Indian Schizophrenia Genome-wide association study - Phase 2
Approved Research ID: 64593
Approval date: November 10th 2020
1. To increase our already collected southern Indian dataset with genetic data from Indian ancestry UK Biobank healthy controls in order to increase sample size and thereby discover additional genetic findings for schizophrenia.
2. To attempt to replicate our findings in other major world ancestry datasets available via our membership of the Psychiatric Genomics Consortium (PGC).
Although Indians constitute ~20% of the world's population, they are perhaps the least represented population in genetic studies. This is the case across the disease spectrum, and is nowhere more obvious than in psychiatric disorders, in particular schizophrenia. Most schizophrenia genetic findings have been discovered in European and more recently East Asian genome-wide association studies (GWAS). There is a need to survey other major world populations in order to enrich the global diversity of genetic findings for this disease. The outcome will contribute to the advancement of schizophrenia research in people of South Asian ancestry (25% of the global population).
Professor Mowry has a 20-year collaboration with Professor Thara at the Schizophrenia Research Foundation, Chennai. We have recruited, diagnosed, and collected DNA samples on more than 6000 individuals from schizophrenia families, unrelated cases and controls. Our recent publication, JAMA Psychiatry (July 3, 2019), described the first schizophrenia GWAS conducted in an Indian population, identifying a gene for a rate-limiting enzyme in niacin metabolism. We need to replicate this finding in a larger Indian sample comprising additional in-house samples and UK Biobank healthy controls. We plan to genotype 1400 of our own samples and integrate these with our other samples (total n=~3500) and ~10,000 UK Biobank genotyped samples of south Asian ancestry. By increasing the sample size, we aim to discover additional genetic findings associated with schizophrenia risk. We will attempt to replicate these findings in a large PGC European and East-Asian ancestry dataset.
Public Health Impact
Our results will contribute to determining whether our niacin finding (see above) will be confirmed in a larger sample, and if so, whether it will be translatable to the clinic as a supplemental treatment. Moreover, this work will facilitate future South Asian schizophrenia collaborative projects to discover additional genetic findings for eventual translation into the clinic. Further, the generated Indian-specific GWAS results may be utilized for predicting the presence of disease in other south Asian schizophrenia studies.
- What loci are significantly associated with schizophrenia in our Indian dataset when supplemented with UK Biobank genotypes from healthy controls of Indian ancestry?
- Are the significantly associated loci discovered in our combined Indian dataset (in-house; UK Biobank) be replicated in a large European and East-Asian ancestry dataset available via our membership of the Psychiatric Genomics Consortium (PGC)?
- To augment our in-house Indian dataset with genotypes from UK Biobank healthy controls in order to increase sample size and thereby discover additional risk loci for schizophrenia.
- To attempt to replicate our findings in a large European and East-Asian ancestry dataset available via our membership of the Psychiatric Genomics Consortium.
- To make our dataset (summary statistics only - not individual-level data) available for future collaborative projects involving south Asian groups.
To attempt to replicate our Indian finding utilising the UKBB dataset.
- In the entire UKBB dataset:
(a) To determine the relative frequencies of the risk allele and protective allele of our lead SNP (rs10866912);
(b) To replicate an association between the risk allele and a vegetarian diet
(c) To replicate results made in an independent small dataset (n=500) that the risk allele is associated with (I) a significantly decreased thickness of both temporal lobes, as well as the supramarginal and pericalcarine areas; (ii) significantly lower cognitive ability scores and social ability scores. our risk allele show: a significantly decreased thickness of both temporal lobes; (also supramarginal and pericalcarine) in those with the risk allele. Cognitive ability and social ability scores are lower in those with the risk allele. These results remained robust when the covariates were included.