[Show abstract][Hide abstract] ABSTRACT: The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.
The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.
Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).
Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
Journal of the American Academy of Child and Adolescent Psychiatry 06/2014; 53(8):910-919. · 6.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obsessive-compulsive disorder (OCD) impacts family functioning as family members modify their personal and family routines, participate in rituals, and provide reassurance. These behaviors have been identified as family accommodation (FA), a phenomenon that, if ignored, may facilitate OCD symptoms and lead to poorer prognosis. Because FA has been recognized as a predictor of treatment outcome, we examined the prevalence of FA and identified patient and family socio-demographic and clinical variables associated with FA in an outpatient sample.
The study comprised 228 subjects, namely, 114 patients with OCD and 114 family members, assessed before the patients entered a 12-session cognitive-behavioral group therapy program. A multivariate linear regression model was used to control for confounding factors and to evaluate variables independently associated with FA. FA was evaluated using the Family Accommodation Scale for Obsessive-Compulsive Disorder - Interviewer Rated (FAS-IR).
FA was found to be highly prevalent among family members. Two patient factors positively associated with FA were OCD severity as measured by the Clinical Global Impressions Scale (CGI) and higher scores on the Obsessions dimension of the Obsessive-Compulsive Inventory - Revised (OCI-R). Family members' characteristics positively associated with FA were higher scores on the OCI-R hoarding subscale and being the patient's spouse.
Our findings suggest that the early identification of patients and family members who could benefit from interventions aimed at reducing FA could improve treatment outcomes.
Psychiatry and Clinical Neurosciences 02/2014; · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5–3.0 Mb) at 22q11.2—the reciprocal of the well-known, risk-inducing deletion of this locus—are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Sleep PostersSESSION TYPE: Original Investigation PosterPRESENTED ON: Wednesday, October 30, 2013 at 01:30 PM - 02:30 PMPURPOSE: Insomnia is highly prevalent amongst patients with mental illness and has been implicated as both a risk factor and marker of disease severity in various psychiatric diseases, including schizophrenia. Recent studies have delineated distinct subtypes of insomnia based on overall sleep duration, with the "short sleep duration" variant associated with increased risk of cardiovascular diseases such as hypertension, coronary heart disease and stroke in a community-based cohort. However, no previous study has examined this relationship in schizophrenic patients. We evaluated the association between short sleep duration insomnia and select cardiovascular diseases in schizophrenics.METHODS: A total of 2,152 participants enrolled in the multi-center Genomic Psychiatric Cohort (GPC) self-reported their baseline sleep duration and medical comorbidities. In participants with schizophrenia or schizoaffective-depressed disorder, 1417 had symptoms of insomnia (mean age 42.4 years, 62% male, 55% non-white). This group was further stratified into "short sleep duration" insomnia, defined as sleep time ≤ six hours per night (n = 316) and normal sleep duration insomnia, defined as sleep time seven to nine hours per night, (n=989). Participates who reported greater than nine hours of sleep (n=112) were not included here. Chi square analysis was performed.RESULTS: Of the 1417 patients with insomnia, those with short sleep duration insomnia self-reported significantly more coronary heart disease (n=44, OR 1.58; 95% CI 1.09-2.31; p <0.05), hypertension (n=127, OR 1.42; 95% CI 1.10-1.84; p < 0.05) and stroke (n=26, OR 2.54; 95% CI 1.54-4.33; p <0.05) when compared to those who self-reported a normal sleep duration.CONCLUSIONS: Schizophrenics who self-reported insomnia symptoms and short sleep duration may have increased incidence of cardiovascular diseases such as hypertension, coronary heart disease and stroke. Further study to examine the strength of the association and possible confounders is warranted.CLINICAL IMPLICATIONS: Short sleep duration insomnia may be a distinct and modifiable risk factor for cardiovascular diseases such as hypertension, coronary heart disease and stroke in schizophrenics.DISCLOSURE: The following authors have nothing to disclose: Terese Hammond, Joleen Aguon, Janet Sobell, Brooke Sklar, Michele PatoNo Product/Research Disclosure Information.
[Show abstract][Hide abstract] ABSTRACT: The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
[Show abstract][Hide abstract] ABSTRACT: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
[Show abstract][Hide abstract] ABSTRACT: Abstract The journal club offers a model for lifelong learning and maintenance of certification (MOC) for residents and faculty staff. First, it sharpens participants' critical appraisal skills by providing a space to discuss relevant medical literature. Second, it motivates participants to seek new medical literature on their own using technology. Our model sets forth a four-year journal club curriculum that could be used as one continuous curriculum or in bits and pieces. In the first year, the focus is teaching residents how to read an article. The second year focuses on what is of interests to the reader. The third year applies the resident's appraisal skills to assigned articles to test whether they can determine which have reliable and valid findings and which are flawed. In the fourth year residents are asked to distinguish whether articles are well researched and referenced. Our model also motivates participants to read articles in faculty journal clubs throughout their career. In most academic settings category 1 continuing medical education (CME) credits can be awarded so journal club can have the added benefit of satisfying maintenance of certification CME credits. From journal club both residents and faculty can learn what is new and learn to apply this new information in their practice. Finally, because technology creates an overabundance of relevant medical literature, participants using our model can develop strong critical appraisal skills and methods for organizing the information they find that make this information readily available for future use and retrieval.
International Review of Psychiatry 06/2013; 25(3):276-83. · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.
To identify SCZ susceptibility genes.
We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.
Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.
We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.
Case-control status for SCZ.
Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).
