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

Abstract

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.

Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort

“…We did not detect significantly differentially methylated loci associated with exclusive cannabis use at the epigenome-wide level. However, an assessment of those top loci reaching nominal significance (P < 0.05) identified CpG sites within genes involved in brain function and mood disorders, including MUC3L 81,82 , CDC20 83 , DUS3L 84 , TMEM190 85 , FOXB1 [86][87][88] , KIAA1324L/GRM3 82,[89][90][91][92][93][94] , DDX25 81,95,96 , TNRC6B 97,98 and SP9 99 .…”

Neurexins in autism and schizophrenia—a review of patient mutations, mouse models and potential future directions

“…This approach would, moreover, offer the advantage to further control NRXN expression spatio-temporally, allowing independent interrogation of specific neurocircuitries. Interestingly, a versatile gene-silencing technology has been recently developed for the zebrafish animal model which has been used to study the role of the SCZ risk gene miR-137 and NAPRT1 [99][100][101][102]. Furthermore, the zebrafish is an attractive model to study the effect of NRXNs on brain development and function.…”

Current Aspects of the Role of Autoantibodies Directed Against Appetite-Regulating Hormones and the Gut Microbiome in Eating Disorders

“…Negative genetic correlations were documented between anorexic patients and metabolic traits such as type 2 diabetes, insulin resistance, blood plasma insulin, leptin, and a significant positive genetic correlation was found with high-density lipoprotein (HDL) cholesterol. Disordered niacin metabolism leading to niacin deficiency was shown to provoke schizophrenia-like symptoms in neuropsychiatric diseases such as pellagra (11), which was seen as a secondary complication associated with a tryptophan-deficient diet in AN and BN (12,13).…”