SA84 - PLEIOTROPIC GENES IN PSYCHIATRY: EFFECTS OF CALCIUM CHANNELS AND THE STRESS-RELATED FKBP5 GENE ON ANTIDEPRESSANT RESPONSE AND TREATMENT RESISTANCE

Abstract

Background The substantial contribution of genetic variants to inter-individual variance in antidepressant response makes genetic polymorphisms a unique opportunity to provide tailored antidepressant treatments. The present study combined a candidate approach of variants with strong previous evidence and a genome-wide approach in order to investigate the role of eight genes that appear optimal candidates for involvement in antidepressant response on the basis of their biological function and previous literature suggesting a pleiotropic effect across several psychiatric traits. Methods Three samples of patients with major depressive disorder (n=357, 218 and 96) were genotyped for 44 SNPs in genes involved in neurotransmission (CACNA1C, CACNB2, ANK3), neural differentiation, synaptic plasticity, adhesion processes, structural organization (GRM7, TCF4, ITIH3, SYNE1) and glucocorticoid signaling (FKBP5). Phenotypes were response/remission at week 4 and Treatment-Resistant Depression (TRD: non response/non remission to at least two antidepressants). STAR⁎D genome-wide data were used to replicate findings for response/remission (Level 1, n=1409) and TRD (Level 2, n=620). Standard quality control and genotype imputation were performed and pathways including the most promising candidate genes for involvement in TRD were investigated in STAR⁎D Level 2. Top pathway(s) were investigated also using machine learning (R cran Caret package). At SNP-level results with p Results Several FKBP5 SNPs (rs3800373, rs1360780, rs9470080) showed consistent associations with response, remission or TRD across at least two samples. Results involving CACNA1C SNPs (rs2283326, rs10848635, rs1006737) had contradictory direction of association across samples. ANK3 rs1049862 AA genotype showed a consistent association with a more favorable outcome in two samples. In STAR⁎D pathway analysis for the top candidate genes did not identify significant results after permutation. The best pathway associated with TRD included the CACNA1C gene (GO:0006942, regulation of striated muscle contraction, corrected p=0.15). Neural networks and gradient boosted machine showed that independent SNPs in this pathway predicted TRD with a mean accuracy of 0.73, sensitivity of 0.83 and specificity of 0.56. Discussion According to the present results and previous literature, FKBP5 polymorphisms should be considered for inclusion in pharmacogenetic tests for the prediction of antidepressant response and TRD. The contribution of CACNA1C polymorphisms was unclear, but further investigation is supported by previous literature and interesting findings for GO:0006942 pathway that includes several genes coding for ion channels that are expressed in the central nervous system as well as other genes relevant for excitatory mechanisms.