Digital Point Solutions for Extending Contact Tracing Capacity.

BACKGROUND: Initial COVID-19 surges in the United States created a need for technology to supplement human resources to increase efficiency and efficacy. METHODS: Resolve to Save Lives worked with jurisdictions to co-design four technology solutions-Epi Viaduct data pipeline, Epi Contacts contact elicitation webform, Epi Locator contact information search plugin, and Epi Viewpoint case management system (CMS)-to expand the capacity of case investigation and contact tracing (CI/CT) teams. We assessed impact on reducing CI/CT time intervals for COVID-19 using product data and user feedback. RESULTS: Epi Viaduct accelerated the transfer of approximately 7,400,000 records from an electronic laboratory reporting system in a single jurisdiction to the respective CMS from more than 2.5 hours to less than 1 minute and reduced time to remove duplicate laboratory results from multiple days to less than 6 hours. Epi Contacts focused on increasing the efficacy of contact elicitation, and during a single period, 10% of index cases (9,440 of 96,319) completed Epi Contacts for a total of approximately 18,700 contacts elicited. User interviews indicated the tool increased speed of CI/CT workflows. In total, 134,410 searches were run in Epi Locator by 7320 distinct users-75% of which returned 1 or more person matches. A simple CMS, Epi Viewpoint, was developed and completed, but not deployed. CONCLUSIONS: Systems to mount large-scale population-based contact tracing programs were developed and implemented during the COVID-19 pandemic and can be adapted for CI/CT programs aiming to control the spread of other communicable diseases such as sexually transmitted diseases.

Genetic insights into the neurodevelopmental origins of schizophrenia.

Schizophrenia is a severe neuropsychiatric disorder with a longstanding history of neurobiological investigation. Although the underlying causal mechanisms remain unknown, early neurodevelopmental events have been implicated in pathogenesis, initially by epidemiological and circumstantial data but more recently by brain-specific molecular and genetic findings. Notably, genomic research has recently uncovered discrete risk variants and risk loci associated with schizophrenia, with the potential to elucidate disease mechanisms. This Review revisits the neurodevelopmental model of schizophrenia from a current genetics perspective, delineating the complex genetic basis of the disorder and highlighting gene expression and epigenetic analyses of post-mortem cortical tissue that suggest that early brain development mediates genetic risk associated with schizophrenia. Future functional genomics investigations will accordingly need to characterize schizophrenia risk loci in relevant neurodevelopmental models.

Special Article: Translational Science Update. Pharmacological Implications of Emerging Schizophrenia Genetics: Can the Bridge From 'Genomics' to 'Therapeutics' be Defined and Traversed?

Recent schizophrenia genome-wide association studies (GWAS) have identified genomic variants of common and rare frequency, significantly associated with schizophrenia. While numerous functional genomics efforts are ongoing to elucidate the biological effects of schizophrenia risk variants, a consideration of their therapeutic implications is timely and imperative, for patients as well as for an iterative effect on elucidating the underlying biology and pathophysiology of illness. The current article reviews efforts to translate emerging schizophrenia genomics into novel approaches to target discovery and therapeutic intervention. Though the path from 'genetic risk to therapy' is far from straightforward, there are provocative early possibilities that harbor the promise of treatment based on causation rather than phenomenology, as well as 'precision psychiatry,' a basis for stratifying patients to enable more precise and effective, personalized therapy.

The Genesis of Schizophrenia: An Origin Story.

Schizophrenia is routinely referred to as a neurodevelopmental disorder, but the role of brain development in a disorder typically diagnosed during early adult life is enigmatic. The authors revisit the neurodevelopmental model of schizophrenia with genomic insights from the most recent schizophrenia clinical genetic association studies, transcriptomic and epigenomic analyses from human postmortem brain studies, and analyses from cellular models that recapitulate neurodevelopment. Emerging insights into schizophrenia genetic risk continue to converge on brain development, particularly stages of early brain development, that may be perturbed to deviate from a typical, normative course, resulting in schizophrenia clinical symptomatology. As the authors explicate, schizophrenia genetic risk is likely dynamic and context dependent, with effects of genetic risk varying spatiotemporally, across the neurodevelopmental continuum. Optimizing therapeutic strategies for the heterogeneous collective of individuals with schizophrenia may likely be guided by leveraging markers of genetic risk and derivative functional insights, well before the emergence of psychosis. Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory.

