M82 - RARE CODING VARIANTS IN TREATMENT-RESISTANT DEPRESSION

Abstract

Background Approximately 30% of patients with Major Depressive Disorder (MDD) meet criteria for Treatment-Resistant Depression (TRD), defined as non-response to two or more different classes of antidepressants. Pharmacogenomics research has shown that genetic factors can impact medication effectiveness and tolerability by modulating drug levels or target affinity. Antidepressant response is heritable, but genome-wide association studies of common variants have failed to find consistent signals. Since patients with TRD occupy the extreme end of the treatment response distribution, they may also carry alleles that occupy an extreme of frequency and functional impact. Methods Study participants included 146 unrelated patients, 130 with MDD or bipolar TRD and 16 with good response to antidepressants, drawn from several sources. All participants had experienced at least two failed antidepressant trials not explained by non-adherence or severe comorbidities. Exomes were captured with various arrays and sequenced by use of Illumina or SOLiD platforms. Variants were called and assessed for quality using the GATK best practices pipeline. Results After quality control, 348,077 variants were identified, of which 99,711 were exonic and had allele frequencies 1 TRD patient, but LIST GENES each carried the same qualifying variant in >2 individuals. A total of 820 genes carried at least 2 qualifying variants. This set of genes was tested for overlap with genes implicated in MDD (Hyde et al., 2016) or antidepressant treatment response (GENDEP, MARS, and STAR⁎ D Investigators, 2013). Significant excess overlap of genes was detected for both MDD (OR=1.5, p=0.035) and response to 2 wks of antidepressant treatment (OR=2.16; P=1×10-5). The latter gene set was enriched for “actin cytoskeleton” by ENRICHR (q=0.01). Discussion Some of the same genes implicated in MDD or antidepressant treatment response through common variants may also harbor rare, functional variants in patients with TRD. Further study of these genes could yield new insights into the pathophysiology of treatment-resistant depression.