We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
Archives of General Psychiatry 06/2013; 70(6):573-81. · 13.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE To address nationally recognized needs for increased numbers of psychiatric clinician-scholars and physician-scientists, the American Association of Directors of Psychiatric Residency Training (AADPRT) has provided a series of full-day conferences of psychiatry residency training directors designed to increase their competence in evidence-based medicine, enhance their research literacy, and aid them in transmitting that knowledge to their programs. METHOD These conferences take place on the day before AADPRT's annual meeting. Each year's pre-meeting conference includes a series of morning plenary sessions covering new information pertaining to a contemporary clinical theme. RESULTS The clinical theme serves as a vehicle to teach evidence-based practice and research and neuroscience literacy. The theme is carried into the afternoon with a series of highly interactive small-group teaching sessions designed to consolidate knowledge and provide pragmatic teaching tools appropriate for residents. A detailed report of the first 5 years documented the excellent attendance, perceived satisfaction, and usefulness of the material. CONCLUSION This report highlights the evolution of the program from the first 5 years to Years 6 and 7, details how new pedagogic and funding challenges have been approached, discusses the strengths and weaknesses of the revised format, and describes plans for the future.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE A multi-year conference grant (R13) supported an annual pre-meeting that served as a forum for psychiatry residency training directors to learn about and develop educational programs in their residencies in the area of scholarly activity. METHODS The authors sought to measure the success of these programs through both a between-pre-meeting online survey and a hardcopy evaluation form collected at the close of each annual pre-meeting. All data collection methods were careful to preserve the anonymity of respondents. RESULTS Reaction to the conference was overwhelmingly positive, with the majority of participants finding the instruction highly useful and beneficial, as well as having great confidence in their retention of the material and ability to integrate it into their own curricula. CONCLUSION Attendees at the annual pre-meeting series dedicated to evidence-based medicine and research literacy techniques received well-regarded and highly useful knowledge, training, and educational tools. Incorporation of this knowledge and material into their curricula will likely have a lasting positive impact on their residents and home institutions.
[Show abstract][Hide abstract] ABSTRACT: This report describes one in a series of National Institute of Health (NIH) supported conferences aimed at enhancing the ability of leaders of psychiatry residency training to teach research literacy and produce both clinician-scholars and physician-scientists in their home programs. Most psychiatry training directors would not consider themselves research scholars or even well-schooled in evidence based practice. Yet they are the front line educators to prepare tomorrow's psychiatrists to keep up with, critically evaluate, and in some cases actually participate in the discovery of new and emerging psychiatric knowledge. This annual conference is meant to help psychiatry training directors become more enthusiastic, knowledgeable and pedagogically prepared to create research-friendly environments at their home institutions, so that more trainees will, in turn, become research literate, practice evidence-based psychiatry, and enter research fellowships and careers. The overall design of each year's meeting is a series of plenary sessions introducing participants to new information pertaining to the core theme of that year's meeting, integrated with highly interactive small group teaching sessions designed to consolidate knowledge and provide pragmatic teaching tools appropriate for residents at various levels of training. The theme of each meeting, selected to be a compelling and contemporary clinical problem, serves as a vehicle to capture training directors' attention while teaching relevant brain science, research literacy and effective pedagogy. This report describes the content and assessment of the 2011 annual pre-meeting, "Evidence-based Approaches to Suicide Risk Assessment and Prevention: Insights from the Neurosciences and Behavioral Sciences for use in Psychiatry Residency Training."
[Show abstract][Hide abstract] ABSTRACT: Recent family and genome-wide association studies strongly suggest shared genetic risk factors for schizophrenia (SZ) and bipolar disorder (BP). However, linkage studies have not been used to test for statistically significant genome-wide overlap between them. Forty-seven Portuguese families with sibpairs concordant for SZ, BP, or psychosis (PSY, which includes either SZ or psychotic BP) were genotyped for over 57,000 markers using the Affymetrix 50K Xba SNP array. NPL and Kong and Cox LOD scores were calculated in Merlin for all three phenotypes. Empirical significance was determined using 1,000 gene-dropping simulations. Significance of genome-wide genetic overlap between SZ and BP was determined by the number of simulated BP scans having the same number of loci jointly linked with the real SZ scan, and vice versa. For all three phenotypes, a number of regions previously linked in this sample remained so. For BP, chromosome 1p36 achieved significance (11.54-15.71 MB, LOD = 3.51), whereas it was not even suggestively linked at lower marker densities, as did chromosome 11q14.1 (89.32-90.15 MB, NPL = 4.15). Four chromosomes had loci at which both SZ and BP had NPL ≥ 1.98, which was more than would be expected by chance (empirical P = 0.01 using simulated SZ scans; 0.07 using simulated BP scans), although they did not necessarily meet criteria for suggestive linkage individually. These results suggest that high-density marker maps may provide greater power and precision in linkage studies than lower density maps. They also further support the hypothesis that SZ and BP share at least some risk alleles.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2012; 159B(4):383-91. · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a clinically important neuropsychiatric developmental disorder that affects children, adolescents, and adults. The disorder is characterized by core symptoms of inattention, hyperactivity, distractibility, impulsivity, and impaired executive functioning. It is estimated that 2% to 5% of the adult population in the United States has ADHD. Adults with ADHD are at an increased risk for experiencing comorbid psychiatric disorders, including mood disorders, anxiety disorders, and substance use disorders. The authors provide a brief clinical overview of ADHD and the treatment of adults with this disorder.
The Journal of the American Osteopathic Association 11/2011; 111(11):610-4.
[Show abstract][Hide abstract] ABSTRACT: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).