Rediscovering tandem repeat variation in schizophrenia: challenges and opportunities.

Tandem repeats (TRs) are prevalent throughout the genome, constituting at least 3% of the genome, and often highly polymorphic. The high mutation rate of TRs, which can be orders of magnitude higher than single-nucleotide polymorphisms and indels, indicates that they are likely to make significant contributions to phenotypic variation, yet their contribution to schizophrenia has been largely ignored by recent genome-wide association studies (GWAS). Tandem repeat expansions are already known causative factors for over 50 disorders, while common tandem repeat variation is increasingly being identified as significantly associated with complex disease and gene regulation. The current review summarizes key background concepts of tandem repeat variation as pertains to disease risk, elucidating their potential for schizophrenia association. An overview of next-generation sequencing-based methods that may be applied for TR genome-wide identification is provided, and some key methodological challenges in TR analyses are delineated.

A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia.

BACKGROUND: Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia. DESIGN: We used data from 1 647 298 individuals born between 1980 and 2006 available through Danish population registers. 79 078 of those individuals were exposed to doxycycline, defined as redemption of at least 1 prescription. Survival analysis models stratified for sex with time-varying covariates were constructed to assess incidence rate ratios (IRRs) for schizophrenia (ICD-10 code F20.xx), with adjustment for age, calendar year, parental psychiatric status, and educational level. RESULTS: In the non-stratified analysis, there was no association between doxycycline exposure and schizophrenia risk. However, men who redeemed doxycycline had a significantly lower incidence rate for schizophrenia onset compared to men that did not (IRR 0.70; 95% CI 0.57-0.86). By contrast, women had a significantly higher incidence rate for schizophrenia onset, compared to women that did not redeem doxycycline prescriptions (IRR 1.23; 95% CI 1.08, 1.40). The effects were not found for other tetracycline antibiotics (IRR 1.00; 95% CI 0.91, 1.09). CONCLUSIONS: Doxycycline exposure is associated with a sex-dependent effect on schizophrenia risk. The next steps are replication of the results in independent well-characterized population cohorts, as well as preclinical studies to investigate sex-specific effects of doxycycline on biological mechanisms implicated in schizophrenia.

Clinical Characterization of Copy Number Variants Associated With Neurodevelopmental Disorders in a Large-scale Multiancestry Biobank.

IMPORTANCE: Past studies identified rare copy number variants (CNVs) as risk factors for neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the clinical characterization of NDD CNVs is understudied in population cohorts unselected for neuropsychiatric disorders and in cohorts of diverse ancestry. OBJECTIVE: To identify individuals harboring NDD CNVs in a multiancestry biobank and to query their enrichment for select neuropsychiatric disorders as well as association with multiple medical disorders. DESIGN, SETTINGS, AND PARTICIPANTS: In a series of phenotypic enrichment and association analyses, NDD CNVs were clinically characterized among 24 877 participants in the BioMe biobank, an electronic health record-linked biobank derived from the Mount Sinai Health System, New York, New York. Participants were recruited into the biobank since September 2007 across diverse ancestry and medical and neuropsychiatric specialties. For the current analyses, electronic health record data were analyzed from May 2004 through May 2019. MAIN OUTCOMES AND MEASURES: NDD CNVs were identified using a consensus of 2 CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by novel in-silico clinical assessments. RESULTS: Of 24 877 participants, 14 586 (58.7%) were female; self-reported ancestry categories included 5965 (24.0%) who were of African ancestry, 7892 (31.7%) who were of European ancestry, and 8536 (34.3%) who were of Hispanic ancestry; and the mean (SD) age was 50.5 (17.3) years. Among 24 877 individuals, the prevalence of 64 NDD CNVs was 2.5% (n = 627), with prevalence varying by locus, corroborating the presence of some relatively highly prevalent NDD CNVs (eg, 15q11.2 deletion/duplication). An aggregate set of NDD CNVs were enriched for congenital disorders (odds ratio, 2.0; 95% CI, 1.1-3.5; P = .01) and major depressive disorder (odds ratio, 1.5; 95% CI, 1.1-2.0; P = .01). In a meta-analysis of medical diagnoses (n = 195 hierarchically clustered diagnostic codes), NDD CNVs were significantly associated with several medical outcomes, including essential hypertension (z score = 3.6; P = 2.8 × 10-4), kidney failure (z score = 3.3; P = 1.1 × 10-3), and obstructive sleep apnea (z score = 3.4; P = 8.1 × 10-4) and, in another analysis, morbid obesity (z score = 3.8; P = 1.3 × 10-4). Further, NDD CNVs were associated with increased body mass index in a multiancestry analysis (ß = 0.19; 95% CI, 0.10-0.31; P = .003). For 36 common serum tests, there was no association with NDD CNVs. CONCLUSIONS AND RELEVANCE: Clinical features of individuals harboring NDD CNVs were elucidated in a large-scale, multiancestry biobank, identifying enrichments for congenital disorders and major depressive disorder as well as associations with several medical outcomes, including hypertension, kidney failure, and obesity and obesity-related phenotypes, specifically obstructive sleep apnea and increased body mass index. The association between NDD CNVs and obesity outcomes indicate further potential pleiotropy of NDD CNVs beyond neurodevelopmental outcomes previously reported. Future clinical genetic investigations may lead to insights of at-risk individuals and therapeutic strategies targeting specific genetic variants. The importance of diverse inclusion within biobanks and considering the effect of rare genetic variants in a multiancestry context is evident.

