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Original Investigation
July 3, 2019

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

Author Affiliations
  • 1Queensland Brain Institute, University of Queensland, Brisbane, Australia
  • 2Schizophrenia Research Foundation, Chennai, India
  • 3Queensland Centre for Mental Health Research, West Moreton Hospital and Health Service, University of Queensland, Brisbane, Australia
  • 4Mater Research Institute and University of Queensland, Translational Research Institute, Brisbane, Australia
  • 5Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
  • 6Public Health Program, Hunter Medical Research Institute, Newcastle, Australia
  • 7QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 8School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
  • 9Department of Surgery, University of Michigan, Ann Arbor
  • 10Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
  • 11Psychiatric Rehabilitation Service, Hunter New England Mental Health, Newcastle, Australia
  • 12Athma Hospitals and Research, Tiruchirapalli, India
  • 13Asha Hospital, Hyderabad, India
  • 14Vazhikatti Mental Health Centre and Research Institute, Coimbatore, India
  • 15Manathin Maiyam Hospital, Erode, India
  • 16Department of Human Genetics, University of Utah, Salt Lake City
  • 17Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia
JAMA Psychiatry. 2019;76(10):1026-1034. doi:10.1001/jamapsychiatry.2019.1335
Key Points

Question  Can new causes of schizophrenia be identified within the Indian population, given its unique genetic makeup and environment?

Findings  In this genome-wide association study that included 3092 individuals from southern India, a genome-wide significant association with schizophrenia was observed on chromosome 8q24.3. Bioinformatic, cellular, and animal model evidence points to NAPRT1, a gene that encodes a key niacin metabolism enzyme, as the top gene within this locus.

Meaning  These findings suggest that the genotype of the top association signal and niacin status may be relevant in schizophrenia susceptibility and treatment.

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.

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