa N. Guo, Charles S. Parsons, Jose Santiago, Charles H. Cook, and Benjamin B Scott

Subjects
medicine.medical_specialty, Abdominal pain, Bile duct, business.industry, Gallbladder, medicine.medical_treatment, gallbladder torsion, Public Health, Environmental and Occupational Health, Acute care surgery, Case Report, gallbladder volvulus, Critical Care and Intensive Care Medicine, medicine.disease, Gallbladder perforation, Surgery, Volvulus, medicine.anatomical_structure, Emergency Medicine, medicine, Cystic duct, Cholecystectomy, Surgical emergency, medicine.symptom, business
Abstract

Gallbladder volvulus is a rare condition that most commonly occurs in elderly women and often mimics acute cholecystitis in its presentation. This condition is a surgical emergency requiring cholecystectomy as it can lead to gallbladder perforation and bilious peritonitis with high morbidity to the patient. An 85-year-old woman with chronic lymphocytic leukemia presented with acute-onset right upper-quadrant abdominal pain and associated nausea with emesis. After admission to the surgical service and initiation of intravenous antibiotics, the patient was taken to the operating room for surgical management due to the persistence of symptoms. Intraoperative findings included a necrotic appearing gallbladder that was twisted on the cystic duct. Laparoscopic cholecystectomy was performed, which was complicated by bile leak requiring endoscopic retrograde cholangiopancreatography with bile duct stenting followed by operative washout. Gallbladder volvulus can be challenging to diagnose. This condition should be suspected in elderly women with acute-onset abdominal pain and imaging concerning for acute cholecystitis. Emergent cholecystectomy is the treatment of choice for gallbladder volvulus.

Published
2019

12. Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

Author

Xue Zhong, Edwin H. Cook, Nancy J. Cox, Ying Ji, Quan Wang, James S. Sutcliffe, Yi Jiang, Zhexing Wen, Chongchong Xu, Feixiong Cheng, Bingshan Li, Hai Yang, Qiang Wei, and Rui Chen

Subjects
Schizophrenia, Dendrite (mathematics), medicine, Sub threshold, Morphology (biology), Genome-wide association study, Computational biology, Genetic risk, Biology, medicine.disease
Abstract

Schizophrenia (SCZ) is highly polygenic, and thousands of genes contribute to its risk. The 145 GWAS loci identified to date do not fully reveal SCZ genetic risk pathways. In this study, we explore a cost-effective strategy to increase power of inference of novel pathways, by expanding the analysis to include sub-threshold GWAS (subGWAS) loci. We identify 180 subGWAS loci (e.g., 5 x10-8 < P ≤ 10-6) based on SCZ summary statistics of 40,675 cases and 64,643 controls from CLOZUK and PGC datasets, and show that subGWAS loci contain substantial true genetic association signals. We merge GWAS (sigGWAS) and subGWAS loci and identify in total 304 high-confidence risk genes (HRGs) by jointly modeling the expanded set of loci. We identify dendrite development and morphogenesis (DDM, GO:0016358 and GO:0048813) as a novel category of biological processes implicated in SCZ genetic risk. SigGWAS loci fail to detect DDM, which is predominantly enriched in subGWAS loci. Further, DDM genes are significantly enriched for heritability of SCZ, as well as bipolar disorder and major depression. Genes in this functional process show cell type specificity in neurons in both fetal and adult brains, and their involvement in SCZ risk is further supported by eQTL analysis of SCZ risk alleles. We derived induced pluripotent stem cell (iPSC) lines from sporadic SCZ patients and normal controls and observe increased neurite lengths and soma sizes in patient-derived iPSC lines along multiple time points during neuronal development, further validating the genetic findings. We also find that the implicated genes are enriched in FDA-approved drug targets, suggesting a therapeutic potential for targeting the implicated biological processes for prevention and treatment. Our results showcase that expanding the analysis to include subGWAS loci is a valuable strategy for enhancing power of uncovering disease mechanisms, especially those of weak effect size, for SCZ and other complex diseases.

Published
2021

13. An Emerging Syndemic of Smoking and Cardiopulmonary Diseases in People Living with HIV in Africa

Author

Mari Armstrong-Hough, Conrad Iyegbe, Joyce Gyamfi, Andre Pascal Kengne, Stephanie H. Cook, Anya Snyder, Temitope Ojo, Emmanuel Peprah, Nessa Ryan, Juliet Iwelunmor, Linda Chang, Paul F. O'Reilly, Jacquelyn Y. Taylor, Oliver Ezechi, Huichun Xu, and Barbara Mukasa

Subjects
medicine.medical_specialty, Health, Toxicology and Mutagenesis, Population, lcsh:Medicine, HIV Infections, Context (language use), 030204 cardiovascular system & hematology, tobacco, smoking, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Syndemic, Acquired immunodeficiency syndrome (AIDS), cardiovascular disease, Environmental health, Tobacco Smoking, medicine, Humans, syndemics, 030212 general & internal medicine, low- and middle-income countries, education, Cardiopulmonary disease, education.field_of_study, business.industry, Public health, Mortality rate, lcsh:R, Public Health, Environmental and Occupational Health, medicine.disease, Africa, Commentary, HIV/AIDS, business, Cohort study
Abstract

Background: African countries have the highest number of people living with HIV (PWH). The continent is home to 12% of the global population, but accounts for 71% of PWH globally. Antiretroviral therapy has played an important role in the reduction of the morbidity and mortality rates for HIV, which necessitates increased surveillance of the threats from pernicious risks to which PWH who live longer remain exposed. This includes cardiopulmonary comorbidities, which pose significant public health and economic challenges. A significant contributor to the cardiopulmonary comorbidities is tobacco smoking. Indeed, globally, PWH have a 2–4-fold higher utilization of tobacco compared to the general population, leading to endothelial dysfunction and atherogenesis that result in cardiopulmonary diseases, such as chronic obstructive pulmonary disease and coronary artery disease. In the context of PWH, we discuss (1) the current trends in cigarette smoking and (2) the lack of geographically relevant data on the cardiopulmonary conditions associated with smoking; we then review (3) the current evidence on chronic inflammation induced by smoking and the potential pathways for cardiopulmonary disease and (4) the multifactorial nature of the syndemic of smoking, HIV, and cardiopulmonary diseases. This commentary calls for a major, multi-setting cohort study using a syndemics framework to assess cardiopulmonary disease outcomes among PWH who smoke. Conclusion: We call for a parallel program of implementation research to promote the adoption of evidence-based interventions, which could improve health outcomes for PWH with cardiopulmonary diseases and address the health inequities experienced by PWH in African countries.

Published
2021

14. Psychotic Symptoms and Spiritual Phenomena

Author

Christopher C. H. Cook

Subjects
Psychotherapist, media_common.quotation_subject, Possession (law), medicine.disease, humanities, Prayer, Faith, Schizophrenia, Spirituality, medicine, Pastoral care, Discernment, Psychology, Demon, media_common
Abstract

Psychotic symptoms and spiritual phenomena may either be understood as being on a continuum or else as being discontinuous, categorically separate phenomena. Christian scripture and tradition may be interpreted within either model, but in either case, there is a need for discernment in diagnosis and pastoral care. Hearing the voice of God and belief in demon possession are particularly complex phenomena, being both a part of normal Christian life in many churches worldwide and also potentially symptoms of psychosis for some. For those who are suffering from psychosis, the relationship between faith and illness needs to be treated with sensitivity and respect. Christian spirituality has a significant part to play in recovery. A spiritual assessment and integration of spirituality/faith in treatment will be important. Much more mutual understanding and collaborative work are needed between clergy and clinicians to achieve optimum pastoral and clinical care.

Published
2021

15. Cytomegalovirus: Another Source of Antibody-mediated Graft Injury?

Author

Charles H. Cook

Subjects
Transplantation, biology, business.industry, Graft Survival, Congenital cytomegalovirus infection, Cytomegalovirus, medicine.disease, Virology, Article, Text mining, Cytomegalovirus Infections, medicine, biology.protein, Humans, Antibody, business
Abstract

BACKGROUND: Human cytomegalovirus (HCMV) infection is associated with renal allograft dysfunction and loss, particularly in combination with acute rejection. Emerging literature suggests that non-HLA antibodies may contribute to antibody-mediated rejection, but pathogen-induced antibodies have not been investigated in this context. This study examines the presence of CMV-induced antibodies in murine CMV (MCMV) infected renal allografts during acute rejection. METHODS: Intragraft IgG and complement C3 immunostaining were compared among allogeneic MCMV D−/R−, D+/R−, and D+/R+ renal transplants. Intragraft antibody deposition was examined in B cell deficient (μMT) recipients treated with MCMV immune sera. Antibody binding and complement dependent cytotoxicity (CDC) of D−/R− and D+/R+ sera against infected renal tubular epithelial cells (TECs) were measured in-vitro. IgG immunostaining was performed in D+/R+ allografts and native kidneys, and in D+/R− allografts treated with ganciclovir to inhibit viral replication. RESULTS: D+/R− and D+/R+ transplants had more abundant IgG and C3 deposition compared to D−/R− recipients. Greater IgG deposition was associated with more severe allograft injury in μMT recipients treated with MCMV immune sera compared to nonimmune sera. D+/R+ sera induced greater CDC of infected TECs compared to D−/R− sera. Native kidneys had lower IgG deposition compared to allografts, despite similar organ viral loads. Ganciclovir-treated allografts had reduced IgG deposition compared to untreated allografts. CONCLUSIONS: In this murine model, complement-fixing antibodies can deposit into MCMV-infected renal allografts, are associated with allograft damage, and can induce CDC of MCMV-infected renal TECs. The allogeneic response and viral replication may also contribute to intragraft antibody deposition.

Published
2021

16. Perioperative Considerations for Tracheostomies in the Era of COVID-19

Author

Andre F. Gosling, Akiva Leibowitz, Somnath Bose, Ernest D. Gomez, Mihir Parikh, Todd Sarge, Charles H. Cook, and Shahzad Shaefi

Subjects
medicine.medical_specialty, Infectious Disease Transmission, Patient-to-Professional, Time Factors, Narrative Review Article, medicine.medical_treatment, Operative Time, Pneumonia, Viral, Risk Assessment, Perioperative Care, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Tracheostomy, 030202 anesthesiology, Risk Factors, Occupational Exposure, Health care, medicine, Infection control, Humans, Intensive care medicine, Pandemics, Personal Protective Equipment, Mechanical ventilation, Aerosols, Patient Care Team, Infection Control, business.industry, Critical Care and Resuscitation, SARS-CoV-2, COVID-19, Perioperative, medicine.disease, Anesthesiology and Pain Medicine, Treatment Outcome, Respiratory failure, Middle East respiratory syndrome, business, Risk assessment, Airway, Coronavirus Infections, 030217 neurology & neurosurgery
Abstract

The morbidity, mortality, and blistering pace of transmission of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented worldwide health crisis. Coronavirus disease 2019 (COVID-19), the disease produced by SARS-CoV-2 infection, is remarkable for persistent, severe respiratory failure requiring mechanical ventilation that places considerable strain on critical care resources. Because recovery from COVID-19-associated respiratory failure can be prolonged, tracheostomy may facilitate patient management and optimize the use of mechanical ventilators. Several important considerations apply to plan tracheostomies for COVID-19-infected patients. After performing a literature review of tracheostomies during the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, we synthesized important learning points from these experiences and suggested an approach for perioperative teams involved in these procedures during the COVID-19 pandemic. Multidisciplinary teams should be involved in decisions regarding timing and appropriateness of the procedure. As the theoretical risk of disease transmission is increased during aerosol-generating procedures (AGPs), stringent infectious precautions are warranted. Personal protective equipment (PPE) should be available and worn by all personnel present during tracheostomy. The number of people in the room should be limited to those absolutely necessary. Using the most experienced available operators will minimize the total time that staff is exposed to an infectious aerosolized environment. An approach that secures the airway in the safest and quickest manner will minimize the time any part of the airway is open to the environment. Deep neuromuscular blockade (train-of-four ratio = 0) will facilitate surgical exposure and prevent aerosolization due to patient movement or coughing. For percutaneous tracheostomies, the bronchoscopist should be able to reintubate if needed. Closed-loop communication must occur at all times among members of the team. If possible, after tracheostomy is performed, waiting until the patient is virus-free before changing the cannula or downsizing may reduce the chances of health care worker infection. Tracheostomies in COVID-19 patients present themselves as extremely high risk for all members of the procedural team. To mitigate risk, systematic meticulous planning of each procedural step is warranted along with strict adherence to local/institutional protocols.

