Schizophrenia is used to describe a set of conditions that represent a fragmented psyche. People with schizophrenia often hear strange voices or see unreal visions. They may even start believing these hallucinations and have trouble expressing their emotions or rational thought in real-life situations. Schizophrenia manifests in early adulthood and may persist throughout the lifetime of an individual. The disease affects 23 million people worldwide and may double the risk of premature mortality. Previous studies have shown that a variety of genetic changes may be responsible for this heritable ailment.
In India, 3 out of 1000 individuals have schizophrenia. In spite of this, there is no local data available, and we rely on genetic data from European population to look for genetic variations responsible for the disease among Indians. Now, researchers from Australia and India have come together to address this challenge. They have conducted a two-decade-long study, involving more than 3,000 participants, to identify the genetic causes of schizophrenia among Indians. The study was published in the journal JAMA Psychiatry.
The researchers analysed the genetic data of 1,321 schizophrenia patients and 1,771 healthy individuals. A genetic variation associated with the disease will be found more often in patients with schizophrenia than in healthy people, implicating the gene responsible. Hence, to minimise other genetic variations, the study focused on individuals who were of Tamil ethnicity. The researchers also ensured that the participants had very low incidences of alcohol or substance abuse since drugs and alcohol are one of the few non-genetic, environmental causes of schizophrenia.
The study found that a particular region on the chromosome 8q24.3 — termed rs10866912 — was different in people with schizophrenia. Abnormalities of chromosome 8q24.3 are associated with epilepsy, developmental delay, and facial and skeletal abnormalities. The researchers compared data from the Indian population with that from Europe and found the schizophrenia-linked gene variant present in both. This finding confirms the association of this gene with schizophrenia.
The identified mutation was found in a gene regulatory variant which is known to regulate an enzyme called NAPRT1, involved in the metabolism of niacin or vitamin B3. This enzyme helps in the process of converting niacin into nicotinamide adenine dinucleotide (NAD), which is essential for many biochemical processes in the body, like the aerobic respiration in cells. Interestingly, the amount of NAPRT1 enzyme in the brain changes with age. The study found that the amount of NAPRT1 in the brain is highest before birth, and decreases thereafter. It functions during a critical time window when the young brain is forming, implying that there may be differences in brain development in healthy people and those who have schizophrenia.
While the seeds of the disease might be sown early on, schizophrenia does not occur before adolescence.
“There might be some environmental or age-related triggers for a physical presentation of schizophrenia,” says Dr Sathish Periyasamy, a researcher involved in the study.
The researchers speculate that the genetic variation, found in patients with schizophrenia, disturbs the production of NAPRT1, leading to abnormal structural or functional changes during early brain development. They suggest that vitamin B3 is linked with schizophrenia since the pathway for synthesising NAD uses NAPRT1 and vitamin B3. A disturbance in either the level of vitamin B3 or the enzyme metabolising it might increase the risk for schizophrenia.
To understand how the schizophrenia-linked gene mutation affects brain development, the scientists removed the gene responsible for the production of NAPRT1 from zebrafish embryos. They observed that zebrafish with no NAPRT1 developed holoprosencephaly — a condition where the brain fails to grow the two hemispheres. These two hemispheres control different body functions, such as hearing, vision and movement, in close coordination with each other.
In humans, failure in the development of these lobes can lead to severe intellectual disabilities as well as loss of temperature control, feeding behaviour and hormonal release. Studies have also observed disruptions within the corpus callosum, a structure that connects the two hemispheres, in human patients with schizophrenia. This observation suggests that NAPRT1 is involved in brain development across species.
The researchers also studied the spread of the schizophrenia-linked Indian gene regulatory variant across the globe. They compared the populations from Europe and Africa with the South Asian population including Sri Lankan Tamil, Indian Telugu, Gujarati, Bengali and Punjabi of Pakistan. They found that the risk variant occurred at a lower frequency of 43% in the European population. However, the variant occurred at a much higher incidence of 98% in the African population.
The researchers attribute this difference to the fact that the African genetic structure includes parts of the ancient human genome, and our ancestors have passed on the schizophrenia risk gene to us. Since survival was difficult in the wild, only a few ancient humans could have produced offspring that would carry the variation. Hence, when humans migrated from Africa to Europe and India, the incidence of this variant further reduced.
Since the diet is an external factor contributing to schizophrenia, the researchers analysed the participants who had lower levels of NAPRT1 based on whether they were vegetarians or non-vegetarians. Interestingly, a higher number of schizophrenia patients had a vegetarian diet. A vegetarian diet lacks tryptophan — an amino acid used by the body to produce NAD without using vitamin B3. A gene-linked deficiency of NAPRT1 and the lack of tryptophan in the diet may aggravate the overall scarcity of NAD. This condition could lead to developmental anomalies and increase the risk of schizophrenia, say the researchers.
“In principle, niacin supplementation can increase NAD levels. However, we are uncertain whether this will improve health outcomes,” remarks Dr Periyasamy. “Since schizophrenia has a developmental origin, the effects of the risk factors during prenatal stages can be permanent, and these treatments may not work in such cases,” he adds.
As a next step, the researchers plan to conduct clinical trials to test if niacin supplements can reverse the symptoms.
“These supplements might have to be prescribed during pregnancy, similar to how folic acid is being prescribed,” suggests Dr Periyasamy.
This article has been run past the researchers, whose work is covered, to ensure accuracy.