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders.

BACKGROUND: Recent studies report an important-and previously underestimated-role of rare variation in risk of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD). Using data from a large epidemiological study, we evaluate the distribution of potentially damaging copy number variation (pdCNV) in OCD and CTD, examining associations between pdCNV and the phenotypes of probands, including a consideration of early- vs. late-diagnoses. METHOD: The Obsessive-Compulsive Inventory-Revised (OCI-R) questionnaire was used to ascertain psychometric profiles of OCD probands. CNV were identified genome-wide using chromosomal microarray data. RESULTS: For 993 OCD cases, 86 (9%) were identified as pdCNV carriers. The most frequent pdCNV found was at the 16p13.11 region. There was no significant association between pdCNV and the OCI-R total score. However, pdCNV was associated with Obsessing and Checking subscores. There was no significant difference in pdCNV frequency between early- vs. late-diagnosed OCD probands. Of the 217 CTD cases, 18 (8%) were identified as pdCNV carriers. CTD probands with pdCNV were significantly more likely to have co-occurring autism spectrum disorder (ASD). CONCLUSIONS: pdCNV represents part of the risk architecture for OCD and CTD. If replicated, our findings suggest pdCNV impact some OCD symptoms. Genes within the 16p13.11 region are potential OCD risk genes.

A Genetics Perspective on the Role of the (Neuro)Immune System in Schizophrenia.

The immune system has long been hypothesized to play a role in schizophrenia pathogenesis based on data from diverse disciplines. Recent reports of the identification of schizophrenia-associated genetic variants and their initial biological characterization have renewed investigation of the role of the immune system in schizophrenia. In the current review, the plausibility of a role of the immune system in schizophrenia pathogenesis is examined, by revisiting epidemiology, neuroimaging, pharmacology, and developmental biology from a genetics perspective, as well as by synthesizing diverse findings from the emerging and dynamic schizophrenia genomics field. Genetic correlations between schizophrenia and immunological disorders are inconsistent and often contradictory, as are neuroimaging studies of microglia markers. Small therapeutic trials of anti-inflammatory agents targeting immune function have been consistently negative. Some gene expression analyses of post-mortem brains of patients with schizophrenia have reported an upregulation of genes of immune function though others report downregulation, and overall transcriptome profiling to date does not support an upregulation of immune pathways associated with schizophrenia genetic risk. The currently reviewed genetic data do not converge to reveal consistent evidence of the neuroimmune system in schizophrenia pathogenesis, and indeed, a substantive role for the neuroimmune system in schizophrenia has yet to be established.

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients. Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4. There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted. This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.

A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons.

BACKGROUND: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap. METHODS: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 103 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. RESULTS: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways. CONCLUSIONS: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.

A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue.