Published
2020

17. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki

Subjects
Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Published
2020

18. A framework for an evidence-based gene list relevant to autism spectrum disorder

Author

Peter Szatmari, Mayada Elsabbagh, Wendy K. Chung, Helen V. Firth, Ny Hoang, Jacques L. Michaud, Catalina Betancur, Janet A. Buchanan, Jennifer L. Howe, Jacob A. S. Vorstman, Louise Gallagher, Christian P. Schaaf, Edwin H. Cook, Joseph D. Buxbaum, Kira A. Dies, Olivia Rennie, Stephen W. Scherer, Raphael Bernier, Jeremy R. Parr, Ryan K. C. Yuen, Patrick Bolton, Thomas W. Frazier, Christian R. Marshall, Chun-An Chen, David Skuse, Betancur, Catalina, Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, Newcastle University [Newcastle], University College of London [London] (UCL), Trinity College Dublin, University of Washington [Seattle], Children's Autism Center [Seattle, WA, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Autism Speaks [Cleveland, OH, USA], Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre for Addiction and Mental Health [Toronto] (CAMH), Columbia University Medical Center (CUMC), Columbia University [New York], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Illinois [Chicago] (UIC), University of Illinois System, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], and CHU Sainte Justine [Montréal]-Université de Montréal (UdeM)

Subjects
Evidence-based practice, Research groups, Autism Spectrum Disorder, MEDLINE, MESH: Cognition, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, behavioral disciplines and activities, MESH: Intellectual Disability, 03 medical and health sciences, MESH: Brain, Cognition, 0302 clinical medicine, Intellectual Disability, mental disorders, Genetics, medicine, Humans, Molecular Biology, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, MESH: Genetic Association Studies, MESH: Autism Spectrum Disorder, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Evidence-Based Medicine, MESH: Humans, Extramural, Brain, Evidence-based medicine, medicine.disease, Clinical Practice, Autism spectrum disorder, Gene list, 030217 neurology & neurosurgery, MESH: Evidence-Based Medicine
Abstract

International audience; Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Published
2020

19. Maternal Serotonin Levels Are Associated With Cognitive Ability and Core Symptoms in Autism Spectrum Disorder

Author

Lauren C. Shuffrey, George M. Anderson, Alicia K. Montgomery, John A. Sweeney, Jeremy Veenstra-VanderWeele, Stephen J. Guter, J. Blake Turner, Suma Jacob, Matthew W. Mosconi, James S. Sutcliffe, and Edwin H. Cook

Subjects
Adult, Male, Serotonin, Autism Spectrum Disorder, Offspring, Mothers, Neuropsychological Tests, Fathers, 03 medical and health sciences, Nonverbal communication, Cognition, 0302 clinical medicine, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Prospective Studies, Child, Adaptive behavior, Pregnancy, business.industry, 05 social sciences, medicine.disease, Latent class model, Psychiatry and Mental health, Autism spectrum disorder, Autism, Female, business, Biomarkers, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology
Abstract

Objective The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes. Method WB5-HT levels were obtained from 181 individuals (3–27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes. Results Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales−II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F2,46.048 = 17.394, p Conclusion Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings.

Published
2018

20. Have you 'CORED' lately? A comprehensive operating room evacuation drill

Author

Bryan Sears, Meg S. Femino, Alok Gupta, Alexander Hart, Charles H. Cook, and Adam Wolberg

Subjects
Patient Transfer, Operating Rooms, Drill, business.industry, Debriefing, education, Direct observation, Disaster Planning, General Medicine, medicine.disease, Hospital planning, Personnel, Hospital, Leadership, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Median time, Surveys and Questionnaires, 030225 pediatrics, medicine, Hospital Planning, Humans, Training needs, Medical emergency, business
Abstract

Introduction: Crises in the operating room (OR) are uncommon events that require an expeditious response from all providers to minimize morbidity and mortality to both patients and staff. Evacuation during a surgical procedure presents a unique challenge. There is a paucity of data on the ideal response, ideal times, and training needs for hospital staff. Methods: The authors herein describe a full-scale simulation exercise of the emergent mid-procedure evacuation of seven ORs. Results: Median time to evacuate from the OR and reach the Post-Anesthesia Care Unit safety point was 3:50 minutes (range, 1:22 minutes to 6:00 minutes). Multiple lessons were learned from direct observation, post-drill debrief, and post-drill survey of participants. Conclusions: Emergent mid-procedure evacuation of ORs can be expeditious if needed. Critical themes in leadership, communication, and coordination of care were discovered. Surgeons, anesthesiologists, and OR staff should consider performing an OR evacuation drill to improve their local efficacy and efficiency in emergent OR evacuation.

Published
2018

21. The role of mesoscale convective systems in the diurnal cycle of rainfall and its seasonality over sub-Saharan Northern Africa

Author

Edward K. Vizy, Kerry H. Cook, and Weiran Liu

Subjects
Atmospheric Science, 010504 meteorology & atmospheric sciences, Tropical wave, Mesoscale meteorology, Nocturnal, Seasonality, Sensible heat, 010502 geochemistry & geophysics, medicine.disease, 01 natural sciences, 13. Climate action, Diurnal cycle, Climatology, Moist static energy, medicine, Environmental science, Precipitation, 0105 earth and related environmental sciences
Abstract

This study evaluates the role of MCSs in the total rainfall distribution as a function of season from a climatological perspective (1998–2014) over sub-Saharan northern Africa and examines how the diurnal cycle of rainfall changes with season. Tropical Rainfall Measuring Mission (TRMM) 3B42V7 rainfall estimates and European Centre for Medium-Range Weather Forecasts ERA-Interim reanalysis are used to evaluate the climatology. The percentages of the full TRMM precipitation delivered by MCSs have meridional structures in spring, fall and winter, ranging from 0 to 80% across sub-Saharan northern Africa, while the percentages are homogenous in summer (> 80%). The diurnal cycles of MCS-associated precipitation coincide with the full TRMM rainfall. Attributes of MCSs, including size, count, and intensity, vary synchronously with the diurnal cycle of rainfall. The diurnal peaks are classified into three categories: single afternoon peak, continuous afternoon peak, and nocturnal peak. Single afternoon peaks dominate in spring and fall while continuous afternoon and nocturnal peaks are more common in summer, indicating the seasonality of the diurnal cycle. The continuous afternoon peak combines rainfall from two system types—one locally-generated and one propagating. The seasonality of the diurnal cycle is related to the seasonality of MCS lifetimes, and propagation speeds and directions. The moisture component of the MSE profile contributes to the instability most in summer when convection is more frequent. Low-level temperature, which is related to surface warming and sensible heat fluxes, influences the instability more during winter and spring.

Published
2018

22. Seasonality of the Observed Amplified Sahara Warming Trend and Implications for Sahel Rainfall

Author

Edward K. Vizy and Kerry H. Cook

Subjects
Atmospheric Science, 010504 meteorology & atmospheric sciences, Atmospheric circulation, 0208 environmental biotechnology, Latent heating, Longwave, 02 engineering and technology, Seasonality, medicine.disease, Monsoon, Atmospheric sciences, 01 natural sciences, 020801 environmental engineering, Atmosphere, Trend analysis, Climatology, medicine, Environmental science, Precipitation, 0105 earth and related environmental sciences
Abstract

Prior results indicate an amplified annual mean warming trend over the Sahara, with temperature trends that are 2–4 times that of the tropical mean rate. Trend analysis is conducted using five atmospheric reanalyses and three observational datasets to better understand the seasonality and physical processes of this amplified warming and the implications for Sahel precipitation. The seasonality of the amplified warming is maximum during July–October with a minimum during June. Two processes related to the amplified warming are identified. A “dry process” supports amplified warming over the Sahara when there is limited latent heating and/or evaporation to cool the surface and distribute heat to the atmosphere. In this mechanism, the warming results from changes in the upward longwave and downward longwave fluxes that are tightly coupled to each other. The second, termed a “wet process,” occurs during the summer West African monsoon season. In this mechanism there are increases in the low- and midlevel atmospheric moisture over the Sahara that add to the surface warming by increasing the longwave downward radiation. This additional atmospheric moisture is transported over the Sahara because of a strengthening of the thermal low/Saharan high circulation system. A positive feedback mechanism is discussed in which enhanced moisture transport due to the stronger Saharan warming leads to increased Sahel rainfall that further strengthens the meridional temperature and height gradients by cooling the Sahel surface, further enhancing moisture transport into the region. Both processes contribute to the amplified warming, with the amplification being greater during the summer.

Published
2017

23. Does MAOA increase susceptibility to prenatal stress in young children?

Author

Amalia E. Hatcher, Kimberly Andrews Espy, Daniel S. Pine, Edwin H. Cook, James L. Burns, Daniel K. Mroczek, Caron A. C. Clark, Lauren S. Wakschlag, Suena H. Massey, Andrew D. Skol, and David Goldman

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Physiology, Toxicology, Article, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Pregnancy, Internal medicine, Tobacco Smoking, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Young adult, Child, Prospective cohort study, Monoamine Oxidase, Problem Behavior, Sex Characteristics, biology, medicine.disease, 030227 psychiatry, Endocrinology, Prenatal stress, Child, Preschool, Prenatal Exposure Delayed Effects, Cohort, biology.protein, Female, Gene-Environment Interaction, Monoamine oxidase A, Psychology, Stress, Psychological, 030217 neurology & neurosurgery, Sex characteristics
Abstract

Background We previously demonstrated a gene-by-prenatal-environment interaction whereby the monoamine oxidase A gene (MAOA) modified the impact of prenatal tobacco exposure (PTE) on adolescent disruptive behavior (DB), with the MAOA risk genotype varying by sex. We extend this work by examining whether this mechanism is evident with another common adversity, prenatal stress exposure (PSE), and whether sex differences are present earlier in development in closer proximity to exposure. Methods Participants were 281 mothers and their 285 children derived from a prenatal cohort with in-depth prospective measures of PSE and PTE. We assessed DB at age 5 via dimensional developmentally-sensitive measurement. Analyses were stratified by sex based on prior evidence for sex differences. Results Concurrent stress exposure predicted DB in children (β = 0.310, p = 0.001), while main effects of prenatal exposures were seen only in boys. We found a three-way interaction of MAOA × PSE × sex on DB (β = 0.813, p = 0.022). Boys with MAOA-H had more DB as a function of PSE, controlling for PTE (β = 0.774, p = 0.015), and as a function of PTE, controlling for PSE (β = 0.362, p = 0.037). Boys with MAOA-L did not show this susceptibility. MAOA did not interact with PSE (β = − 0.133, p = 0.561) nor PTE (β = − 0.144; p = 0.505) in predicting DB in girls. Examination of gene-environment correlation (rGE) showed a correlation between paternal MAOA-L and daughters' concurrent stress exposure (r = − 0.240, p = 0.013). Discussion Findings underscore complex mechanisms linking genetic susceptibility and early adverse exposures. Replication in larger cohorts followed from the pregnancy through adolescence is suggested to elucidate mechanisms that appear to have varying developmental expression.

Published
2017

24. Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?

Author

Lauren C. Shuffrey, Jeremy Veenstra-VanderWeele, George M. Anderson, Edwin H. Cook, Suma Jacob, James S. Sutcliffe, Stephen J. Guter, and Shannon Delaney

Subjects
education.field_of_study, General Neuroscience, 05 social sciences, Population, Quantitative trait locus, medicine.disease, behavioral disciplines and activities, Developmental psychology, Sexual dimorphism, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Biomarker (medicine), 0501 psychology and cognitive sciences, Neurology (clinical), Psychology, education, 030217 neurology & neurosurgery, Genetics (clinical), 050104 developmental & child psychology, Genetic association, Sex characteristics
Abstract

Approximately 30% of individuals with autism spectrum disorder (ASD) have elevated whole blood serotonin (5-HT) levels. Genetic linkage and association studies of ASD and of whole blood 5-HT levels as a quantitative trait have revealed sexual dimorphism. Few studies have examined the presence of a sex difference on hyperserotonemia within ASD. To assess whether the rate of hyperserotonemia is different in males than in females with ASD, we measured whole blood 5-HT levels in 292 children and adolescents with ASD, the largest sample in which this biomarker has been assessed. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on the 182 pre-pubertal children with ASD. 42% of pre-pubertal participants were within the hyperserotonemia range. In this population, we found that males were significantly more likely to manifest hyperserotonemia than females (P = 0.03). As expected, no significant difference was found in the post-pubertal population. Additional work will be needed to replicate this intriguing finding and to understand whether it could potentially explain differences in patterns of ASD risk between males and females. Autism Res 2017, 10: 1417-1423. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Published
2017

25. Pharmacogenomics of autism spectrum disorder

Author

Edwin H. Cook, Jacob T. Brown, Seenae Eum, and Jeffrey R. Bishop

Subjects
Autism Spectrum Disorder, Fluvoxamine, Pharmacology, Irritability, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Medicine, Escitalopram, Risperidone, business.industry, Methylphenidate, medicine.disease, 030227 psychiatry, Pharmacogenetics, Autism spectrum disorder, Pharmacogenomics, Molecular Medicine, Central Nervous System Stimulants, medicine.symptom, business, 030217 neurology & neurosurgery, Antipsychotic Agents, Clinical psychology, medicine.drug
Abstract

Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interactions as well as restricted, repetitive behaviors and interests. Pharmacologic interventions are often needed to manage irritability, aggressive behaviors and hyperactivity. Pharmacogenomic studies have investigated genetic associations with treatment response and side effects in an attempt to better understand drug mechanisms in hopes of optimizing the balance of symptom improvement versus side effects. The majority of pharmacogenomic studies to date have focused on antipsychotics, antidepressants and stimulants that are the most commonly utilized medication classes for ASD. This review is a comprehensive examination of the existing pharmacogenomic studies in ASD highlighting the current state of knowledge regarding genetic variation influencing pharmacokinetics and pharmacodynamics, and associated clinical outcomes.

