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Novel genetic variant affects schizophrenia susceptibility in Indian population

The nicotinate phosphoribosyltransferase gene, or NAPRT1, was identified as a novel susceptibility gene for schizophrenia, according to data from an Indian genome-wide association study.

“NAPRT1 is the key rate-limiting enzyme involved in metabolizing nicotinic acid, the major dietary source of niacin,” researchers wrote in JAMA Psychiatry.

Because most schizophrenia genome-wide association studies (GWASs) have been conducted in Europeans and common genetic variants of schizophrenia are shared across ethnicities, Sathish Periyasamy, PhD, of the University of Queensland Brain Institute in Australia, and colleagues examined genetic loci for schizophrenia in a unique Indian population.

In their GWAS, the researchers examined 1,321 individuals with schizophrenia, 885 family members and 886 unrelated control participants with no personal or family history of psychotic disorder to determine the associations of single-nucleotide polymorphisms and gene expression with schizophrenia.

Analyses yielded a novel genome-wide significant association between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; OR = 1.27; 95% CI, 1.17-1.38), which was replicated in a previous European GWAS that yielded more than 100 schizophrenia-relevant variants (rs10866912, allele A; OR = 1.04; 95% CI, 1.02-1.06). The investigators found that NAPRT1 was likely the top gene within this locus.

According to the findings, “rs10866912 directly modifies the abundance of NAPRT1 transcript in brain cortex,” (normalized effect size = 0.79; 95% CI, 0.6-1.). Periyasamy and colleagues found that the rs10866912 allele A was linked to NAPRT1 downregulation in Indian lymphoblastoid cell lines.

Furthermore, “preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development,” the researchers wrote.

"When we knocked out the NAPRT1 gene in zebrafish, brain development of the fish was impaired. The zebrafish brain failed to divide symmetrically which is significant, because MRI studies in people with schizophrenia have shown defects in the corpus callosum — the bridge between the left and right sides of the brain,” Bryan Mowry, MD, of the Queensland Brain Institute, Australia, said in a press release.

"There are now a multitude of genetic variants linked to schizophrenia, but we don't yet know what the hundreds of genes involved do,” he said in the release. “The next phase is to study their function in normal and diseased states using computational approaches and animal models, such as the zebrafish.”

This study highlights the importance of increasing the number of GWAS in India, which has a vast multiethnic population and many highly-regarded geneticists, Vishwajit Nimgaonkar, MD, PhD, professor of psychiatry and human genetics at University of Pittsburgh, and colleagues wrote in an accompanying editorial.

“Indian scientists and mental health advocacy groups need to educate Indian population and policy makers alike regarding the potential payoffs of psychiatric research in general and psychiatric genetics research in particular,” they wrote. “Such efforts are urgently needed to address the massive mental health problems that affect a country with a population of more than 1.3 billion people.” – by Savannah Demko

Disclosures: Mowry reports grants from the Australian National Health and Medical Research Council. Please see the study for all other authors’ relevant financial disclosures.