Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway (BRCA2, ATM and CHEK2) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes (HOXB13, CHEK2, BIK) significantly associated with increased risk of overall prostate cancer and in four genes (ANO7, SPDL1, AR, TERT) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

An evolutionary perspective on complex neuropsychiatric disease.

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

The neurobiology of duration of untreated psychosis: a comprehensive review.

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 [11C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.

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 (ß = -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.

The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders.

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.

High-impact rare genetic variants in severe schizophrenia.

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.

Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants.

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.

A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders.

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.

Schizotypal personality disorder in individuals with the Attenuated Psychosis Syndrome: Frequent co-occurrence without an increased risk for conversion to threshold psychosis.

The Attenuated Psychosis Syndrome (APS), proposed as a condition warranting further study in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is a controversial diagnostic construct originally developed to identify individuals at clinical high-risk for psychosis. The relationship of APS and Schizotypal Personality Disorder (SPD) remains unclear with respect to their potential co-occurrence and the effect of SPD on risk for conversion to threshold psychosis. We examined the prevalence and effect on conversion of SPD in a cohort of 218 individuals whose symptoms met APS criteria. Results indicated that SPD was highly prevalent (68%), and that SPD did not influence risk for conversion. Rather, total positive symptom burden measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS; OR 1.12, p = 0.02) emerged as the strongest predictor of conversion. These data suggest that when encountering a patient whose presentation meets SPD criteria, the clinician should assess whether APS criteria are also met and, for 1-2 years, carefully monitor positive symptoms for possible conversion to threshold psychosis.

The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review.

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.

Alive but not well: the limited validity but continued utility of the concept of schizophrenia.

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.