Complement genes contribute sex-biased vulnerability in diverse disorders.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Extent to which array genotyping and imputation with large reference panels approximate deep whole-genome sequencing.

Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array genotyping followed by genotype imputation can approximate WGS in studies of individuals of African, Hispanic/Latino, and European ancestry in the US and of Finnish ancestry in Finland (a population isolate). For each study, we performed genotype imputation by using the genetic variants present on the Illumina Core, OmniExpress, MEGA, and Omni 2.5M arrays with the 1000G, HRC, and TOPMed imputation reference panels. Using the Omni 2.5M array and the TOPMed panel, ≥90% of bi-allelic single-nucleotide variants (SNVs) are well imputed (r2 > 0.8) down to minor-allele frequencies (MAFs) of 0.14% in African, 0.11% in Hispanic/Latino, 0.35% in European, and 0.85% in Finnish ancestries. There was little difference in TOPMed-based imputation quality among the arrays with >700k variants. Individual-level imputation quality varied widely between and within the three US studies. Imputation quality also varied across genomic regions, producing regions where even common (MAF > 5%) variants were consistently not well imputed across ancestries. The extent to which array genotyping and imputation can approximate WGS therefore depends on reference panel, genotype array, sample ancestry, and genomic location. Imputation quality by variant or genomic region can be queried with our new tool, RsqBrowser, now deployed on the Michigan Imputation Server.

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). CONCLUSIONS: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology.

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia.

Construct validity, sensitivity and specificity of the USCD Performance-based Skill Assessment 2 in a mixed Portuguese sample.

Assessment batteries of functional capacity provide robust indicators of real-world functioning in major psychiatric illnesses and important information on an individual's ability to live autonomously and pursue relevant psychosocial goals. OBJECTIVES: This study explores the psychometric properties of the Portuguese USCD Performance-based Skill Assessment 2 (UPSA-2-PT) in a mixed sample of Portuguese participants. METHOD: A sample of 110 participants, 37 patients diagnosed with schizophrenia, 27 first-degree relatives of patients and 46 controls were administered the UPSA-2-PT and self-report questionnaires. The UPSA-2-PT reliability was assessed through inter-rater reliability and internal consistency, convergent validity with community integration and a receiver operating curve analysis was conducted to establish scores' sensitivity and specificity. Youden's Index was used to determine an optimal UPSA-2-PT cutoff score. RESULTS: Findings show an excellent inter-rater reliability, good internal consistency and construct validity, consistent with previous studies in Western countries. The UPSA-2-PT also showed a good discriminant ability between patients and controls, and an overall percentage of correct classification of 86.7% based on the 81.59 cutoff. DISCUSSION: Findings are congruous with previous versions, strengthening the body of evidence supporting the construct validity and providing a useful tool for research and clinical purposes to practitioners.

A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

The Role of Regional Conferences in Research Resident Career Development: The California Psychiatry Research Resident Retreat.

OBJECTIVE: For psychiatry research resident career development, there is a recognized need for improved cross-institutional mentoring and networking opportunities. One method to address this need is via regional conferences, open to current and recently graduated research residents and their mentors. With this in mind, we developed the biennial California Psychiatry Research Resident Retreat (CPRRR) and collected feedback from participants to 1) Assess resident satisfaction, 2) Determine the utility of the retreat as a networking and mentorship tool, and 3) Identify areas for improvement. METHODS: We gathered survey data from resident attendees at the two first CPRRRs. We analyzed the data to look for trends in satisfaction as well as areas that need improvement. RESULTS: Thirty-two residents from five California training programs attended the CPRRR in 2013 while 33 attended from six programs in 2015. The residents were from all years of training, but concentrated in their second and third years. Approximately 41% and 49% of the attendees were female and 53% and 39% had an MD/PhD in 2013 and 2015, respectively. Twenty-four and 32 residents provided anonymous feedback in 2013 and 2015, respectively. Mean feedback scores were very high (> 4/5) for overall satisfaction, peer- and faculty-networking, the keynote speaker and the flash talks for both years. Mean feedback scores for the ethics debates and mentoring sessions were somewhat lower (≤ 4/5), however, both showed significant improvement from 2013 to 2015. CONCLUSION: The CPRRRs appear to be an effective mechanism for providing psychiatry research residents with a meaningful cross-institutional opportunity for networking and mentorship. Feedback-driven changes to the CPRRRs improved participant satisfaction for several components of the conference. Future efforts will be aimed at broadening mentorship and networking opportunities, optimizing teaching approaches for research ethics, and considering different feedback-gathering approaches to allow for improved longitudinal follow-up and subgroup analysis.