Published
2017

26. BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

Author

Regina Miller, Nicholas J. Lodge, John E. Macor, Wendy Clarke, Lizbeth Gallagher, Linda J. Bristow, Daniel G. Morgan, Christiana I. Iwuagwu, Ryan Westphal, Haiquan Fang, Kimberley A. Lentz, Debra J. Post-Munson, Amy Easton, Matthew D. Hill, Bei Wang, Robert A. Mate, Ivar M. McDonald, James H. Cook, Yulia Benitex, Dalton King, Thaddeus F. Molski, Ronald J. Knox, F. Christopher Zusi, Richard E. Olson, Rex Denton, Jingsong Fan, Rulin Zhao, and Robert Zaczek

Subjects
0301 basic medicine, business.industry, Organic Chemistry, Cognition, Pharmacology, medicine.disease, Biochemistry, Partial agonist, 03 medical and health sciences, Nicotinic acetylcholine receptor, 030104 developmental biology, 0302 clinical medicine, Nicotinic agonist, In vivo, Schizophrenia, Drug Discovery, medicine, business, Receptor, 030217 neurology & neurosurgery, Acetylcholine, medicine.drug
Abstract

The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

Published
2017

27. Age and Its Impact on Outcomes with Intra-Abdominal Infection

Author

Pamela A. Lipsett, E. P. Dellinger, James M. Sanders, Jeffrey M. Tessier, Ori D. Rotstein, Joseph Cuschieri, Therese M. Duane, Charles H. Cook, Reza Askari, Robert G. Sawyer, Christopher A. Guidry, Drew Farmer, Preston R. Miller, and Billy J. Moore

Subjects
Adult, Male, Microbiology (medical), medicine.medical_specialty, Adolescent, Rectum, 030230 surgery, Sepsis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Post-hoc analysis, medicine, Humans, Surgical Wound Infection, 030212 general & internal medicine, Antibiotic prophylaxis, Aged, Randomized Controlled Trials as Topic, Retrospective Studies, Peritoneal Infection, Aged, 80 and over, business.industry, Abdominal Infection, Age Factors, Middle Aged, medicine.disease, Anti-Bacterial Agents, Surgery, Clinical trial, Infectious Diseases, medicine.anatomical_structure, Etiology, Drainage, Intraabdominal Infections, Female, business
Abstract

Age has been shown to play a significant role in the etiology of complicated intra-abdominal infections (cIAIs), but the correlation between age and outcomes after therapy was not investigated in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial.Data were obtained by post hoc analysis of the STOP-IT trial database. Patients were stratified by age65 or ≥65 years. Primary outcomes were surgical site infection (SSI), recurrent IAI (recIAI), and death. Multivariable analysis was performed to identify independent predictors of outcomes.There were 398 subjects65 and 120 ≥ 65 years. Overall baseline characteristics of the two groups were similar. The site of infection was similar between groups except: Colon or rectum (48.3% vs. 29.9%, p = 0.0002) and biliary tree (16.7% vs. 9.1%, p = 0.02), which were more common in the older group, whereas small intestine (6.7% vs. 16.3%, p = 0.008) and appendix (4.2% vs.17.1%, p = 0.0004) were more common in the younger group. Among the primary outcomes, only death was significantly different between the age groups and was more prevalent in the ≥65 years group (4 [3.3%] vs. 1 [0.3%], p = 0.01). Surgical site infection (9.2% vs. 7.3%, p = 0.50), recIAI (15.8% vs. 14.4%, p = 0.69), and a composite outcome (26.7% vs. 20.4%, p = 0.14) were statistically similar between the age groups, and this remained true when controlling for other co-variables. Multivariable analyses did not reveal age as an independent predictor of the composite or individual outcomes.Patients with a more advanced age demonstrated variable sources of infection relative to the younger cohort, yet received similar treatments. Patient age was not an independent predictor of the undesired cIAI outcomes. These findings suggest that advanced age itself does not play a significant role in predicting these adverse outcomes for cIAIs and does not necessitate an altered treatment tactic.

Published
2017

29. Elevated polygenic burden for ASD is associated with the broad autism phenotype

Author

Edwin H. Cook, Molly Losh, Lea K. Davis, Nell Maltman, Julia M. Sealock, Lauren Bush, and Kritika Nayar

Subjects
0303 health sciences, genetic structures, Protective factor, Biology, medicine.disease, behavioral disciplines and activities, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Autism spectrum disorder, mental disorders, Genotype, polycyclic compounds, medicine, Etiology, Autism, 030217 neurology & neurosurgery, 030304 developmental biology, Subclinical infection, Clinical psychology
Abstract

BackgroundAutism spectrum disorder (ASD) is a multifactorial, neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP) have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explored polygenic scores related to the BAP.MethodsPhenotypic and genotypic information were obtained from 2,614 trios from Simons Simplex Sample. Polygenic scores of ASD (ASD-PGS) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and Paternal ASD-PGS was explored in relation to BAP traits and their child ASD symptomatology.ResultsMaternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGS was related to the pragmatic language and rigid BAP domains.ConclusionsDomain- and sex-specific associations emerged between parent and child phenotypes. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

Published
2019

30. Elevated Polygenic Burden for Autism Spectrum Disorder Is Associated With the Broad Autism Phenotype in Mothers of Individuals With Autism Spectrum Disorder

Author

Nell Maltman, Lauren Bush, Lea K. Davis, Julia M. Sealock, Molly Losh, Kritika Nayar, and Edwin H. Cook

Subjects
0301 basic medicine, Male, animal structures, genetic structures, Autism Spectrum Disorder, Protective factor, Mothers, behavioral disciplines and activities, Article, 03 medical and health sciences, Fathers, 0302 clinical medicine, Neurodevelopmental disorder, mental disorders, polycyclic compounds, medicine, Humans, Autistic Disorder, Child, Biological Psychiatry, Subclinical infection, medicine.disease, Phenotype, 030104 developmental biology, Autism spectrum disorder, Endophenotype, Etiology, Autism, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Background Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP. Methods Phenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology. Results Maternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains. Conclusions Associations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

Published
2019

31. CSIG-19. CYTOMEGALOVIRUS INFECTION LEADS TO NF-kB DEPENDENT UPREGULATION OF c-MET AND MGMT IN GLIOBLASTOMA AND RESISTANCE TO TEMOZOLOMIDE IN VIVO

Author

Ennio Antonio Chiocca, Mykola Zdioruk, Sean E. Lawler, Charles H. Cook, Harald Krenzlin, and M. Oskar Nowicki

Subjects
Cancer Research, C-Met, Temozolomide, biology, Congenital cytomegalovirus infection, Cell Signaling and Signaling Pathways, O-6-methylguanine-DNA methyltransferase, medicine.disease, biology.organism_classification, NFKB1, chemistry.chemical_compound, Oncology, chemistry, Downregulation and upregulation, Tumor progression, Betaherpesvirinae, medicine, Cancer research, Neurology (clinical), medicine.drug
Abstract

INTRODUCTION Cytomegalovirus (CMV), a member of the betaherpesvirinae subfamily widespread in human populations has been reported to be detectable in glioblastoma (GBM). We have recently shown that CMV latent infection promotes GBM growth in a mouse model. The mechanisms involved are not well-defined and treatment responses have not been evaluated. METHODS To investigate the effects of CMV on GBM cells we performed an RNAseq study. Differentially expressed genes were identified and validated in vitro and in vivo. RESULTS RNAseq analysis showed multiple alterations induced by CMV infection of GBM cells including significant upregulation of c-MET (8.2 log2 fold change) and MGMT (3.9 log2 fold change) transcripts after CMV infection. c-MET is a tyrosine kinase receptor known to promote GBM growth, and MGMT expression leads to resistance to the alkylating agent temozolomide (TMZ). These findings were validated in vitro in both mouse and human GBM cells, and shown to be dependent on CMV-induced upregulation of NF-kB by siRNA knockdown of the essential RelA NF-kB subunit. The c-MET co-receptor CD44 was also upregulated suggesting a role for the c-MET signalling axis in CMV induced tumor progression. CMV-infected tumor cells were resistant to TMZ treatment as expected due to MGMT upregulation. Treatment of our murine GBM model with TMZ led to a significant increase in survival in control mock-infected mice (median survival 38 days control, 48 days TMZ), whereas the CMV infected mice did not respond (median survival 35 days control, 35 days TMZ; p value between TMZ treated groups = 10–4). CONCLUSIONS Our results define novel and relevant mechanisms by which CMV may influence both GBM growth and resistance to treatment. Further therapeutic and mechanistic studies are underway to investigate these pathways in the context of CMV in GBM. These data support further study of CMV targeting in GBM.

Published
2019

32. Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study

Author

Carol Macmillan, Catalina Betancur, Stephen J. Guter, Erin K. Bojanek, Matthew W. Mosconi, Edwin H. Cook, Schiefelbusch Institute for Life Span Studies [Lawrence, KS, USA] (Clinical Child Psychology Program), University of Kansas [Kansas City], Kansas Center for Autism Research and Training [Overland Park, KS, USA] (K-CART), University of Kansas Medical Center [Lawrence], Institute for Juvenile Research [Chicago, IL, USA], University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/ Award Number: U54 HD090216-01, National Institute of Child Health and Human Development, Grant/Award Number: P50HD055751, National Institute of Mental Health, Grant/Award Numbers: K23 MH092696-05, R01 MH112734-01, National Institutes of Health, Grant/Award Numbers: HHSN268201200008I, X01 HG007235, Betancur, Catalina, University of Kansas Medical Center [Kansas City, KS, USA], Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Autism Spectrum Disorder, cognitive discrepancy, Developmental Disabilities, Visual impairment, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, autism, 030105 genetics & heredity, Audiology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Young Adult, Atrophy, Intellectual Disability, Exome Sequencing, Genetics, Medicine, Humans, Genetic Predisposition to Disease, Bosch-Boonstra-Schaaf optic atrophy syndrome, Genetics (clinical), Exome sequencing, Optic nerve hypoplasia, COUP Transcription Factor I, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, Eye movement, medicine.disease, NR2F1, Optic Atrophy, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Codon, Nonsense, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Autism, Female, medicine.symptom, business, Neurocognitive
Abstract

International audience; Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced non-verbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.

Published
2019

33. Vocabulary comprehension in adults with fragile X syndrome (FXS)

Author

Sandra S. Block, Stephen J. Guter, Sue Ellen Krause, Anne Hoffmann, Sue Leurgans, Jeff Salt, Elizabeth Berry-Kravis, Joanne Wuu, Dominick M. Maino, and Edwin H. Cook

Subjects
Adult, Male, Vocabulary, Adolescent, Cognitive Neuroscience, media_common.quotation_subject, lcsh:RC321-571, Pathology and Forensic Medicine, Developmental psychology, Young Adult, 03 medical and health sciences, Cognition, 0302 clinical medicine, Peabody Picture Vocabulary Test, medicine, Adults, Humans, 0501 psychology and cognitive sciences, Cognitive skill, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Language, Randomized Controlled Trials as Topic, media_common, Mental age, Language Tests, Research, 05 social sciences, Neuropsychology, Middle Aged, medicine.disease, Comprehension, Fragile X Syndrome, Pediatrics, Perinatology and Child Health, Autism, Female, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Background Receptive and expressive vocabulary in adult and adolescent males with fragile X syndrome (FXS) have been shown as significantly lower than their chronological age; however, receptive vocabulary has been considered a strength relative to mental age. This has not been formally examined, however, and data are needed to compare receptive vocabulary with other language skills and with mental age in individuals with FXS. This is especially important as vocabulary measures are sometimes used as a proxy to estimate language ability. Methods This preliminary study examined receptive vocabulary, global language, and cognitive skills in 42 adults (33 males and 9 females) with FXS as a portion of the baseline evaluation prior to randomization in a clinical trial of ampakine CX516. The battery of standardized tests addressed receptive vocabulary with the Peabody Picture Vocabulary Test, Third Edition (PPVT-III), receptive and expressive language (termed henceforth as global language) via the Preschool Language Scale, Fourth Edition or the Clinical Evaluation of Language Fundamentals, Third Edition, and non-verbal cognition via the Stanford-Binet Intelligence Scales, Fourth Edition (SB-IV). Results Results showed (1) significantly higher receptive vocabulary than global language, (2) significantly better receptive vocabulary than non-verbal cognition, (3) equivalent non-verbal cognition and global language, and (4) severity of autism symptomatology was not correlated to receptive vocabulary or global language once non-verbal cognition was removed as factor. The scores from the PPVT-III did not represent the global language skills in our sample of adults with FXS. Conclusions Findings from this investigation strongly suggest that the PPVT-III should not be used as a screening tool for language levels or cognitive function in clinical studies since the scores from the PPVT-III were not representative of global language or non-verbal cognitive skills in adults with intellectual disabilities. This finding is critical in order to understand how to evaluate, as well as to treat, language in individuals with FXS. Development of efficient and appropriate tools to measure language, cognition, and behavior in individuals with FXS is essential.

