Association of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at amino acid level in individuals with schizophrenia: A study from South India.

BACKGROUND: Schizophrenia, a chronic severe psychiatric illness of unknown aetiology, has been shown to be associated with HLA alleles but at varied degree in different population. The present study has focussed on analysing the frequency of HLA class I and class II alleles in persons with schizophrenia from South India. METHODS: Ninety seven individuals with schizophrenia and 103 age- and gender-matched controls were typed for HLA- A, B, C, DRB1 and DQB1 loci by next-generation sequencing in Illumina MiniSeq using MIA FORA NGS FLEX HLA typing kit. RESULTS: The results showed that HLA-A*01:01:01, B*37:01:01 and C*01:02:01 were positively associated with schizophrenia while HLA-B*35:03:01 and DRB1*04:03:01 were negatively associated. Gender-specific associations revealed that DRB1*10:01:01 and DQB1*05:01:01 were positively associated while DQB1*03:02:01 was negatively associated with female subjects with schizophrenia. A*24:02:01~B*37:01:01~C*06:02:01~DRB1*10:01:01~DQB1*05:01:01 is the predominant haplotype in schizophrenia population when compared to healthy controls. Amino acid association in susceptible and protective alleles has shown that the presence of peptide in the peptide-binding groves of mature HLA-A protein (K, M, V, R and V at 44th, 67th, 150th, 156th and 158th position), HLA-B protein (D and S at 77th and 99th position) and HLA-C protein (M at 99th position) confer susceptibility to the disease, only in the absence of E (Glutamic acid) at 74th position in mature HLA-DRB1 protein. Interaction of amino acids in protective alleles namely B*35:01:01 and DRB1*04:03:01 has revealed that aspartic acid at 114th (D) position in mature HLA-B protein and glutamic acid (E) at 74th position of mature HLA-DRB1 protein have a combined effect in protecting against the disease. CONCLUSION: The study has revealed the HLA association with schizophrenia in south Indian population. The amino acid interaction with the disease needs to be confirmed in a larger population.

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.