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.

An in-silico approach for discovery of microRNA-TF regulation of DISC1 interactome mediating neuronal migration.

Neuronal migration constitutes an important step in corticogenesis; dysregulation of the molecular mechanisms mediating this crucial step in neurodevelopment may result in various neuropsychiatric disorders. By curating experimental data from published literature, we identified eight functional modules involving Disrupted-in-schizophrenia 1 (DISC1) and its interacting proteins that regulate neuronal migration. We then identified miRNAs and transcription factors (TFs) that form functional feedback loops and regulate gene expression of the DISC1 interactome. Using this curated data, we conducted in-silico modeling of the DISC1 interactome involved in neuronal migration and identified the proteins that either facilitate or inhibit neuronal migrational processes. We also studied the effect of perturbation of miRNAs and TFs in feedback loops on the DISC1 interactome. From these analyses, we discovered that STAT3, TCF3, and TAL1 (through feedback loop with miRNAs) play a critical role in the transcriptional control of DISC1 interactome thereby regulating neuronal migration. To the best of our knowledge, regulation of the DISC1 interactome mediating neuronal migration by these TFs has not been previously reported. These potentially important TFs can serve as targets for undertaking validation studies, which in turn can reveal the molecular processes that cause neuronal migration defects underlying neurodevelopmental disorders. This underscores the importance of the use of in-silico techniques in aiding the discovery of mechanistic evidence governing important molecular and cellular processes. The present work is one such step towards the discovery of regulatory factors of the DISC1 interactome that mediates neuronal migration.

Erratum: Figure Correction.

[This corrects the article on p. 68 in vol. 13, PMID: 25912540.].

Effect of polymorphisms of three genes mediating monoamine signalling on brain morphometry in schizophrenia and healthy subjects.

OBJECTIVE: We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o-methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism. METHODS: The study was carried out on patients with recent onset schizophrenia (n=41) recruited from the outpatient department of National Institute of Mental Health and Neurosciences, Bangalore, India and healthy control subjects (n=39), belonging to South Indian Dravidian ethnicity. Individual and additive effects of risk alleles of the above gene polymorphisms on brain morphometry were explored using voxel-based morphometry. RESULTS: Irrespective of phenotypes, individuals with the risk allele T of the rs6314 polymorphism of 5HT2A gene showed greater (at cluster-extent equivalent to family wise error-correction [FWEc] p<0.05) regional brain volumes in the left inferior temporal and left inferior occipital gyri. Those with the risk alleles of the other two polymorphisms showed a trend (at p<0.001, uncorrected) towards lower regional brain volumes. A trend (at p<0.001, uncorrected) towards additive effects of the above 3 risk alleles (subjects with 2 or 3 risk alleles vs. those with 1 or no risk alleles) on brain morphology was also noted. CONCLUSIONS: The findings of the present study have implications in understanding the role of individual and additive effects of genetic variants in mediating regional brain morphometry in health and disease.

An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India.

Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia.