SA81: UNRAVELING GENOMIC CONTRIBUTIONS TO VENLAFAXINE REMISSION IN OLDER ADULTS WITH LATE-LIFE DEPRESSION USING A GENOME-WIDE APPROACH

Abstract

Background In geriatric depression, antidepressant treatment response is often slow and incomplete; new biomarkers for antidepressant response could lead to precision medicine and uncover new mechanisms of illness. Therefore, we conducted a Genome-Wide Association Study (GWAS) in older adults treated with venlafaxine. Methods Three-hundred and fifty participants (>60 years) of mixed ethnic ancestry, diagnosed with major depression (MADRS>15), were treated with venlafaxine (~12 weeks). Individuals were genotyped using the Illumina PsychArray, and genetic data was imputed to 7.5 million variants per individual. Associations with remission status (MADRS≤10) and change in MADRS score were conducted using logistic/ linear regressions, adjusted for ancestry, sex, recruitment site, length in treatment, depressive episode duration, and baseline depressive severity. We also conducted pathway enrichment analysis using DEPICT. Results Our top hits in association with MADRS score change were with variants near MIR1246 and in ERBB4, a schizophrenia susceptibility gene. ERBB4 has been implicated in post-ketamine treatment down regulation of GABA and glutamate levels in the rat prefrontal cortex and hippocampus, resulting in an antidepressant effect. We also observed a suggestive association between remission status and a variant in phosphodiesterase gene PDE9A, suggesting a role in synaptic neurotransmitter signaling. Our top hit pathways included processes in the metabolic pathway of amyloid precursor protein. However, no variants survived corrections for multiple testing (p Discussion Our findings suggest novel gene variant associations with measures of venlafaxine remission in older adults, as well as interesting neuro-relevant genetic pathways. A new, larger study of geriatric depression treatment will confirm these novel findings.