Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.

Importance: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. Objective: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. Design, Setting, and Participants: This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Main Outcomes and Measures: Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. Results: The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Conclusions and Relevance: Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.

Insight and psychopathology in never-treated schizophrenia.

Insight is a feature of schizophrenia related to psychopathology, which could be modified by treatment. The real relationship will be more evident in the never-treated state. This study compared insight and its relationship to psychopathology in 143 never-treated patients with chronic schizophrenia with 183 treated patients. The treated patients had not received any structured intervention for improvement of insight. The item on insight and judgment from the Positive and Negative Syndrome Scale for schizophrenia was used as a measure of insight. Never-treated patients were more ill and poorer in insight than the TT group. Sex, age, duration of illness, negative symptoms related to insight only in the TT group. Positive symptoms score correlated with insight in both the groups, but negative symptoms correlated with insight only among the treated patients. Delusions, uncooperativeness, and poor attention predicted 27% of variation in the level of insight in the never-treated, whereas age; duration of illness; and symptoms of emotional withdrawal, difficulty in abstract thinking, and uncooperativeness predicted 30.3% of variation in insight of the TT group. The observed differences between the never-treated and treated subjects were due to influence of treatment on the association between insight and psychopathology. A subgroup of patients with a treatment-resistant trait of negative symptoms associated with poor insight was hypothesized.

Extrapyramidal symptoms in unmedicated schizophrenia.

Studies of spontaneous extrapyramidal symptoms, dyskinesia and parkinsonism, in unmedicated schizophrenia are of importance in understanding their underlying pathology and relation to the psychosis. This is a study of extrapyramidal symptoms using Abnormal Involuntary Movements Scale for dyskinesia and Simpson-Angus Scale for parkinsonism in 143 schizophrenia patients who never received antipsychotic medication. Psychopathology was measured using the Positive and Negative Syndrome Scale. Dyskinesia was present in 35% of patients and parkinsonism in 15%. The two disorders coexisted in 11 subjects. Orofacial dyskinesia, rigidity and tremor were common symptoms noted. There was no significant change in the rates and total scores of dyskinesia and parkinsonism with gender, age, duration of illness or age at onset of psychosis. Dyskinesia was unrelated to psychopathology. Parkinsonism score correlated positively with the motor symptom cluster of psychopathology. Dyskinesia and parkinsonism scores correlated positively with each other and parkinsonism score discriminated presence of dyskinesia. The associations between the spontaneous abnormal movements and other aspects of schizophrenia differed from those described in treated patients. Dyskinesia and parkinsonism are an integral part of the schizophrenia disease process whose relationship with other factors could be influenced by antipsychotic drug treatment.