Integrative Genetic Variation, DNA Methylation, and Gene Expression
Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A
CAN-BIND-1 Study
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Abstract
Introduction Little is known about the interplay between genetics and
epigenetics on antidepressant treatment (1) response and remission, (2) side
effects, and (3) serum levels. This study explored the relationship among single
nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four
pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and
ABCB1, and its effect on these outcomes.
Methods The Canadian Biomarker Integration Network for Depression-1
dataset consisted of 177 individuals with major depressive disorder treated for
8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or
augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified
by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were
tested for associations with our outcomes, followed by causal inference tests
(CITs) to identify methylation-mediated genetic effects.
Results Eleven cis-SNP-CpG pairs (q<0.05) constituting four
unique SNPs were identified. Although no significant associations were observed
between mQTLs and response/remission, CYP2C19 rs4244285 was associated
with treatment-related weight gain (q=0.027) and serum concentrations of
ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of
those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers)
genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2
genotype (poor metabolizers) did not report weight gain during this period and
demonstrated the highest ESCadj concentrations. CITs did not indicate
that these effects were epigenetically mediated.
Discussion These results elucidate functional mechanisms underlying the
established associations between CYP2C19 rs4244285 and ESC
pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight
gain needs to be further explored.
