Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response.
BACKGROUND
Variations in the brain-derived neurotrophic factor gene (BDNF) have been associated with psychiatric disorders. Deep sequencing of the BDNF gene may identify new variations and bring further insight into psychiatric genetics.


OBJECTIVE
To better characterize sequence variability in the BDNF gene by resequencing a genomic DNA region of 22 kilobases that contained all BDNF exons and their flanking regions.


METHODS
Case-control study.


METHODS
University of California, Los Angeles, and University of Miami.


METHODS
Two hundred sixty-four controls and 272 Mexican Americans with major depressive disorder (MDD) from Los Angeles who were assessed by the same bilingual clinical research team.


METHODS
Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or antidepressant response.


RESULTS
We identified 83 novel single-nucleotide polymorphisms (SNPs): 30 in untranslated regions, 4 in coding sequences, 37 in introns, and 12 in upstream regions; 3 of 4 rare novel coding SNPs were nonsynonymous. Association analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and 2 haplotypes in different blocks (one including Val66, another near exon VIIIh) were significantly associated with MDD. One recently reported 5' untranslated region SNP, rs61888800, was associated with antidepressant response after adjusting for age, sex, medication, and baseline score on the 21-item Hamilton Depression Rating Scale.


CONCLUSIONS
Our data support the concept that extensive resequencing of key candidate genes can lead to the discovery of substantial numbers of new variants. Further studies using larger independent samples are needed to confirm the association of the rs61888800 SNP with antidepressant response.


BACKGROUND
clinicaltrials.gov Identifier: NCT00265291.
Licinio
Julio
J
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. licinio@miami.edu
Dong
Chuanhui
C
Wong
Ma-Li
ML
D000328:Adult; D000368:Aged; D000483:Alleles; D000928:Antidepressive Agents / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D003891:Desipramine / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D015141:Los Angeles; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D020506:Untranslated Regions; D044465:White People / Q000235:genetics; D055815:Young Adult
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D005819:Genetic Markers; D020506:Untranslated Regions; D005473:Fluoxetine; D003891:Desipramine