Psychosis affects 3% of the world's population. 1 The most common diagnosis associated with psychosis is schizophrenia, with a worldwide prevalence of 1%. Schizophrenia is a chronic, frequently disabling, lifelong illness. Patients may experience hallucinations, delusions, paranoia, catatonia, disorganized thinking, functional impairment, poor planning, flattening behaviour and social withdrawal.Schizophrenia has a strong genetic component, with about 80% to 85% heritability as estimated through family, twin and adoption studies. 2 In the past 2 decades, worldwide collaborations have enabled genome-wide association studies with large cohorts, in search of genetic risk loci associated with schizophrenia. More than 176 loci have been associated with schizophrenia through case-control association studies of 56 000 patients with schizophrenia and 78 000 controls. 3 Many copy-number variants have also been implicated as causes of schizophrenia. 4 Although schizophrenia is considered to be a complex disorder with common variants of multiple genes involved in causing the phenotype, rare high-impact variants also contribute to the disorder. In a large cohort study, whole-genome sequencing was performed in 112 patients affected with extreme early-onset, treatment-resistant schizophrenia and whole-exome sequencing was completed for 4185 controls. 5 The research revealed several rare, damaging missense variants in multiple genes, of which ACACA:p.(Asp251Gly), CACNA1C:p.(Ile1153Arg) and GABRA:p.(Thr234Ala) had been previously associated with schizophrenia. A total of 48.2% of patients with treatmentresistant schizophrenia had at least 1 damaging missense or loss-of-function variant in a variant-intolerant gene, compared to 25.4% in controls. Interestingly, loss-of-function variants in genes were significantly enhanced for Mendelian syndromes in which some patients also exhibit aggressive behaviours or hallucinations. Moreover, many genes previously associated with schizophrenia had higher numbers of both missense and lossof-function variants compared to controls. 5
Background Psychiatric disorders are characterized by alteration in emotions, mood and behavior. Genetics is known to play a significant role in the development of psychiatric disorders. Genome-wide association studies have identified several loci associated with psychiatric illnesses. We hypothesize the existence of rare variants following Mendelian recessive mode of inheritance. These variants can be identified in families with multiple affected individuals born to unaffected consanguineous parents. Methods We visited psychiatric outpatient departments of multiple hospitals in Lahore, Pakistan. We focused on psychosis, as it can occur in several DSM disorders such as schizophrenia, dementia and bipolar disorder. After clinical diagnosis by an American trained psychiatrist, detailed clinical assessments using Diagnostic Interview for Genetic Studies (DIGS), Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD), Positive and Negative Syndrome Scale (PANSS), Hamilton Depression and Anxiety Rating Scale (HAM-D; HAM-A) were administered to all willing affected and unaffected participants. Results We identified eight pedigrees with two or more psychotic individuals in each family. Clinical diagnoses determined by their psychiatrists included ten individuals with schizophrenia; four individuals with psychosis and bipolar disorder; and two patients with “unspecified psychosis.” The rating instruments rigorously confirmed the diagnosis of psychosis in the affected patients from the six families as well as the absence of psychotic disorders in unaffected individuals from the six families. We obtained DNA samples from willing members of all eight families for future genetic analyses. Conclusion Our research highlights an alternative approach to discovery of rare recessively inherited genetic variants causing psychiatric disorders that have remained unidentified to date. These findings could illuminate underlying biological mechanisms leading toward development of targeted therapies in future.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.