A Randomized Controlled Trial of Team-Based Learning Versus Lectures with Break-Out Groups on Knowledge Retention.

OBJECTIVE: This goal of this study was to evaluate the efficacy of team-based learning (TBL) on knowledge retention compared to traditional lectures with small break-out group discussion (teaching as usual (TAU)) using a randomized controlled trial. METHODS: This randomized controlled trial was conducted during a daylong conference for psychiatric educators on attention-deficit hyperactivity disorder and the research literacy topic of efficacy versus effectiveness trials. Learners (n = 115) were randomized with concealed allocation to either TBL or TAU. Knowledge was measured prior to the intervention, immediately afterward, and 2 months later via multiple-choice tests. Participants were necessarily unblinded. Data enterers, data analysts, and investigators were blinded to group assignment in data analysis. Per-protocol analyses of test scores were performed using change in knowledge from baseline. The primary endpoint was test scores at 2 months. RESULTS: At baseline, there were no statistically significant differences between groups in pre-test knowledge. At immediate post-test, both TBL and TAU groups showed improved knowledge scores compared with their baseline scores. The TBL group performed better statistically on the immediate post-test than the TAU group (Cohen's d = 0.73; p < 0.001), although the differences in knowledge scores were not educationally meaningful, averaging just one additional test question correct (out of 15). On the 2-month remote post-test, there were no group differences in knowledge retention among the 42 % of participants who returned the 2-month test. CONCLUSIONS: Both TBL and TAU learners acquired new knowledge at the end of the intervention and retained knowledge over 2 months. At the end of the intervention day and after 2 months, knowledge test scores were not meaningfully different between TBL and TAU completers. In conclusion, this study failed to demonstrate the superiority of TBL over TAU on the primary outcome of knowledge retention at 2 months post-intervention.

Substance use associated with short sleep duration in patients with schizophrenia or schizoaffective disorder.

STUDY OBJECTIVES: To examine the association between substance use and short sleep duration in individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). DESIGN: Cross-sectional, retrospective study. SETTING: Urban, suburban, and rural centers across the United States. PARTICIPANTS: 2,462 consented, adult individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). Participants included inpatients in acute or chronic care settings as well as outpatients and residents in community dwellings. MEASUREMENTS: Substance use was assessed with 10 questions adopted from well-validated measures (e.g., CAGE questionnaire) for alcohol, marijuana, and illicit drugs. Short sleep duration was defined as <6 hr of self-reported sleep per night. RESULTS: Close to 100% of our sample used nicotine while 83% used substances other than nicotine. More importantly, there was a significant association between substance use and short sleep duration. Interestingly, this association was strongest among African-Americans with schizophrenia or SADD. CONCLUSIONS: Because psychiatric medications often target chemical receptors involved with both sleep and substance use, understanding the association between short sleep duration and substance use in individuals with schizophrenia and SADD is important. Given that the majority of premature deaths in individuals with psychotic illness are due to medical conditions associated with modifiable risk factors, prospective studies designed to examine the effect of short sleep duration on behaviors like substance use should be undertaken. Finally, analyzing genetic and environmental data in a future study might help illuminate the strong association found between short sleep duration and substance use in African-Americans with schizophrenia and SADD. © 2015 Wiley Periodicals, Inc.

Nicotine dependence and psychosis in Bipolar disorder and Schizoaffective disorder, Bipolar type.

