When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population.

Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 48 putative affected and 180 putative carriers for TGDs were identified, with known or likely pathogenic variants in 79 genes. Despite screening for only 108 genetic disorders, this study showed a two-fold (2.09%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases is greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.

Investigation of the Gut Microbiome in Patients with Schizophrenia and Clozapine-Induced Weight Gain: Protocol and Clinical Characteristics of First Patient Cohorts.

BACKGROUND: Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans. PURPOSE: Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics. METHODS: Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

High Rates of Genetic Diagnosis in Psychiatric Patients with and without Neurodevelopmental Disorders: Toward Improved Genetic Diagnosis in Psychiatric Populations.

OBJECTIVE: There is a paucity of literature on genetic diagnosis in psychiatric populations, particularly the vulnerable population of patients with concomitant neurodevelopmental disorder (NDD). In this cross-sectional study, we investigated the genetic diagnostic rate in 151 adult psychiatric patients from two centers in Ontario, Canada, including a large subset (73.5%) with concurrent NDD, and performed phenotypic analysis to determine the strongest predictors for the presence of a genetic diagnosis. METHOD: Patients 16 years of age or older and affected with a psychiatric disorder plus at least one of NDD, neurological disorder, congenital anomaly, dysmorphic features, or family history of NDD were recruited through the genetics clinics between 2012 and 2016. Patients underwent genetic assessment and testing according to clinical standards. Chi-squared test was used for phenotypic comparisons. Multivariate logistic regression analysis was performed to determine which phenotypic features were predictive of genetic diagnosis types. RESULTS: Overall, 45.7% of patients in the total cohort were diagnosed with genetic disorders with the vast majority of diagnoses (89.9%) comprising single gene and chromosomal disorders. There were management and treatment implications for almost two-thirds (63.8%) of diagnosed patients. Presence of a single gene disorder or chromosomal diagnosis was predicted by differing combinations of neurological, NDD, and psychiatric phenotypes. CONCLUSION: The results of this study highlight the frequency and impact of genetic diagnosis in psychiatric populations, particularly those with concomitant NDD. Genetic assessment should be considered in psychiatric patients, particularly those with multiple brain phenotypes (psychiatric, neurodevelopmental, neurological).

Enrichment of pathogenic variants in genes associated with inborn errors of metabolism in psychiatric populations.

Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected inborn errors of metabolism (IEMs). Using next-generation sequencing, 2046 psychiatric patients were screened for pathogenic variants in genes associated with four IEMs, Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Among the 2046 cases, carrier rates of 0.83, 0.98, and 0.20%, for NPC, WD and HOM, and affected rates of 0.10 and 0.24% for NPC and AIP were seen, respectively. An enrichment of known and predicted pathogenic variants in the genes associated with NPC and AIP was found in the psychiatric cohort and especially in schizophrenia patients. The results of this study support that pathogenic variants in genes associated with IEMs are enriched in psychiatric populations. Underlying undiagnosed IEMs could account for the psychiatric symptomatology in a subset of psychiatric patients. Further studies are warranted to investigate the possibility that carriers for IEMs may have an increased risk for psychiatric disorders, particularly in the context of poor treatment response.

Copy number variant syndromes are frequent in schizophrenia: Progressing towards a CNV-schizophrenia model.

The genetic underpinnings of schizophrenia (SCZ) remain unclear. SCZ genetic studies thus far have only identified numerous single nucleotide polymorphisms with small effect sizes and a handful of copy number variants (CNVs). This study investigates the prevalence of well-characterized CNV syndromes and candidate CNVs within a cohort of 348 SCZ patients, and explores correlations to their phenotypic findings. There was an enrichment of syndromic CNVs in the cohort, as well as brain-related and immune pathway genes within the detected CNVs. SCZ patients with brain-related CNVs had increased CNV burden, neurodevelopmental features, and types of hallucinations. Based on these results, we propose a CNV-SCZ model wherein specific phenotypic profiles should be prioritized for CNV screening within the SCZ patient population.

Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update.

INTRODUCTION: Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment. AREA COVERED: This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein. EXPERT OPINION: Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.