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We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes ( P = 5.7 × 10 −10 ) and had lower glycosylated hemoglobin (β = −0.14 SD units, P = 1.1 × 10 −24 ). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study ( P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype ( P = 6.0 × 10 −4 ). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes ( P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in

Obsessive–compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case–control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4–22.5, P = 2.3 × 10−6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10−3). These data support a contribution of rare coding variants to OCD genetic risk. An analysis of the largest exome sequencing dataset of people with obsessive–compulsive disorder to date (n = 1,313 affected individuals), where both case–control and de novo variant studies support a contribution of rare damaging coding variants to risk.

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10(−5)) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10(−9)). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10(−3)) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10(−7)). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10(−8)). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach called “transcriptome reversal” for these disorders. This approach, originally developed for cancer, attempts to identify compounds that reverse gene-expression signatures associated with disease states.

There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. In mouse, knockout of tmprss2 led to protection against SARS-CoV-1 with no deleterious phenotypes, and in human populations genetic loss of TMPRSS2 does not appear to be selected against. Here, we mined publicly available gene expression data to identify several compounds that down-regulate TMPRSS2. Recognizing the need for immediately available treatment options, we focused on FDA-approved drugs. We found 20 independent studies that implicate estrogenic and androgenic compounds as transcriptional modulators of TMPRSS2, suggesting these classes of drugs may be promising therapeutic candidates for clinical testing and observational studies of COVID-19. We also note that expression of TMPRSS2 is highly variable and skewed in humans, with a minority of individuals having extremely high expression. Combined with literature showing that inhibition of TMPRSS2 protease activity reduces SARS-CoV-2 viral entry in human cells, our results raise the hypothesis that modulation of TMPRSS2 expression is a promising therapeutic avenue for COVID-19.

There is an urgent need to identify effective therapies for COVID-19 given that a broadly available and effective vaccine is likely at least one year away. Here, we identify compounds that transcriptionally inhibit host proteins required for SARS-CoV-2 entry and should be evaluated for efficacy in SARS-CoV-2 viral infection assays. Recognizing the need for immediately available treatment options, we focused particular attention on FDA-approved drugs that could be immediately repurposed to treat COVID-19 patients. By mining publicly available gene expression data, we identify several compounds that down-regulate TMPRSS2, a protein required for SARS-CoV-2 entry that has emerged as a promising therapeutic target. Among these, we find twenty independent studies that implicate estrogen-related and androgen-related compounds as transcriptional modulators of TMPRSS2 expression, suggesting that these drugs and others acting on the pathway may be promising therapeutic candidates for COVID-19 for further testing. It is also noteworthy that TMPRSS2 has highly variable and skewed expression in humans, spanning two orders of magnitude with a small minority of individuals having extremely high expression. Combined with literature showing that TMPRSS2 loss-of-function in mouse is protective against SARS while anti-estrogen treatment predicted to increase TMPRSS2 expression exacerbates SARS, this observation raises the hypothesis that TMPRSS2 expression may positively correlate with severity in COVID-19.

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10

Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of opiate addiction. Both increased and decreased serum BDNF levels have been reported in heroin addicts. Moreover, the role of BDNF in heroin-dependent patients during withdrawal has not been studied. This study aimed to explore the differences in serum BDNF levels of heroin addicts and healthy controls, and investigate the changes of serum BDNF levels in heroin addicts at baseline and at one month after heroin cessation. Seventy-two heroin-dependent patients and ninety age- and gender-matched healthy controls were enrolled in this study. We measured serum BDNF levels at baseline (both heroin addicts and healthy controls) and one month after heroin cessation (heroin addicts only). A total of 37 (51.4%) heroin addicts completed the one-month study. We found that baseline serum BDNF levels were significantly higher in heroin addicts compared to controls (F = 36.5, p = 0.001). There was no difference in serum BDNF levels among heroin addicts at baseline and one month after heroin cessation (F = 1.101, p = 0.301). These results indicate that BDNF may play a critical role in the course of opiate addiction and withdrawal.

Guloksuz & van Os boldly challenge the status quo as pertains to schizophrenia. In ‘The Slow Death of the Concept of Schizophrenia, and the Painful Birth of the Psychosis Spectrum’ (Guloksuz & van Os, 2017) they thoughtfully review long-standing concerns about this diagnostic category and present a new conceptualization. The authors question the validity of the schizophrenia concept citing variable clinical outcomes, transdiagnostic manifestations of psychosis, and the difficulty in identifying biomarkers, among other concerns. They also point toward the over-representation of schizophrenia in the psychosis literature and lament that patients and clinicians have come to associate this illness with predominantly poor outcomes. Finally, they propose removing the diagnosis of schizophrenia from the diagnostic nomenclature and instituting a broad new classification system, ‘psychosis spectrum disorder’ (PSD), to capture the many manifestations of psychosis. In this commentary, we advise against the institution of a psychosis spectrum due to the potential negative effects this framework would have on clinical care and progress in biological research.

The lifetime risk of suicide in patients with schizophrenia is estimated to be 4.9-13%. While there are many known risk factors for suicide in schizophrenia, the relationship between cognitive function and suicide risk is unclear, particularly in non-Caucasian populations. In our cross-sectional study, we administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to 316 Han Chinese chronic inpatients with schizophrenia and compared the performance of those who had attempted suicide (n=25) to non-attempters (n=291). The lifetime suicide attempt data were collected from medical records and interviews with patients and their family members. We found a lifetime suicide attempt rate of 7.9%. Suicide attempters were more likely to be single, but showed no significant differences in other demographic factors such as age, gender, or living arrangements. Contrary to our hypothesis, there was no significant relationship between performance on the RBANS test and lifetime risk of suicide attempts in Han Chinese inpatients with schizophrenia. The literature remains mixed on this topic. Culturally influenced differences in suicidal behavior may have affected the outcome of this study and further investigation of this topic is necessary.

The high prevalence of suicide in schizophrenia may be related to its demographic and clinical characteristics. Because suicide prevalence and its associations with clinical variables are less well characterized in Chinese than European patients with schizophrenia, we assessed the suicide attempts in 520 Chinese inpatients with schizophrenia. The suicide attempt data were collected from medical case notes and interviews with the patients and their family members. Patients were rated on the Positive and Negative Syndrome Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). Smoking severity was evaluated using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND). We found a suicide attempt rate of 9.2% in these schizophrenic inpatients. The attempters were single, had a significantly younger age but more hospitalizations, had higher depressive symptoms, and began smoking at an earlier age, smoked more cigarettes each day and had higher FTND total scores than patients without suicide attempts. The logistic regression analysis also indicated that suicide attempts were associated with the number of hospitalizations, depressive symptoms and FTND total scores. These results suggest that Chinese inpatients with schizophrenia attempt suicide more often than the general population. Further, some demographic and clinical variables are risk factors for suicide attempts in schizophrenia.

SummaryVAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.