Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.
Genetic predisposition may contribute to the differences in drug-specific, class-specific or antidepressant-wide treatment resistance. Clinical studies with the genetic data are often limited in sample sizes. Drug response obtained from self-reports may offer an alternative approach to conduct a study with much larger sample size. Using the phenotype data collected from 23andMe 'Antidepressant Efficacy and Side Effects' survey and genotype data from 23andMe's research participants, we conducted genome-wide association study (GWAS) on subjects of European ancestry using four groups of phenotypes (a) non-treatment-resistant depression (n=7795) vs treatment-resistant depression (TRD, n=1311), (b) selective serotonin reuptake inhibitors (SSRI) responders (n=6348) vs non-responders (n=3340), (c) citalopram/escitalopram responders (n=2963) vs non-responders (n=2005), and (d) norepinephrine-dopamine reuptake inhibitor (NDRI, bupropion) responders (n=2675) vs non-responders (n=1861). Each of these subgroups was also compared with controls (n ~ 190 000). The most significant association was from bupropion responders vs non-responders analysis. Variant rs1908557 (P=2.6 × 10(-8), OR=1.35) passed the conventional genome-wide significance threshold (P=5 × 10(-8)) and was located within the intron of human spliced expressed sequence tags in chromosome 4. Gene sets associated with long-term depression, circadian rhythm and vascular endothelial growth factor (VEGF) pathway were enriched in the bupropion analysis. No single-nucleotide polymorphism passed genome-wide significance threshold in other analyses. The heritability estimates for each response group compared with controls were between 0.15 and 0.25, consistent with the known heritability for major depressive disorder.
Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville, NJ, USA.
Q S
QS
Li
23andMe, Inc., Mountain View, CA, USA.
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C
Tian
Janssen Research & Development, Menlo Park, CA, USA.
G R
GR
Seabrook
Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville, NJ, USA.
W C
WC
Drevets
Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville, NJ, USA.
V A
VA
Narayan
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D016642:Bupropion / Q000627:therapeutic use*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D015283:Citalopram / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A
D000928:Antidepressive Agents; D016642:Bupropion; D015283:Citalopram; D018765:Dopamine Uptake Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; D042461:Vascular Endothelial Growth Factor A