Published
2019

34. Retrospective evaluation of prognostic factors in metastatic spine disease: serum albumin and primary tumour type are key

Author

Joseph F. Baker and William H Cook

Subjects
Oncology, medicine.medical_specialty, Multivariate analysis, medicine.medical_treatment, Population, Serum albumin, Disease, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Lung cancer, education, Serum Albumin, Retrospective Studies, education.field_of_study, Spinal Neoplasms, biology, business.industry, Univariate, General Medicine, medicine.disease, Prognosis, Survival Analysis, Radiation therapy, 030220 oncology & carcinogenesis, Cohort, biology.protein, 030211 gastroenterology & hepatology, Surgery, business, New Zealand
Abstract

Background Treatment decisions for metastatic spine disease are complex and depend on prognosis. Four prognostic systems in use are the Oswestry Risk Index, modified Bauer score (MBS), van der Linden score and New England Spinal Metastasis Score (NESMS). We aimed to determine the performance of these scoring systems in a New Zealand cohort of patients and develop a prognostic score specific to this demographic. Methods A retrospective review of a patient cohort from 2009 to 2016 was undertaken. Scores and individual scoring items were evaluated with univariate and multivariate analyses. Significant items were used to design a simple, population-specific objective scoring system, which was then tested. Results A total of 106 patients receiving either surgery and radiotherapy (65) or radiotherapy alone (41) were included. Mean post-treatment survival time was 13.7 months. All scoring systems were significantly correlated with survival and had similar concordances. The MBS had the largest coefficient of determination (Cox and Snell's R2 = 0.18), followed by the NESMS (R2 = 0.14). On multivariate analysis, the lung cancer (MBS) and serum albumin (NESMS) items were significant. A modified Oswestry Risk Index primary tumour item and NESMS serum albumin outperformed the MBS (R2 = 0.20), providing the basis for a prognostic scoring tool specific to our demographic. Conclusion Based on serum albumin and primary tumour type, we propose the 'Metastatic Spine Risk Index' as a simple and objective tool, specific to our population for predicting survival, which can be used in conjunction with other clinical information when considering treatment options.

Published
2019

35. Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Author

Phil Lee, Richard Anney, Pieter J. Hoekstra, Barbara Franke, Geschwind Dh, Michael C. Neale, Yen-Chen Anne Feng, Edwin H. Cook, Anttila, E Stahl, Borglum Ad, Kenneth S. Kendler, Santangelo Sl, Wray Nr, Danielle Posthuma, Carol A. Mathews, Sintia Iole Belangero, Amanda B Zheutlin, Cynthia M. Bulik, Jeremiah M. Scharf, Laramie E. Duncan, Luis Augusto Rohde, Jacob Rosenthal, Anna Keski-Rahkonen, Stein Mb, Fanous Ah, Zhaozhong Zhu, Karen S. Mitchell, J Kaprio, Breen G, Michel G. Nivard, G. Kirov, John I. Nurnberger, Patrick F. Sullivan, Daly Mj, Michael Conlon O'Donovan, Andreassen Oa, Hyejung Won, Wang Mm, Faraone Sv, Mattheisen M, Benjamin M. Neale, Gelernter J, Smoller Jw, Henry R. Kranzler, Thornton Lm, Clement C. Zai, Ripke S, Elliot M. Tucker-Drob, Howard J. Edenberg, Lewis Cm, McIntosh Am, Tobias Banaschewski, Dongmei Yu, Andrew D. Grotzinger, Walters Jt, Raymond K. Walters, Giovanni Coppola, and Jurjen J. Luykx

Subjects
0303 health sciences, medicine.medical_specialty, Biology, medicine.disease, Genome, Tourette syndrome, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy, Anorexia nervosa (differential diagnoses), Autism spectrum disorder, Schizophrenia, medicine, Bipolar disorder, Psychiatry, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

SummaryGenetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019
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36. An Anatomic Approach to Minimally Invasive Spine Surgery

Author

Nima Salari, Mick J. Perez-Cruet, Richard A. Shapack, Richard G. Fessler, David R. Nerenz, George D. Picetti, John A. Redmond, Luis Marchi, Patricia Zadnik Sullivan, Steven L. Gogela, Anthony T. Yeung, James M. Moran, Efrem M. Cox, Rory Goodwin, Verdú-López Francisco, Curtis A. Dickman, Jeffrey P. Mullin, Zachary D. Patterson, Daniel K. Fahim, Eli M. Baron, Rodrigo Amaral, Ann T. Hollenbeck, Daniel K. Resnick, Gabriel A. Smith, Noel I. Perin, Hiroshi W. Nakano, Joshua E. Medow, Moumita S.R. Choudhury, Rudolf W. Beisse, Michael G. Fehlings, Holly Weissman, John E. O’Toole, E. Emily Bennett, Matthew L. Rontal, Fred H. Geisler, A. Karim Ahmed, Richard N.W. Wohns, Robert E. Isaacs, Peter F. Picetti, Sina Rajamand, William D. Tobler, Ronnie I. Mimran, Jake P. Heiney, Esam A. Elkhatib, Michael Wang, Laura Miller Dyrda, Fernando G. Diaz, Edward C. Benzel, Carter S. Gerard, Andrea Simmonds, Hasan A. Zaidi, Christopher Yeung, Neel Anand, Devanand A. Dominique, Trent L. Tredway, David L. Downs, Leonardo Oliveira, Luiz Pimenta, Hyun-Chul Shin, Lee A. Tan, R. Patrick Jacob, Daniel Roy Pieper, Zeeshan M. Sardar, David J. Hart, Michael A. Leonard, Stephen W. Bartol, Steven H. Cook, Mengqiao Alan Xi, Alexander R. Vaccaro, Anthony A. Turk, Daniel M. Sciubba, Mendoza-Torres Jorge, Jonathan B. Lesser, Manish K. Kasliwal, Roman Chornij, Larry T. Khoo, Kevin R. O’Neill, Maha Saada Jawad, Charles D. Ray, Alp Yurter, Henry Tong, D Samartzis, Rick Placide, and K. Daniel Riew

Subjects
medicine.medical_specialty, Percutaneous, business.industry, medicine.medical_treatment, Arthrodesis, Anterior cervical discectomy and fusion, Scoliosis, Anatomy, medicine.disease, Surgery, Degenerative disc disease, Lumbar, Foraminotomy, Discectomy, medicine, business
Abstract

Fundamentals Historical Background of Minimally Invasive Spine Surgery Michael A. Leonard, Dino Samartzis, Mick J. Perez-Cruet Anatomy of the Spine: An Overview Joshua E. Medow, Daniel K. Resnick Biomechanical Role of the Osseous, Ligamentous, and Muscular Structures of the Spine Rick Placide, Edward C. Benzel Degenerative Disc Disease and Discogenic Pain Charles D. Ray Rationale for Minimally Invasive Spine Surgery Larry T. Khoo Clinical Outcome Analyses Dino Samartzis, Devanand A. Dominique, Mick J. Perez-Cruet, Michael G. Fehlings Complications of Minimally Invasive Spine Procedures Mick J. Perez-Cruet, Noel I. Perin Informed Consent for Minimally Invasive Spine Surgery Harold D. Portnoy Establishing a Minimally Invasive Spine Center Richard N. W. Wohns, Karen L. Saban, Amelia Malick, Faith Berinti, Mick J. Perez-Cruet Image Guidance, Monitoring, and Nonsurgical Techniques Applications of Image Guidance in Minimally Invasive Spine Surgery Kurt M. Eichholz, Sunanda Nioguy, Dino Samartzis, Ron von Jako, Mick J. Perez-Cruet Intraoperative Monitoring During Spine Surgery Steven M. Zak, Blair Calancie, Satish Krishnamurthy Electrophysiologic Monitoring of Percutaneous Pedicle Screw Placement Sylvain Palmer Injection-Based Spine Procedures Lawrence W. Frank, Emil S. Cheng, Howard W. Robinson, Brian A. Couri Stereotactic Radiosurgery for Tumors of the Spine Deborah L. Benzil, Chitti R. Moorthy Surgical Techniques Cervical Spine Microendoscopic Cervical Foraminotomy and Discectomy Faheem A. Sandhu, Mick J. Perez-Cruet, Richard G. Fessler Microendoscopic Cervical Laminectomy Mick J. Perez-Cruet, Dino Samartzis, Richard G. Fessler Anterior Cervical Foraminotomy J. Patrick Johnson, Dino Samartzis, Mick J. Perez-Cruet Microendoscopic Anterior Cervical Discectomy and Fusion Luiz Pimenta, Mick J. Perez-Cruet, Manuel Da Silva Martins, Federico Figueredo Endoscopic Posterior Fixation of the Middle and Lower Cervical Spine Larry T. Khoo, Tooraj Gravori Artificial Cervical Disc Replacement Jan Goffin, Vincent Bryan Thoracic Spine Minimally Invasive Implantation of Epidural Spinal Cord Stimulation Electrodes Matthew R. Johnson, Joanna Swartzbaugh, Daniel J. Tomes, Lyal G. Leibrock Microendoscopic Thoracic Discectomy Mick J. Perez-Cruet, Dino Samartzis, Richard G. Fessler Anterior Thoracoscopic Sympathectomy Curtis A. Dickman Thoracoscopic Discectomy: Lessons Learned and Avoidance of Complications Hyun-Chul Shin, Jonathan Lesser, Robert E. Isaacs, Noel I. Perin Anterior Thoracoscopic Vertebral Reconstruction and Instrumentation Daniel H. Kim, Raju S. V. Balabhadra, Michael Potulski, Rudolf W. Beisse Anterior Thoracoscopic Instrumentation Correction and Fusion for the Treatment of Scoliosis George D. Picetti III Thoracic and Lumbar Vertebroplasty Michael A. Leonard, Mick J. Perez-Cruet Percutaneous Kyphoplasty Sepehr Sani, Richard D. Fessler, Mick J. Perez-Cruet Lumbar Spine Microendoscopic Lumbar Discectomy Mick J. Perez-Cruet, James R. Bean, Richard G. Fessler Microendoscopic Far-Lateral Lumbar Discectomy Kevin T. Foley, Sanjay Gupta, Mick J. Perez-Cruet Endoscopic Lumbar Laminectomy for Stenosis Ronnie I. Mimran, Mick J. Perez-Cruet, Richard G. Fessler, R. Patrick Jacob Percutaneous Pedicle Screw Placement for Spinal Instrumentation Mick J. Perez-Cruet CD Horizon Sextant Percutaneous Pedicle Screw System Eric S. Wieser, Mick J. Perez-Cruet, Larry T. Khoo Percutaneous Pedicle Screw Fixation of the Lumbar Spine Using the PathFinder System Randall R. McCafferty, Larry T. Khoo, Mick J. Perez-Cruet Aperture System: An Approach to Lumbar Arthrodesis and Instrumentation Stephen L. Ritland Posterior Lumbar Instrumentation Using the Atavi System Mick J. Perez-Cruet, Adam M. Shuster eXtreme Lateral Interbody Fusion Luiz Pimenta, Thomas Dan Schaffa, Manuel Da Silva Martins, Federico Figueredo, Roberto Diaz Percutaneous Axial Lumbar Spine Surgery Allen L. Carl, Eric H. Ledet, Carlos Oliviera, Luiz Pimenta, Roberto Diaz Orduz, Andrew H. Cragg Far-Lateral Lumbar Interbody Techniques Paul M. Tsou Mini-Open Anterior Lumbar Interbody Fusion Todd Y. Nida, Sunanda Nioguy, Hormoz Sheikh, Mustafa A. Hares, Mick J. Perez-Cruet Laparoscopic Fusion of the Lumbosacral Spine Stephen E. Heim, Anthony F. Altimari, John L. Andreshak Lumbar Disc Replacement: The Artificial Disc Fred H. Geisler Lumbar Artificial Disc Nucleus Replacement Anthony T. Yeung Percutaneous Osteobiologic Vertebral Reconstruction Sunanda Nioguy, Elizabeth M. H. Kim, Fred H. Geisler, Hormoz Sheikh, Mick J. Perez-Cruet

Published
2019

37. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. Davis, Lenka Slachtova, Olav B. Smeland, Erin C. Dunn, Nicholas G. Martin, Allan L. Naarden, Jo Knight, Cristina Sánchez-Mora, Masashi Ikeda, Lorraine Southam, Sandro Sorbi, Barbara Franke, Martin Schalling, Russell Schachar, Yen-Chen Anne Feng, Kirsten R. Müller-Vahl, André Scherag, Zhaozhong Zhu, Eric A. Storch, Páll Magnússon, David Cohen, Olafur O Gudmundsson, Harvey S. Singer, Brian Kelly, Jonas Bybjerg-Grauholm, Blanca Garcia-Delgar, Thomas Hansen, Carmel M. Loughland, Christine Lochner, Stacy Steinberg, Martin Woods, Jorge A. Quiroz, Raquel Rabionet, Alden Y. Huang, Janice M. Fullerton, María Soler Artigas, Hans J. Grabe, Philip Asherson, Margit Burmeister, Alicia R. Martin, Martin A. Kennedy, Janet Treasure, Anders D. Børglum, Eva C. Schulte, Andreas Hartmann, Frans Henskens, Youl-Ri Kim, Jens Treutlein, Joanna Hauser, Manfred M. Fichter, Damiaan Denys, Ann E. Pulver, Kelly L. Klump, Paul Sandor, Michael Wagner, Philippe Courtet, Sandra Van der Auwera, Susanne Lucae, Eystein Stordal, Michel G. Nivard, Maurizio Clementi, Astrid Morer, Philip B. Mitchell, Huda Akil, Edwin H. Cook, Jennifer L. Moran, Donald W. Black, Jeremiah M. Scharf, Jana Strohmaier, Colm McDonald, Meg M.-J. Wang, Richard M. Myers, Stephanie Godard, Pablo V. Gejman, Athanasios Maras, Marcella Rietschel, Nancy G. Buccola, Konstantinos Hatzikotoulas, Dalila Pinto, Jouke-Jan Hottenga, Kari Stefansson, James S. Sutcliffe, Andres Metspalu, Amaia Hervás, Joel Gelernter, Wolfgang Herzog, Paula Rovira, Gunnar Morken, Tara Murphy, Mark Weiser, Vincent Millischer, Frank Dudbridge, Dan Rujescu, Vladimir Bencko, Valdo Ricca, Kimberly Chambert, Guy A. Rouleau, James J. Crowley, Thomas G. Schulze, Toni-Kim Clarke, Triinu Peters, Gudrun Wagner, Daniel A. Geller, Henry R. Kranzler, G. Bragi Walters, Vera Golimbet, Clement C. Zai, Nigel Williams, Andreas Birgegård, Joseph D. Buxbaum, Elliot M. Tucker-Drob, Jerome C. Foo, Tracey L. Petryshen, Daniel P. Howrigan, Hunna J. Watson, Franziska Degenhardt, Peter R. Schofield, Jesper Buchhave Poulsen, Stefan Herms, Johannes Hebebrand, Mario Maj, George Kirov, Fabrizio Piras, Sara McDevitt, James T. McCracken, Carol A. Mathews, Michael John Owen, Peter Falkai, Donald L. Gilbert, Enda M. Byrne, Fernando Fernández-Aranda, Csaba Barta, Stéphane Jamain, Jubao Duan, Dongmei Yu, Danielle C. Cath, Ole Mors, Sigrun Hope, Laramie E. Duncan, Alan R. Sanders, Sang-Yun Oh, Carsten Bøcker Pedersen, Henning Tiemeier, Roseann E. Peterson, Raymond K. Walters, Margarita C T Slof-Op 't Landt, Madeline Alexander, Stephanie Le Hellard, Ina Giegling, Annemarie A. van Elburg, Steven P. Hamilton, Vesna Boraska Perica, Thomas V. Fernandez, Danielle M. Dick, Francesco Bettella, Roel A. Ophoff, Grant W. Montgomery, Gerald Nestadt, Nakao Iwata, Jessica H. Baker, Walter H. Kaye, Jeremy M. Silverman, Mark J. Daly, Robert A. King, Sarah E. Medland, Anastasios Konstantinidis, Robert D. Oades, Samuel H. Zinner, Steven Crawford, Daniel H. Geschwind, Patrick W. L. Leung, Martin Alda, Marie Navratilova, Pak C. Sham, Paul A. Tooney, Tian Ge, Veit Roessner, Martin Preisig, Thomas Werge, Eli A. Stahl, David A. Collier, Stephanie H. Witt, Dermot Walsh, Miquel Casas, Anna Keski-Rahkonen, Jane H. Christensen, Silvia De Rubeis, Giorgio Pistis, Sven Cichon, Bruno Etain, Dominique Campion, O. Joseph Bienvenu, Christian Dina, Manolis Kogevinas, Thomas Espeseth, Benjamin M. Neale, Ditte Demontis, Klaus-Peter Lesch, Marina Mitjans, Tiffany A. Greenwood, Marcos Madruga-Garrido, Sibylle G. Schwab, Oedegaard Ketil Joachim, Hreinn Stefansson, Sara A. Paciga, Monica Forzan, Dieter B. Wildenauer, Lena Backlund, A. Jeremy Willsey, Carlos N. Pato, Nicholas John Craddock, Inge A. Meijer, Sandra K. Loo, Filip Rybakowski, Tracey D. Wade, Scott J. Crow, Bernard Lerer, Valsamma Eapen, Esben Agerbo, Andrew M. McIntosh, Luis Augusto Rohde, Susan L. McElroy, Stephan Zipfel, Peter P. Zandi, Cathryn M. Lewis, Lars Klareskog, Martin Begemann, Phil Lee, Richard Anney, Mark A. Bellgrove, Lisa Jones, Andreas J. Forstner, Agnieszka Słopień, Hilary Coon, Dong Li, Alessandro Serretti, Carsten Horn, Christos Pantelis, Ryan L. Collins, David M. Howard, Lucía Colodro-Conde, Pippa A. Thomson, Martin Hautzinger, Alysa E. Doyle, Julie Hagstrøm, Oliver S. P. Davis, Karen S. Mitchell, Jordan W. Smoller, Michael Strober, John I. Nurnberger, Andrea G. Ludolph, Monika Budde, Anna Maaser, Lambertus Klei, Aribert Rothenberger, Yulia Worbe, Fabian Streit, James L. Kennedy, Barbara E. Stranger, Ashley Dumont, Jianxin Shi, Dale R. Nyholt, Craig Johnson, Jonna Kuntsi, Yun-Joo Koh, Loes M. Olde Loohuis, Robert B. Freedman, Anke Hinney, Susanne Walitza, Enrico Domenici, Margarita Rivera, Sodahm Kook, Erica Greenberg, Tetyana Zayats, Josef Frank, Gary A. Heiman, Andrew McQuillin, Abraham Reichenberg, Piotr M. Czerski, Humberto Nicolini, Lee P.H., Anttila V., Won H., Feng Y.-C.A., Rosenthal J., Zhu Z., Tucker-Drob E.M., Nivard M.G., Grotzinger A.D., Posthuma D., Wang M.M.-J., Yu D., Stahl E.A., Walters R.K., Anney R.J.L., Duncan L.E., Ge T., Adolfsson R., Banaschewski T., Belangero S., Cook E.H., Coppola G., Derks E.M., Hoekstra P.J., Kaprio J., Keski-Rahkonen A., Kirov G., Kranzler H.R., Luykx J.J., Rohde L.A., Zai C.C., Agerbo E., Arranz M.J., Asherson P., Baekvad-Hansen M., Baldursson G., Bellgrove M., Belliveau R.A., Buitelaar J., Burton C.L., Bybjerg-Grauholm J., Casas M., Cerrato F., Chambert K., Churchhouse C., Cormand B., Crosbie J., Dalsgaard S., Demontis D., Doyle A.E., Dumont A., Elia J., Grove J., Gudmundsson O.O., Haavik J., Hakonarson H., Hansen C.S., Hartman C.A., Hawi Z., Hervas A., Hougaard D.M., Howrigan D.P., Huang H., Kuntsi J., Langley K., Lesch K.-P., Leung P.W.L., Loo S.K., Martin J., Martin A.R., McGough J.J., Medland S.E., Moran J.L., Mors O., Mortensen P.B., Oades R.D., Palmer D.S., Pedersen C.B., Pedersen M.G., Peters T., Poterba T., Poulsen J.B., Ramos-Quiroga J.A., Reif A., Ribases M., Rothenberger A., Rovira P., Sanchez-Mora C., Satterstrom F.K., Schachar R., Artigas M.S., Steinberg S., Stefansson H., Turley P., Walters G.B., Werge T., Zayats T., Arking D.E., Bettella F., Buxbaum J.D., Christensen J.H., Collins R.L., Coon H., De Rubeis S., Delorme R., Grice D.E., Hansen T.F., Holmans P.A., Hope S., Hultman C.M., Klei L., Ladd-Acosta C., Magnusson P., Naerland T., Nyegaard M., Pinto D., Qvist P., Rehnstrom K., Reichenberg A., Reichert J., Roeder K., Rouleau G.A., Saemundsen E., Sanders S.J., Sandin S., St Pourcain B., Stefansson K., Sutcliffe J.S., Talkowski M.E., Weiss L.A., Willsey A.J., Agartz I., Akil H., Albani D., Alda M., Als T.D., Anjorin A., Backlund L., Bass N., Bauer M., Baune B.T., Bellivier F., Bergen S.E., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boen E., Budde M., Bunney W., Burmeister M., Byerley W., Byrne E.M., Cichon S., Clarke T.-K., Coleman J.R.I., Craddock N., Curtis D., Czerski P.M., Dale A.M., Dalkner N., Dannlowski U., Degenhardt F., Di Florio A., Elvsashagen T., Etain B., Fischer S.B., Forstner A.J., Forty L., Frank J., Frye M., Fullerton J.M., Gade K., Gaspar H.A., Gershon E.S., Gill M., Goes F.S., Gordon S.D., Gordon-Smith K., Green M.J., Greenwood T.A., Grigoroiu-Serbanescu M., Guzman-Parra J., Hauser J., Hautzinger M., Heilbronner U., Herms S., Hoffmann P., Holland D., Jamain S., Jones I., Jones L.A., Kandaswamy R., Kelsoe J.R., Kennedy J.L., Joachim O.K., Kittel-Schneider S., Kogevinas M., Koller A.C., Lavebratt C., Lewis C.M., Li Q.S., Lissowska J., Loohuis L.M.O., Lucae S., Maaser A., Malt U.F., Martin N.G., Martinsson L., McElroy S.L., McMahon F.J., McQuillin A., Melle I., Metspalu A., Millischer V., Mitchell P.B., Montgomery G.W., Morken G., Morris D.W., Muller-Myhsok B., Mullins N., Myers R.M., Nievergelt C.M., Nordentoft M., Adolfsson A.N., Nothen M.M., Ophoff R.A., Owen M.J., Paciga S.A., Pato C.N., Pato M.T., Perlis R.H., Perry A., Potash J.B., Reinbold C.S., Rietschel M., Rivera M., Roberson M., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Sigurdsson E., Smeland O.B., Stordal E., Streit F., Strohmaier J., Thorgeirsson T.E., Treutlein J., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Wang Y., Witt S.H., Zandi P., Adan R.A.H., Alfredsson L., Ando T., Aschauer H., Baker J.H., Bencko V., Bergen A.W., Birgegard A., Perica V.B., Brandt H., Burghardt R., Carlberg L., Cassina M., Clementi M., Courtet P., Crawford S., Crow S., Crowley J.J., Danner U.N., Davis O.S.P., Degortes D., DeSocio J.E., Dick D.M., Dina C., Docampo E., Egberts K., Ehrlich S., Espeseth T., Fernandez-Aranda F., Fichter M.M., Foretova L., Forzan M., Gambaro G., Giegling I., Gonidakis F., Gorwood P., Mayora M.G., Guo Y., Halmi K.A., Hatzikotoulas K., Hebebrand J., Helder S.G., Herpertz-Dahlmann B., Herzog W., Hinney A., Imgart H., Jimenez-Murcia S., Johnson C., Jordan J., Julia A., Kaminska D., Karhunen L., Karwautz A., Kas M.J.H., Kaye W.H., Kennedy M.A., Kim Y.-R., Klareskog L., Klump K.L., Knudsen G.P.S., Landen M., Le Hellard S., Levitan R.D., Li D., Lichtenstein P., Maj M., Marsal S., McDevitt S., Mitchell J., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., O'Toole J.K., Padyukov L., Pantel J., Papezova H., Rabionet R., Raevuori A., Ramoz N., Reichborn-Kjennerud T., Ricca V., Roberts M., Rujescu D., Rybakowski F., Scherag A., Schmidt U., Seitz J., Slachtova L., Slof-Op't Landt M.C.T., Slopien A., Sorbi S., Southam L., Strober M., Tortorella A., Tozzi F., Treasure J., Tziouvas K., van Elburg A.A., Wade T.D., Wagner G., Walton E., Watson H.J., Wichmann H.