Integrating Genome-wide and Epigenome-wide Associations for Antipsychotic Induced Extrapyramidal Side Effects

Background and HypothesisAntipsychotic medications are the first-line treatment for schizophrenia. However, around 40% of people with schizophrenia who are treated with antipsychotics could develop extrapyramidal side-effects (EPSE) including: 1) Dyskinesias, 2) Parkinsonism, 3) Akathisia, and 4) Dystonia. Study DesignWe conducted Genome-wide association (GWAS) and Epigenome-wide association (EWAS) meta-analysis of EPSE utilising data from previous schizophrenia case control studies. We integrated significant EWAS findings to an EPSE GWAS meta-analysis to enhance our understanding of the functional impact of common variants on EPSE. We also investigated whether polygenic risk scores (PRS) for schizophrenia, Parkinsons disease, and Lewy-body dementia could be predictive of EPSE development. Study ResultsThe top index SNP rs2709733 (A/G) from EPSE GWAS (p=2.214x10-7) mapped to a long intergenic non-protein coding RNA, LINC01162 with consistent effects across all cohorts. We identified 9 differentially methylated positions (DMPs) associated with EPSE when controlling for methylation age, sex, derived estimates of cell composition, smoking score, and schizophrenia PRS. Four of the DMPs cg14531564, cg20647656, cg12004641, cg22845912, and their affiliated genes (SDF4, ANKMY1, TNS1, SLA) were associated with the risk of developing EPSE and not with schizophrenia risk. Another DMP (cg12044923) which mapped to the STK32B gene, showed significant enrichment for association with risk of EPSE. ConclusionsOur study sheds new light on the potential biological mechanisms underlying EPSE development in schizophrenia, highlighting the importance of exploring both methylation shifts and common SNP associations. Further research with larger samples sizes and a focus on the role of STK32B are encouraged.