Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans

• Published in: Molecular psychiatry Vol. 14; no. 12; pp. 1105 - 1118
• Main Authors: Dong, C, Wong, M-L, Licinio, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2009; Nature Publishing Group
• Subjects: Adult; Antidepressants; Antidepressive Agents - therapeutic use; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; Behavioral Sciences; Biological Psychology; Brain research; Cyclic AMP Response Element-Binding Protein - genetics; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dosage and administration; Drug therapy; Female; Gene Frequency; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Hispanic Americans; Humans; Hypotheses; Kinases; Linkage Disequilibrium; Major depressive disorder; Male; Medical research; Medicine; Medicine & Public Health; Membrane Transport Proteins - classification; Membrane Transport Proteins - genetics; Mental depression; Mexican Americans - genetics; Middle Aged; Nervous system; Neurosciences; Norepinephrine Plasma Membrane Transport Proteins - genetics; Original; original-article; Pathophysiology; Pharmacogenetics; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychiatric Status Rating Scales; Psychiatry; Receptor, trkB - genetics; Receptors, Corticotropin-Releasing Hormone - genetics; Sequence Analysis - methods; Serotonin; Serotonin Plasma Membrane Transport Proteins - genetics; United States; Australia; Canberra Australian Capital Territory Australia; antidepressant response; nucleotide polymorphism; fluoxetine; desipramine; major depression
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2009.92

We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 ( ABCB1 ), the noradrenaline, dopamine, and serotonin transporters ( SLC6A2, SLC6A3 and SLC6A4 ), cyclic AMP-responsive element binding protein 1 ( CREB1 ), corticotropin-releasing hormone receptor 1 ( CRHR1 ) and neurotrophic tyrosine kinase type 2 receptor ( NTRK2 ). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054±0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2 -coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.