-E., Woodside D.B., Zeggini E., Zerwas S., Zipfel S., Adams M.J., Andlauer T.F.M., Berger K., Binder E.B., Boomsma D.I., Castelao E., Colodro-Conde L., Direk N., Docherty A.R., Domenici E., Domschke K., Dunn E.C., Foo J.C., de. Geus E.J.C., Grabe H.J., Hamilton S.P., Horn C., Hottenga J.-J., Howard D., Ising M., Kloiber S., Levinson D.F., Lewis G., Magnusson P.K.E., Mbarek H., Middeldorp C.M., Mostafavi S., Nyholt D.R., Penninx B.W., Peterson R.E., Pistis G., Porteous D.J., Preisig M., Quiroz J.A., Schaefer C., Schulte E.C., Shi J., Smith D.J., Thomson P.A., Tiemeier H., Uher R., van der Auwera S., Weissman M.M., Alexander M., Begemann M., Bramon E., Buccola N.G., Cairns M.J., Campion D., Carr V.J., Cloninger C.R., Cohen D., Collier D.A., Corvin A., DeLisi L.E., Donohoe G., Dudbridge F., Duan J., Freedman R., Gejman P.V., Golimbet V., Godard S., Ehrenreich H., Hartmann A.M., Henskens F.A., Ikeda M., Iwata N., Jablensky A.V., Joa I., Jonsson E.G., Kelly B.J., Knight J., Konte B., Laurent-Levinson C., Lee J., Lencz T., Lerer B., Loughland C.M., Malhotra A.K., Mallet J., McDonald C., Mitjans M., Mowry B.J., Murphy K.C., Murray R.M., O'Neill F.A., Oh S.-Y., Palotie A., Pantelis C., Pulver A.E., Petryshen T.L., Quested D.J., Riley B., Sanders A.R., Schall U., Schwab S.G., Scott R.J., Sham P.C., Silverman J.M., Sim K., Steixner A.A., Tooney P.A., van Os J., Vawter M.P., Walsh D., Weiser M., Wildenauer D.B., Williams N.M., Wormley B.K., Zhang F., Androutsos C., Arnold P.D., Barr C.L., Barta C., Bey K., Bienvenu O.J., Black D.W., Brown L.W., Budman C., Cath D., Cheon K.-A., Ciullo V., Coffey B.J., Cusi D., Davis L.K., Denys D., Depienne C., Dietrich A., Eapen V., Falkai P., Fernandez T.V., Garcia-Delgar B., Geller D.A., Gilbert D.L., Grados M.A., Greenberg E., Grunblatt E., Hagstrom J., Hanna G.L., Hartmann A., Hedderly T., Heiman G.A., Heyman I., Hong H.J., Huang A., Huyser C., Ibanez-Gomez L., Khramtsova E.A., Kim Y.K., Kim Y.-S., King R.A., Koh Y.-J., Konstantinidis A., Kook S., Kuperman S., Leventhal B.L., Lochner C., Ludolph A.G., Madruga-Garrido M., Malaty I., Maras A., McCracken J.T., Meijer I.A., Mir P., Morer A., Muller-Vahl K.R., Munchau A., Murphy T.L., Naarden A., Nagy P., Nestadt G., Nestadt P.S., Nicolini H., Nurmi E.L., Okun M.S., Paschou P., Piras F., Pittenger C., Plessen K.J., Richter M.A., Rizzo R., Robertson M., Roessner V., Ruhrmann S., Samuels J.F., Sandor P., Schlogelhofer M., Shin E.-Y., Singer H., Song D.-H., Song J., Spalletta G., Stein D.J., Stewart S.E., Storch E.A., Stranger B., Stuhrmann M., Tarnok Z., Tischfield J.A., Tubing J., Visscher F., Vulink N., Wagner M., Walitza S., Wanderer S., Woods M., Worbe Y., Zai G., Zinner S.H., Sullivan P.F., Franke B., Daly M.J., Bulik C.M., McIntosh A.M., O'Donovan M.C., Zheutlin A., Andreassen O.A., Borglum A.D., Breen G., Edenberg H.J., Fanous A.H., Faraone S.V., Gelernter J., Mathews C.A., Mattheisen M., Mitchell K.S., Neale M.C., Nurnberger J.I., Ripke S., Santangelo S.L., Scharf J.M., Stein M.B., Thornton L.M., Walters J.T.R., Wray N.R., Geschwind D.H., Neale B.M., Kendler K.S., Smoller J.W., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Epidemiology and Data Science, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, APH - Digital Health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Kas lab, Adult Psychiatry, Child Psychiatry, ANS - Complex Trait Genetics, Aarno Palotie / Principal Investigator, Jaakko Kaprio / Principal Investigator, Centre of Excellence in Complex Disease Genetics, Genetic Epidemiology, Department of Public Health, University Management, Anna Keski-Rahkonen / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, HUS Psychiatry, Institute for Molecular Medicine Finland, Research Programs Unit, Genomics of Neurological and Neuropsychiatric Disorders, Biological Psychology, Complex Trait Genetics, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Lee, P. H., Anttila, V., Won, H., Feng, Y. -C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., Wang, M. M. -J., Yu, D., Stahl, E. A., Walters, R. K., Anney, R. J. L., Duncan, L. E., Ge, T., Adolfsson, R., Banaschewski, T., Belangero, S., Cook, E. H., Coppola, G., Derks, E. M., Hoekstra, P. J., Kaprio, J., Keski-Rahkonen, A., Kirov, G., Kranzler, H. R., Luykx, J. J., Rohde, L. A., Zai, C. C., Agerbo, E., Arranz, M. J., Asherson, P., Baekvad-Hansen, M., Baldursson, G., Bellgrove, M., Belliveau, R. A., Buitelaar, J., Burton, C. L., Bybjerg-Grauholm, J., Casas, M., Cerrato, F., Chambert, K., Churchhouse, C., Cormand, B., Crosbie, J., Dalsgaard, S., Demontis, D., Doyle, A. E., Dumont, A., Elia, J., Grove, J., Gudmundsson, O. O., Haavik, J., Hakonarson, H., Hansen, C. S., Hartman, C. A., Hawi, Z., Hervas, A., Hougaard, D. M., Howrigan, D. P., Huang, H., Kuntsi, J., Langley, K., Lesch, K. -P., Leung, P. W. L., Loo, S. K., Martin, J., Martin, A. R., Mcgough, J. J., Medland, S. E., Moran, J. L., Mors, O., Mortensen, P. B., Oades, R. D., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Peters, T., Poterba, T., Poulsen, J. B., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Rothenberger, A., Rovira, P., Sanchez-Mora, C., Satterstrom, F. K., Schachar, R., Artigas, M. S., Steinberg, S., Stefansson, H., Turley, P., Walters, G. B., Werge, T., Zayats, T., Arking, D. E., Bettella, F., Buxbaum, J. D., Christensen, J. H., Collins, R. L., Coon, H., De Rubeis, S., Delorme, R., Grice, D. E., Hansen, T. F., Holmans, P. A., Hope, S., Hultman, C. M., Klei, L., Ladd-Acosta, C., Magnusson, P., Naerland, T., Nyegaard, M., Pinto, D., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Roeder, K., Rouleau, G. A., Saemundsen, E., Sanders, S. J., Sandin, S., St Pourcain, B., Stefansson, K., Sutcliffe, J. S., Talkowski, M. E., Weiss, L. A., Willsey, A. J., Agartz, I., Akil, H., Albani, D., Alda, M., Als, T. 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B., Brandt, H., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Courtet, P., Crawford, S., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Docampo, E., Egberts, K., Ehrlich, S., Espeseth, T., Fernandez-Aranda, F., Fichter, M. M., Foretova, L., Forzan, M., Gambaro, G., Giegling, I., Gonidakis, F., Gorwood, P., Mayora, M. G., Guo, Y., Halmi, K. A., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Imgart, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Julia, A., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kaye, W. H., Kennedy, M. A., Kim, Y. -R., Klareskog, L., Klump, K. L., Knudsen, G. P. S., Landen, M., Le Hellard, S., Levitan, R. D., Li, D., Lichtenstein, P., Maj, M., Marsal, S., Mcdevitt, S., Mitchell, J., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., O'Toole, J. 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A., Schaefer, C., Schulte, E. C., Shi, J., Smith, D. J., Thomson, P. A., Tiemeier, H., Uher, R., van der Auwera, S., Weissman, M. M., Alexander, M., Begemann, M., Bramon, E., Buccola, N. G., Cairns, M. J., Campion, D., Carr, V. J., Cloninger, C. R., Cohen, D., Collier, D. A., Corvin, A., Delisi, L. E., Donohoe, G., Dudbridge, F., Duan, J., Freedman, R., Gejman, P. V., Golimbet, V., Godard, S., Ehrenreich, H., Hartmann, A. M., Henskens, F. A., Ikeda, M., Iwata, N., Jablensky, A. V., Joa, I., Jonsson, E. G., Kelly, B. J., Knight, J., Konte, B., Laurent-Levinson, C., Lee, J., Lencz, T., Lerer, B., Loughland, C. M., Malhotra, A. K., Mallet, J., Mcdonald, C., Mitjans, M., Mowry, B. J., Murphy, K. C., Murray, R. M., O'Neill, F. A., Oh, S. -Y., Palotie, A., Pantelis, C., Pulver, A. E., Petryshen, T. L., Quested, D. J., Riley, B., Sanders, A. R., Schall, U., Schwab, S. G., Scott, R. J., Sham, P. C., Silverman, J. M., Sim, K., Steixner, A. A., Tooney, P. A., van Os, J., Vawter, M. P., Walsh, D., Weiser, M., Wildenauer, D. B., Williams, N. M., Wormley, B. K., Zhang, F., Androutsos, C., Arnold, P. D., Barr, C. L., Barta, C., Bey, K., Bienvenu, O. J., Black, D. W., Brown, L. W., Budman, C., Cath, D., Cheon, K. -A., Ciullo, V., Coffey, B. J., Cusi, D., Davis, L. K., Denys, D., Depienne, C., Dietrich, A., Eapen, V., Falkai, P., Fernandez, T. V., Garcia-Delgar, B., Geller, D. A., Gilbert, D. L., Grados, M. A., Greenberg, E., Grunblatt, E., Hagstrom, J., Hanna, G. L., Hartmann, A., Hedderly, T., Heiman, G. A., Heyman, I., Hong, H. J., Huang, A., Huyser, C., Ibanez-Gomez, L., Khramtsova, E. A., Kim, Y. K., Kim, Y. -S., King, R. A., Koh, Y. -J., Konstantinidis, A., Kook, S., Kuperman, S., Leventhal, B. L., Lochner, C., Ludolph, A. G., Madruga-Garrido, M., Malaty, I., Maras, A., Mccracken, J. T., Meijer, I. A., Mir, P., Morer, A., Muller-Vahl, K. R., Munchau, A., Murphy, T. L., Naarden, A., Nagy, P., Nestadt, G., Nestadt, P. S., Nicolini, H., Nurmi, E. L., Okun, M. S., Paschou, P., Piras, F., Pittenger, C., Plessen, K. J., Richter, M. A., Rizzo, R., Robertson, M., Roessner, V., Ruhrmann, S., Samuels, J. F., Sandor, P., Schlogelhofer, M., Shin, E. -Y., Singer, H., Song, D. -H., Song, J., Spalletta, G., Stein, D. J., Stewart, S. E., Storch, E. A., Stranger, B., Stuhrmann, M., Tarnok, Z., Tischfield, J. A., Tubing, J., Visscher, F., Vulink, N., Wagner, M., Walitza, S., Wanderer, S., Woods, M., Worbe, Y., Zai, G., Zinner, S. H., Sullivan, P. F., Franke, B., Daly, M. J., Bulik, C. M., Mcintosh, A. M., O'Donovan, M. C., Zheutlin, A., Andreassen, O. A., Borglum, A. D., Breen, G., Edenberg, H. J., Fanous, A. H., Faraone, S. V., Gelernter, J., Mathews, C. A., Mattheisen, M., Mitchell, K. S., Neale, M. C., Nurnberger, J. I., Ripke, S., Santangelo, S. L., Scharf, J. M., Stein, M. B., Thornton, L. M., Walters, J. T. R., Wray, N. R., Geschwind, D. H., Neale, B. M., Kendler, K. S., and Smoller, J. W.

