RGD Reference Report - Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. - Rat Genome Database

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

Authors: Dong, C  Wong, ML  Licinio, J 
Citation: Dong C, etal., Mol Psychiatry. 2009 Dec;14(12):1105-18. Epub 2009 Oct 20.
RGD ID: 5684911
Pubmed: PMID:19844206   (View Abstract at PubMed)
PMCID: PMC2834349   (View Article at PubMed Central)
DOI: DOI:10.1038/mp.2009.92   (Journal Full-text)

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 + or - 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NTRK2Humanmajor depressive disorder  IAGP DNA:SNPs: :rs2289657 and rs56142442 (human)RGD 
Ntrk2Ratmajor depressive disorder  ISONTRK2 (Homo sapiens)DNA:SNPs: :rs2289657 and rs56142442 (human)RGD 
Ntrk2Mousemajor depressive disorder  ISONTRK2 (Homo sapiens)DNA:SNPs: :rs2289657 and rs56142442 (human)RGD 
SLC6A4Humanmajor depressive disorder susceptibilityIAGP DNA:SNPs and haplotypes:multipleRGD 
Slc6a4Ratmajor depressive disorder susceptibilityISOSLC6A4 (Homo sapiens)DNA:SNPs and haplotypes:multipleRGD 
Slc6a4Mousemajor depressive disorder susceptibilityISOSLC6A4 (Homo sapiens)DNA:SNPs and haplotypes:multipleRGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SLC6A4HumanDepression susceptibilityIAGP DNA:SNPs and haplotypes:multipleRGD 
Objects Annotated

Genes (Rattus norvegicus)
Ntrk2  (neurotrophic receptor tyrosine kinase 2)
Slc6a4  (solute carrier family 6 member 4)

Genes (Mus musculus)
Ntrk2  (neurotrophic tyrosine kinase, receptor, type 2)
Slc6a4  (solute carrier family 6 (neurotransmitter transporter, serotonin), member 4)

Genes (Homo sapiens)
NTRK2  (neurotrophic receptor tyrosine kinase 2)
SLC6A4  (solute carrier family 6 member 4)


Additional Information