Objective: A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders. Method: We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs). TNF, TNFRSF1A (TNFR1), TNFRSF1B (TNFR2), and ADAM17 mRNA levels were determined in whole blood, and postmortem DLPFC obtained from an independent cohort (n = 80 SCZ, n = 44 BD, and n = 86 HC). Results: In peripheral blood, we show increased TNF-related measures in patients compared to HC, with an increased TNF/sTNFRs ratio (p = 6.00 × 10-5), but decreased TNF mRNA expression (p = 1 × 10-4), with no differences between SCZ and BD. Whole blood ADAM17 mRNA expression was markedly higher in BD vs SCZ patients (p = 1.40 × 10-14) and vs HC (p = 1.22 × 10-8). In postmortem DLPFC, we found no significant differences in mRNA expression of TNF pathway genes between any groups. Conclusions: SCZ and BD patients have increased plasma TNF pathway markers without corresponding increase in blood cell gene expression. ADAM17 expression in leukocytes is markedly different between the two disorders, while alterations in TNF-related gene expression in DLPFC are uncertain. Further studies are necessary to elucidate the aberrant regulation of the TNF pathway in severe mental disorders.

Prenatal expression patterns of genes associated with neuropsychiatric disorders.

OBJECTIVE: Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHOD: The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS: Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS: The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk.

We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.

Se revisan las tendencias más importantes en imágenes y genética aplicadas a la investigación en esquizofrenia y se discuten algunas perspectivas a futuro en este campo. Gran cantidad de estudios de imágenes y genética han investigado el impacto de la variación genética en la función cerebral desde que apareció el paradigma de un fenotipo intermedio de neuroimágenes para la esquizofrenia. Inicialmente se postuló que los efectos de los genes susceptibles para la esquizofrenia tendrían una mayor penetración a nivel de los fenotipos intermedios de neuroimágenes con base biológica que a nivel de un síndrome psiquiátrico complejo y fenotípicamente heterogéneo. Los resultados de muchos estudios apoyan esta hipótesis y la mayoría de ellos muestra variantes genéticas únicas que se asocian con cambios en la actividad de regiones cerebrales localizadas, como se puede determinar a través de la selección de tareas cognitivas controladas. A partir de estos estudios básicos, el análisis de neuroimágenes funcionales de los fenotipos intermedios ha progresado hacia modelos de disfunciones cerebrales más complejos y realistas, incorporando modelos de conectividad funcional y efectiva, que incluyen las modalidades de interacción psicófisiológíca, el modelo causal dinámico y las mediciones de la teoría de losgrafos. Los enfoques de asociación genética aplicados a las imágenes y genética también han progresado hacia efectos multivariados más sofisticados, incluyendo la incorporación de interacciones epistáticas de dos o tres vías, y más recientemente modelos de riesgo poligénico. Las imágenes y genética constituyen una estrategia única y poderosa para la comprensión de los mecanismos neurales de riesgo genético de trastornos complejos del sistema nervioso central a nivel del cerebro humano.

Nous examinons l'évolution déterminante de la neuro-imagerie génétique appliquée a la recherche sur la schizophrénie, puis nous analysons les futures possibilités de ce domaine. Une pléthore d'études associant la neuro-imagerie et la génétique a recherché l'influence de la variation génétique sur la fonction cérébrale, depuis l'émergence initiale d'un paradigme de phénotype intermédiaire de schizophrénie en neuro-imagerie. II a d'abord été postulé que les effets des gènes de susceptibilité a la schizophrénie seraient plus pénétrants au niveau des phénotypes intermédiaires de neuro-imagerie basés sur la biologie, qu'au niveau d'un syndrome psychiatrique complexe et phénotypiquement hétérogène. Les résultats de plusieurs études soutiennent cette hypothèse, la plupart mettant en évidence des variants génétiques uniques associés à des changements de l'activité de régions cérébrales localisées, déterminés par des tâches cognitives contrôlées définies. À partir de ces études fondamentales, l'analyse fonctionnelle de la neuro-imagerie des phénotypes intermédiaires a évolue vers des modèles plus complexes et réels de dysfonction cérébrale, comportant des modèles de connectivite effective et fonctionnelle, comme les modalités d'interaction psychophysiologique, la modélisation causale dynamique et les méthodes théoriques graphiques. Les méthodes d'association génétique appliquées a la neuro-imagerie génétique ont aussi progressé vers des effets multivariés plus sophistiqués, englobant des interactions épistatiques à 2 et 3 voies et plus récemment des modèles de risque polygénique. La neuro-imagerie génétique est une méthode puissante et originale de compréhension des mécanismes neuronaux du risque génétique pour les troubles complexes du SNC chez l'être humain.