Subjects
Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019

38. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Evelise Riber, Suma Jacob, Isabela Maya Wahys Silva, Edwin H. Cook, Jennifer Reichert, Merete Nordentoft, Jiebiao Wang, Kaitlin E. Samocha, John A. Sweeney, Elaine Cristina Zachi, Brooke Sheppard, Yunin Ludena, Maureen Mulhern, Lambertus Klei, Christina M. Hultman, Branko Aleksic, Paige M. Siper, Nell Maltman, Fátima Lopes, Jesslyn Jamison, Astanand Jugessur, Timothy W. Yu, F. Kyle Satterstrom, Tarjinder Singh, Bernie Devlin, Per Magnus, Mara Parellada, Louise Gallagher, Christine Stevens, Susan L. Santangelo, David J. Cutler, Shan Dong, Margaret A. Pericak-Vance, Norio Ozaki, Camilla Stoltenberg, Matthew W. State, Emma Wilkinson, Lauren A. Weiss, Michael L. Cuccaro, Stephen Sanders, Aparna Bhaduri, Brian H.Y. Chung, Maria del Pilar Trelles, Ezra Susser, Somer L. Bishop, Catalina Betancur, Donna M. Werling, Sabine Schlitt, Diego Lopergolo, Abraham Reichenberg, Judith Miller, Gabriela Soares, Karoline Teufel, David M. Hougaard, Enrico Domenici, Thomas Werge, Terho Lehtimäki, Sherif Gerges, Audrey Thurm, Emily Hansen-Kiss, Christopher T. Walsh, Michael Gill, Maria Rita Passos-Bueno, Aurora Currò, Utku Norman, Nancy J. Minshew, Harrison Brand, Elisa Giorgio, A. Ercument Cicek, Elaine T. Lim, Joseph D. Buxbaum, Chiara Fallerini, Caroline Dias, Miia Kaartinen, Gal Meiri, Rachel Nguyen, Isaac N. Pessah, J. Jay Gargus, Ryan N. Doan, Minshi Peng, Matthew W. Mosconi, Elizabeth E. Guerrero, Michael E. Talkowski, Iuliana Ionita-Laza, Carla Lintas, Gerry Schellenberg, Alessandra Renieri, Marcus C.Y. Chan, Stephen J. Guter, Danielle Halpern, Javier González-Peñas, Flora Tassone, So Lun Lee, Elise B. Robinson, Alfredo Brusco, Danielle de Paula Moreira, Bernardo Dalla Bernardina, Benjamin M. Neale, Gun Peggy Knudsen, Behrang Mahjani, Peter Szatmari, Elisabetta Trabetti, Lauren M. Schmitt, Kaija Puura, Mykyta Artomov, Rebecca J. Schmidt, Michael S. Breen, Mark J. Daly, Joon Yong An, Dara S. Manoach, Grace Schwartz, Hilary Coon, Christine M. Freitag, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Montserrat Fernández-Prieto, Stephen W. Scherer, Anders D. Børglum, Jack A. Kosmicki, W. Ian Lipkin, Mullin H.C. Yu, Michael E. Zwick, Irva Hertz-Picciotto, Kathryn Roeder, Moyra Smith, Gail E. Herman, James S. Sutcliffe, Xinyi Xu, A. Jeremy Willsey, Alexander Kolevzon, Itaru Kushima, Menachem Fromer, Jakob Grove, Patrícia Maciel, Preben Bo Mortensen, Xin He, Aarno Palotie, Silvia De Rubeis, Idan Menashe, Jonas Bybjerg-Grauholm, Pål Surén, Antonio M. Persico, Ole Mors, Sven Sandin, Lara Tang, Eric M. Morrow, Pierandrea Muglia, Angel Carracedo, Ryan Yuen, and Giovanni Battista Ferrero

Subjects
False discovery rate, Regulation of gene expression, Genetics, 0303 health sciences, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Published
2019

39. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author

Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Autism, Neurodevelopment, Gene Expression, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, 2.1 Biological and endogenous factors, Pair 10, Copy-number variation, Aetiology, Autism spectrum disorder, Genetics, Adaptor Proteins, Forkhead Transcription Factors, Serious Mental Illness, 3. Good health, Mental Health, Psychiatry and Mental Health, Meta-analysis, Female, Biotechnology, Human, Autismo, Genetic correlation, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Gene-set analysi, Genomics, Locus (genetics), FOXP1, Biology, Chromosomes, Heritability, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Developmental Neuroscience, REVEALS, mental disorders, LINKAGE, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Meta-analysi, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, COPY NUMBER VARIATION, Genetic association, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, Research, Human Genome, Signal Transducing, Neurosciences, Membrane Proteins, medicine.disease, RISK LOCI, R1, Brain Disorders, Repressor Proteins, 030104 developmental biology, Genetic Loci, Case-Control Studies, Perturbações do Desenvolvimento Infantil e Saúde Mental, Schizophrenia, Carrier Proteins, Gene-set analysis, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract

Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)

Published
2017

40. 5HT2Areceptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice

Author

Edwin H. Cook, Elaine Rivera, John A. Sweeney, Michael E. Ragozzino, and Dionisio A. Amodeo

Subjects
0301 basic medicine, 5-HT2A receptor, Perseveration, Cognitive flexibility, Antagonist, Striatum, medicine.disease, 03 medical and health sciences, Behavioral Neuroscience, 030104 developmental biology, 0302 clinical medicine, Neurology, Genetics, medicine, Autism, Orbitofrontal cortex, medicine.symptom, Receptor, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT2A receptor activity is altered in autism, while recent work indicates that systemic 5HT2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors.

Published
2016

41. Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

Author

Christopher M. Watson, Puja M. Shah, Stephen W. Davies, Zachary C. Dietch, Brandy L. Edwards, Robert G. Sawyer, Christopher A. Guidry, Charles H. Cook, Reza Askari, Rhett N. Willis, Therese M. Duane, Nicholas Namias, Patrick J. O'Neill, Lena M. Napolitano, and Daniel L. Dent

Subjects
Adult, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Wilcoxon signed-rank test, Surgical Infection Society Articles, 030106 microbiology, Logistic regression, Drug Administration Schedule, Body Mass Index, law.invention, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Anti-Infective Agents, Randomized controlled trial, Recurrence, law, Internal medicine, medicine, Humans, Obesity, Treatment Failure, 030212 general & internal medicine, Fisher's exact test, Aged, Peritoneal Infection, business.industry, Middle Aged, medicine.disease, Antimicrobial, Surgery, Infectious Diseases, symbols, Intraabdominal Infections, Regression Analysis, business, Body mass index
Abstract

Obesity and commonly associated comorbidities are known risk factors for the development of infections. However, the intensity and duration of antimicrobial treatment are rarely conditioned on body mass index (BMI). In particular, the influence of obesity on failure of antimicrobial treatment for intra-abdominal infection (IAI) remains unknown. We hypothesized that obesity is associated with recurrent infectious complications in patients treated for IAI.Five hundred eighteen patients randomized to treatment in the Surgical Infection Society Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated. Patients were stratified by obese (BMI ≥30) versus non-obese (BMI≥30) status. Descriptive comparisons were performed using Chi-square test, Fisher exact test, or Wilcoxon rank-sum tests as appropriate. Multivariable logistic regression using a priori selected variables was performed to assess the independent association between obesity and treatment failure in patients with IAI.Overall, 198 (38.3%) of patients were obese (BMI ≥30) versus 319 (61.7%) who were non-obese. Mean antibiotic d and total hospital d were similar between both groups. Unadjusted outcomes of surgical site infection (9.1% vs. 6.9%, p = 0.36), recurrent intra-abdominal infection (16.2% vs. 13.8, p = 0.46), death (1.0% vs. 0.9%, p = 1.0), and a composite of all complications (25.3% vs. 19.8%, p = 0.14) were also similar between both groups. After controlling for appropriate demographics, comorbidities, severity of illness, treatment group, and duration of antimicrobial therapy, obesity was not independently associated with treatment failure (c-statistic: 0.64).Obesity is not associated with antimicrobial treatment failure among patients with IAI. These results suggest that obesity may not independently influence the need for longer duration of antimicrobial therapy in treatment of IAI versus non-obese patients.

Published
2016

42. Patients with Complicated Intra-Abdominal Infection Presenting with Sepsis Do Not Require Longer Duration of Antimicrobial Therapy

Author

Casey J. Allen, Heather L. Evans, Reza Askari, Christine S. Cocanour, Pamela A. Lipsett, Nicholas Namias, John E. Mazuski, Patrick J. O'Neill, Charles H. Cook, Rishi Rattan, Therese M. Duane, Robert G. Sawyer, Ori D. Rotstein, Kaysie L. Banton, Preston R. Miller, Joseph Cuschieri, E. Patchen Dellinger, Raul Coimbra, and Jeffrey A. Claridge

Subjects
medicine.medical_specialty, Ileus, medicine.drug_class, business.industry, Antibiotics, 030208 emergency & critical care medicine, medicine.disease, Surgery, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Interquartile range, Internal medicine, medicine, 030212 general & internal medicine, Leukocytosis, medicine.symptom, Prospective cohort study, business, Peritoneal Infection
Abstract

Background A recent prospective, multicenter, randomized controlled trial found that 4 days of antibiotics after source control of complicated intra-abdominal infections resulted in similar outcomes when compared with longer duration. We hypothesized that the subset of patients presenting with sepsis have similar outcomes when treated with the shorter course of antibiotics. Study Design Patients from the STOP-IT (Study to Optimize Peritoneal Infection Therapy) trial database meeting criteria for sepsis (ie, temperature 38°C and a WBC count 3 or >12,000 cells/mm 3 ) were analyzed. Patients had been randomized to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 calendar days of therapy (n = 45), or to receive a fixed short-course of antibiotics for 4 ± 1 calendar days (n = 67). Outcomes included incidence of and time to surgical site infection, recurrent intra-abdominal infection, Clostridium difficile infection, and extra-abdominal infections, as well as hospital days and mortality. Results One hundred and twelve of the 588 patients in the STOP-IT database met criteria for sepsis and were adherent to the protocol. With regard to short- vs long-course therapy, surgical site infection (11.9% vs 8.9%; p = 0.759), recurrent intra-abdominal infection (11.9% vs 13.3%; p = 1.00), extra-abdominal infection (11.9% vs 8.9%; p = 0.759), hospital days (7.4 ± 5.5 days vs 9.0 ± 7.5 days; p = 0.188), days to recurrent intra-abdominal infection (12.5 ± 6.6 days vs 18.0 ± 8.1 days; p = 0.185), days to extra-abdominal infection (12.6 ± 5.8 days vs 17.3 ± 3.9 days; p = 0.194), and mortality (1.5% vs 0%; p = 1.00) were similar. There were no cases of C difficile infection. Days to surgical site infection (6.9 ± 3.5 days vs 21.3 ± 6.1 days; p Conclusions There was no difference in outcomes between short and long-course antimicrobial therapy in patients with complicated intra-abdominal infection presenting with sepsis. Our findings suggest that the presence of systemic illness does not mandate a longer antimicrobial course if source control of complicated intra-abdominal infection is obtained.

Published
2016

43. Broncholaveolar lavage to detect cytomegalovirus infection, latency, and reactivation in immune competent hosts

Author

Michael Gutknecht, Sara Byrd, Varun Dwivedi, Charles H. Cook, Marion Griessl, Sara A. Mansfield, and Joanne Trgovcich

Subjects
0301 basic medicine, Virus quantification, medicine.diagnostic_test, Congenital cytomegalovirus infection, Biology, medicine.disease, Virology, Sepsis, 03 medical and health sciences, 030104 developmental biology, Infectious Diseases, Immune system, Bronchoalveolar lavage, Viral replication, Virus latency, Immunology, medicine, Viral load
Abstract

Roughly 1/3rd of immune competent patients will reactivate latent cytomegalovirus (CMV) during critical illness. There are no standard methods to detect reactivation, and some investigators have postulated that presence of DNA in BAL fluid is indicative of viral replication. To test this hypothesis, we used a murine model that allows inclusion of matched healthy controls which is not possible in human studies. BALB/c mice infected with Smith-murine CMV or PBS (mock) had BAL evaluated 7, 14, or 21 days after acute infections, during latency, or during bacterial sepsis. Plaque assay, PCR, and rtPCR were performed on BALs and concomitantly obtained lung tissue. BAL cellular compositions, including tetramer evaluation of CMV-specific T cells were evaluated by flow cytometry. CMV DNA were detected in BAL at all time-points during acute infection, becoming undetectable in all mice during latency, then were detected again during bacterial sepsis, peaking 3 weeks after onset. mCMV specific T-cells were most numerous in BAL after acute viral infections, decreasing to low levels during latency, then fluctuating during bacterial sepsis. Specifically, mCMV-specific T-cells contracted at sepsis onset, expanding 2-4 weeks post-sepsis, presumably in response to increased viral loads at that time point. Altogether, our results support the use of BAL PCR for the diagnosis of CMV replication in immune competent hosts. Additionally, we demonstrate dynamic changes in CMV-specific T cells that occur in BAL during CMV infection and during sepsis induced viral reactivation. J. Med. Virol. 88:1408-1416, 2016. © 2016 Wiley Periodicals, Inc.