Patients with Bipolar disorder smoke more than the general population. Smoking negatively impacts mortality and clinical course in Bipolar disorder patients. Prior studies have shown contradictory results regarding the impact of psychosis on smoking behavior in Bipolar disorder. We analyzed a large sample of Bipolar disorder and Schizoaffective disorder, Bipolar Type patients and predicted those with a history of psychosis would be more likely to be nicotine dependent. Data from subjects and controls were collected from the Genomic Psychiatry Cohort (GPC). Subjects were diagnosed with Bipolar disorder without psychosis (N = 610), Bipolar disorder with psychosis (N = 1544). Participants were classified with or without nicotine dependence. Diagnostic groups were compared to controls (N = 10065) using logistic regression. Among smokers (N = 6157), those with Bipolar disorder had an increased risk of nicotine dependence (OR = 2.5; P < 0.0001). Patients with Bipolar disorder with psychosis were more likely to be dependent than Bipolar disorder patients without psychosis (OR = 1.3; P = 0.03). Schizoaffective disorder, Bipolar Type patients had more risk of nicotine dependence when compared to Bipolar disorder patients with or without psychosis (OR = 1.2; P = 0.02). Bipolar disorder patients experiencing more severity of psychosis have more risk of nicotine dependence. © 2015 Wiley Periodicals, Inc.

Symptoms of psychosis in schizophrenia, schizoaffective disorder, and bipolar disorder: A comparison of African Americans and Caucasians in the Genomic Psychiatry Cohort.

Several studies have reported differences between African Americans and Caucasians in relative proportion of psychotic symptoms and disorders, but whether this reflects racial bias in the assessment of psychosis is unclear. The purpose of this study was to examine the distribution of psychotic symptoms and potential bias in symptoms assessed via semi-structured interview using a cohort of 3,389 African American and 5,692 Caucasian participants who were diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder. In this cohort, the diagnosis of schizophrenia was relatively more common, and the diagnosis of bipolar disorder and schizoaffective disorder-bipolar type was less relatively common, among African Americans than Caucasians. With regard to symptoms, relatively more African Americans than Caucasians endorsed hallucinations and delusions symptoms, and this pattern was striking among cases diagnosed with bipolar disorder and schizoaffective-bipolar disorder. In contrast, the relative endorsement of psychotic symptoms was more similar among cases diagnosed with schizophrenia and schizoaffective disorder-depressed type. Differential item function analysis revealed that African Americans with mild psychosis over-endorsed "hallucinations in any modality" and under-endorsed "widespread delusions" relative to Caucasians. Other symptoms did not show evidence of racial bias. Thus, racial bias in assessment of psychotic symptoms does not appear to explain differences in the proportion of symptoms between Caucasians and African Americans. Rather, this may reflect ascertainment bias, perhaps indicative of a disparity in access to services, or differential exposure to risk factors for psychosis by race. © 2015 Wiley Periodicals, Inc.

Paternal age effect: Replication in schizophrenia with intriguing dissociation between bipolar with and without psychosis.

Advanced paternal age (APA) is a risk factor for schizophrenia (Sz) and bipolar disorder (BP). Putative mechanisms include heritable genetic factors, de novo mutations, and epigenetic mechanisms. Few studies have explored phenotypic features associated with APA. The Genomic Psychiatry Cohort established a clinically characterized repository of genomic samples from subjects with a Sz-BP diagnosis or unaffected controls, 12,975 with parental age information. We estimated relative risk ratios for Sz, schizoaffective depressed and bipolar types (SA-D, SA-B), and BP with and without history of psychotic features (PF) relative to the control group, comparing each paternal age group to the reference group 20-24 years. All tests were two-sided with adjustment for multiple comparisons. Subjects with fathers age 45+ had significantly higher risk for all diagnoses except for BP w/o PF. APA also bore no significant relation to family psychiatric history. In conclusion, we replicated APA as a risk factor for Sz. To our knowledge, this is the first published report of APA in a BP sample stratified by psychosis history, extending this association only in BP w/PF. This suggests that phenotypic expression of the APA effect in Sz-BP spectrum is psychosis, per se, rather than other aspects of these complex disorders. The lack of a significant relationship between paternal age and familial disease patterns suggests that underlying mechanisms of the paternal age effect may involve a complex interaction of heritable and non-heritable factors. The authors discuss implications and testable hypotheses, starting with a focus on genetic mechanisms and endophenotypic expressions of dopaminergic function. © 2015 Wiley Periodicals, Inc.

Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

Journal club for faculty or residents: a model for lifelong learning and maintenance of certification.

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.

Assessing the impact of population stratification on genetic association studies.

Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.

What to learn and how to teach it: five years of pre-meetings for training directors in psychiatry.

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.

Teaching scholarly activity in psychiatric training: years 6 and 7.

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.

Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm.

BACKGROUND: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. METHODS: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N = 1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. RESULTS: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. CONCLUSIONS: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The genomic psychiatry cohort: partners in discovery.

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.