Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response

• Published in: Translational psychiatry Vol. 6; no. 9; p. e889
• Main Authors: Li, Q S, Tian, C, Seabrook, G R, Drevets, W C, Narayan, V A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.09.2016; Nature Publishing Group
• Subjects: 45/43; 631/208/212/1728; 692/53/2423; Adult; Antidepressive Agents - therapeutic use; Behavioral Sciences; Biological Psychology; Bupropion - therapeutic use; Chromosomes, Human, Pair 4 - genetics; Circadian Rhythm - genetics; Citalopram - therapeutic use; Depressive Disorder - drug therapy; Depressive Disorder - genetics; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Depressive Disorder, Treatment-Resistant - drug therapy; Depressive Disorder, Treatment-Resistant - genetics; Dopamine Uptake Inhibitors - therapeutic use; Drug Resistance - genetics; Female; Genome-Wide Association Study; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Neuronal Plasticity - genetics; Neurosciences; Original; original-article; Pharmacotherapy; Psychiatry; Serotonin Uptake Inhibitors - therapeutic use; Signal Transduction; Surveys and Questionnaires; Treatment Outcome; Vascular Endothelial Growth Factor A
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.171

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.