Published
2016

44. Confirmation of the Factor Structure and Measurement Invariance of the Children's Scale of Hostility and Aggression: Reactive/Proactive in Clinic-Referred Children With and Without Autism Spectrum Disorder

Author

Janet E. Lainhart, Micah O. Mazurek, Michael G. Aman, Eric Butter, Mary Beth Dewitt, Edwin H. Cook, Aaron J. Kaat, and Cristan Farmer

Subjects
Adult, Male, Adolescent, Psychometrics, Autism Spectrum Disorder, Developmental Disabilities, 050109 social psychology, CBCL, Hostility, Developmental psychology, Young Adult, medicine, Humans, 0501 psychology and cognitive sciences, Pharmacology (medical), Measurement invariance, Child, Child Behavior Checklist, Aggression, 05 social sciences, Reproducibility of Results, Construct validity, Original Articles, medicine.disease, Psychiatry and Mental health, Autism spectrum disorder, Pediatrics, Perinatology and Child Health, Female, medicine.symptom, Psychology, 050104 developmental & child psychology
Abstract

The measurement of aggression in its different forms (e.g., physical and verbal) and functions (e.g., impulsive and instrumental) is given little attention in subjects with developmental disabilities (DD). In this study, we confirm the factor structure of the Children's Scale for Hostility and Aggression: Reactive/Proactive (C-SHARP) and demonstrate measurement invariance (consistent performance across clinical groups) between clinic-referred groups with and without autism spectrum disorder (ASD). We also provide evidence of the construct validity of the C-SHARP.Caregivers provided C-SHARP, Child Behavior Checklist (CBCL), and Proactive/Reactive Rating Scale (PRRS) ratings for 644 children, adolescents, and young adults 2-21 years of age. Five types of measurement invariance were evaluated within a confirmatory factor analytic framework. Associations among the C-SHARP, CBCL, and PRRS were explored.The factor structure of the C-SHARP had a good fit to the data from both groups, and strict measurement invariance between ASD and non-ASD groups was demonstrated (i.e., equivalent structure, factor loadings, item intercepts and residuals, and latent variance/covariance between groups). The C-SHARP Problem Scale was more strongly associated with CBCL Externalizing than with CBCL Internalizing, supporting its construct validity. Subjects classified with the PRRS as both Reactive and Proactive had significantly higher C-SHARP Proactive Scores than those classified as Reactive only, who were rated significantly higher than those classified by the PRRS as Neither Reactive nor Proactive. A similar pattern was observed for the C-SHARP Reactive Score.This study provided evidence of the validity of the C-SHARP through confirmation of its factor structure and its relationship with more established scales. The demonstration of measurement invariance demonstrates that differences in C-SHARP factor scores were the result of differences in the construct rather than to error or unmeasured/nuisance variables. These data suggest that the C-SHARP is useful for quantifying subtypes of aggressive behavior in children, adolescents, and young adults with DD.

Published
2016

45. Predictors of dexmedetomidine-associated hypotension in critically ill patients

Author

Stanislaw P Stawicki, Danielle Blais, G. Morgan Jones, Claire V. Murphy, Pamela K Burcham, Charles H. Cook, and Anthony T Gerlach

Subjects
Mean arterial pressure, hypotension, Sedation, critically ill, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, law.invention, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, law, medicine, 030212 general & internal medicine, Dexmedetomidine, Univariate analysis, APACHE II, business.industry, Public Health, Environmental and Occupational Health, dexmedetomidine, medicine.disease, Intensive care unit, Analgosedation, Blood pressure, sedation, Anesthesia, Emergency Medicine, Original Article, medicine.symptom, business, medicine.drug
Abstract

Background: Dexmedetomidine is commonly used for sedation in the Intensive Care Unit (ICU), and its use may be associated with hypotension. We sought to determine predictors of dexmedetomidine-associated hypotension. Methods: Retrospective, single-center study of 283 ICU patients in four adults ICUs over a 12 month period. Univariate analyses were performed to determine factors associated with dexmedetomidine-related hypotension. Risk factors significant at the 0.20 level in the univariate analysis were considered for inclusion into a step-wise multiple logistical regression model. Results: Hypotension occurred in 121 (42.8%) patients with a median mean arterial pressure (MAP) nadir of 54 mmHg. Univariate analyses showed an association between hypotension and age (P = 0.03), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (P = 0.02), baseline MAP (

Published
2016

46. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Author

Shan Dong, Norio Ozaki, Ryan K. C. Yuen, David J. Cutler, Lauren A. Weiss, Catalina Betancur, Abraham Reichenberg, Hassen-Kiss E, Judith Miller, Brooke Sheppard, Yunin Ludena, Astanand Jugessur, Irva Hertz-Picciotto, Donna M. Werling, Aurora Currò, Isaac N. Pessah, Giovanni Battista Ferrero, Somer L. Bishop, Utku Norman, Nancy J. Minshew, Tarjinder Singh, Bernie Devlin, Michael E. Talkowski, Carla Lintas, Susan L. Santangelo, Miia Kaartinen, Gal Meiri, Camilla Stoltenberg, Stephen Sanders, Sherif Gerges, Michael L. Cuccaro, Ryan N. Doan, Suma Jacob, Matthew W. Mosconi, Lambertus Klei, Michael E. Zwick, Kathryn Roeder, Merete Nordentoft, Lauren M. Schmitt, John A. Sweeney, Elizabeth E. Guerrero, Kaija Puura, Alessandra Renieri, Elaine T. Lim, Maureen Mulhern, Danielle de Paula Moreira, Cicek Ae, Nell Maltman, Aparna Bhaduri, Mara Parellada, Sabine Schlitt, Diego Lopergolo, Gun Peggy Knudsen, Christina M. Hultman, Jesslyn Jamison, Rebecca J. Schmidt, So Lun Lee, Iuliana Ionita-Laza, Peter Szatmari, Gerry Schellenberg, Alfredo Brusco, Christine M. Freitag, Andreas G. Chiocchetti, Javier González-Peñas, Michael S. Breen, Jakob Grove, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Elise B. Robinson, Cathy A. Stevens, Gabriela Soares, Benjamin M. Neale, Edwin H. Cook, Jiebiao Wang, David M. Hougaard, Enrico Domenici, Gail E. Herman, Patrícia Maciel, Kaitlin E. Samocha, Preben Bo Mortensen, Stephen W. Scherer, Yu Mhc, Elaine Cristina Zachi, Menachem Fromer, Antonio M. Persico, Anders D. Børglum, Minshi Peng, Megan Smith, Elisabetta Trabetti, Rachel Nguyen, Fátima Lopes, James S. Sutcliffe, Trelles Mdp, Xinyi Xu, Emma Wilkinson, Joseph D. Buxbaum, Audrey Thurm, Chiara Fallerini, Jack A. Kosmicki, Michael Gill, Paige M. Siper, Timothy W. Yu, Grace Schwartz, Thomas Werge, Terho Lehtimäki, Itaru Kushima, Jay Gargus, Dalla Bernardina B, Hilary Coon, Maria Rita Passos-Bueno, Stephen J. Guter, Margaret A. Pericak-Vance, Matthew W. State, Per Magnus, Christopher A. Walsh, Evelise Riberi, Ezra Susser, Xin He, Aarno Palotie, Idan Menashe, Eric M. Morrow, Jonas Bybjerg-Grauholm, Pierandrea Muglia, Pål Surén, De Rubeis S, Angel Carracedo, Sven Sandin, Montse Fernández-Prieto, Lara Tang, Lipkin Wi, Ole Mors, Louise Gallagher, Montenegro M. de Souza E, Brian H.Y. Chung, Anney Rjl, Alexander Kolevzon, Dara S. Manoach, Daniel H. Geschwind, Silva Imw, Caroline Dias, Jeremy Willsey, Jennifer Reichert, Elisa Giorgio, Branko Aleksic, Flora Tassone, Satterstrom Fk, Senthil G, Karoline Teufel, Chan Mcy, Harrison Brand, Danielle Halpern, Behrang Mahjani, Mykyta Artomov, Mark J. Daly, Joon Yong An, and Lehner T

Subjects
Genetics, Regulation of gene expression, 0303 health sciences, medicine.medical_specialty, Neurogenetics, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Medical genetics, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Published
2018
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47. Phenotypic association of 15q11.2 CNVs of the region of breakpoints 1-2 (BP1-BP2) in a large cohort of samples referred for genetic diagnosis

Author

Ye Cao, Sau Wai Cheung, Justin Pham, Z. Zishuo Ou, Lori Hoffner, K. Naga Mohan, Urvashi Surti, Edwin H. Cook, and Arthur L. Beaudet

Subjects
0301 basic medicine, DNA Copy Number Variations, Developmental Disabilities, Context (language use), 030105 genetics & heredity, Biology, Cohort Studies, 03 medical and health sciences, Epilepsy, Chromosome Breakpoints, Intellectual Disability, Genetics, medicine, Humans, Autistic Disorder, Association (psychology), Genetics (clinical), Genetic testing, Chromosomes, Human, Pair 15, medicine.diagnostic_test, Breakpoint, medicine.disease, Phenotype, Penetrance, 030104 developmental biology, Autism
Abstract

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.

Published
2018

48. Advanced Modalities and Rescue Therapies for Severe Respiratory Failure

Author

Charles H. Cook and Charles S. Parsons

Subjects
Mechanical ventilation, medicine.medical_specialty, ARDS, Neuromuscular Blockade, Modalities, business.industry, medicine.medical_treatment, medicine.disease, Intensive care unit, law.invention, Airway pressure release ventilation, Prone position, Respiratory failure, law, medicine, Intensive care medicine, business
Abstract

This chapter focuses on frequently used adjuncts to traditional mechanical ventilation that are now available in the intensive care unit to manage severe respiratory failure and the acute respiratory distress syndrome (ARDS). Modalities discussed will include airway pressure release ventilation, high-frequency mechanical ventilation, prone positioning, neuromuscular blockade, inhaled selective pulmonary vasodilators nitric oxide and epoprostenol, and ECMO. These advanced modalities for severe respiratory failure will be described in some detail, but this is not intended as a definitive exploration of each topic. Where available, current data supporting each intervention is presented, but, importantly, definitive high-quality evidence is lacking for several of these modalities.

Published
2018

49. Psychiatrists, spirituality and religion

Author

Rob Poole, Christopher C. H. Cook, and Robert Higgo

Subjects
Psychiatry, Psychotherapist, Mental Disorders, Religion and Medicine, Special Interest Group, Mental illness, medicine.disease, 030227 psychiatry, law.invention, Religion, Clinical Practice, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, law, Adaptation, Psychological, Spirituality, medicine, CLARITY, Humans, 030212 general & internal medicine, Psychology
Abstract

SummaryThe consensus within psychiatry is that patients' religion/spirituality are legitimate topics in assessment and treatment. Religion/spirituality can help people cope with mental illness, but their use as therapeutic tools is controversial. Despite the publication of position statements by national and international psychiatric organisations, there is no clarity over therapeutic boundaries.Declaration of interestR.P. and R.H. are atheists. C.C.H.C. is an ordained Anglican and a past Chair of the Royal College of Psychiatrists Spirituality and Psychiatry Special Interest Group. He writes here in a personal capacity.

Published
2019

50. Separating Family-Level and Direct Exposure Effects of Smoking During Pregnancy on Offspring Externalizing Symptoms: Bridging the Behavior Genetic and Behavior Teratologic Divide

Author

Suena H. Massey, Lauren S. Wakschlag, Edwin H. Cook, T. Caitlin O'Brien, Ryne Estabrook, James L. Burns, Caron A. C. Clark, Beth Makowski, Brian Mustanski, and Kimberly Andrews Espy

Subjects
Proband, Offspring, Child Behavior Disorders, Genetics, Behavioral, Article, Structural equation modeling, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Genetics, medicine, Humans, Family, 0501 psychology and cognitive sciences, Sibling, Child, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Teratology, Smoking, 05 social sciences, medicine.disease, Child development, Health psychology, Conduct disorder, Prenatal Exposure Delayed Effects, Female, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Maternal smoking during pregnancy (MSDP) has been robustly associated with externalizing problems and their developmental precursors in offspring in studies using behavioral teratologic designs (Wakschlag et al., Am J Public Health 92(6):966-974, 2002; Espy et al., Dev Psychol 47(1):153-169, 2011). In contrast, the use of behavior genetic approaches has shown that the effects commonly attributed to MSDP can be explained by family-level variables (D'Onofrio et al., Dev Psychopathol 20(01):139-164, 2008). Reconciling these conflicting findings requires integration of these study designs. We utilize longitudinal data on a preschool proband and his/her sibling from the Midwest Infant Development Study-Preschool (MIDS-P) to test for teratologic and family level effects of MSDP. We find considerable variation in prenatal smoking patterns both within and across pregnancies within families, indicating that binary smoking measures are not sufficiently capturing exposure. Structural equation models indicate that both conduct disorder and oppositional defiant disorder symptoms showed unique effects of MSDP over and above family level effects. Blending high quality exposure measurement with a within-family design suggests that it is premature to foreclose the possibility of a teratologic effect of MSDP on externalizing problems. Implications and recommendations for future studies are discussed.

Published
2015

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