Missense variants in PLA2G6 contribute to a spectrum of clinical syndromes and provide pharmacogenomic correlates

Background Risk alleles in a gene for a genetic disorder can often cause a spectrum of syndromes. The number of copies, deleteriousness and position in the sequence could influence phenotype manifestation. Methods Whole exome sequencing in 310 individuals from 100 families with severe mental illness revealed 851 instances of variants in the PLA2G6 gene. We assessed the population frequency and deleteriousness of the nonsynonymous variants using in-silico prediction methods. Molecular docking analyses with antipsychotics was performed to investigate possible pharmacogenomic implications of the PLA2G6 mutations identified. Results We found six nonsynonymous variants predicted to be deleterious by VarSome. The frequency of non-synonymous variants was found to vary across populations. The preliminary molecular docking analysis suggests that chlorpromazine and risperidone are predicted to bind at three drug-binding sites however, risperidone has a greater binding affinity to PLA2G6. The occurrence of variants close to these drug-binding sites suggests a possible mechanism for the mediation of parkinsonian side effects on drug intake in patients harboring these variants. Conclusion Variants in the PLA2G6 , a gene previously known to be associated with Parkinson’s disease may thus contribute to the risk of psychiatric phenotypes, as observed in these 9 individuals from 6 families with severe mental illness. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was supported by the Accelerator Program for Discovery in Brain Disorders Using Stem Cells, Department of Biotechnology, Government of India (Grant BT/PR17316/MED/31/326/2015) and Scientific Knowledge for Ageing and Neurological Ailments (SKAN) trust project Genetics of bipolar disorder and related illnesses: a study of intermediate alleles in candidate genes with repeat expansion loci (SKAN/002/208/2021/01480). BV is also funded by a DBT/Wellcome Trust India Alliance Intermediate (Clinical and Public Health) Research Fellowship (IA/CPHI/20/1/505266). We would like to acknowledge SKAN research trust for MJ fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the Institutional Ethics Committee of National Institute of Mental Health and Neurosciences, Bengaluru, India, and the study procedures conformed to the provisions of the Declaration of Helsinki. All participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated and/or analysed during the current study are available from the ADBS bio repository on registration and reasonable request.