Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response

Julio Licinio, Chuanhui Dong, Ma Li Wong

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Context: 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. Design: Case-control study. Setting: University of California, Los Angeles, and University of Miami. Participants: 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. Main Outcome Measures: Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or anti- depressant 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 differ- entblocks(one includingVal66, anothernearexonVIIIh) 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.

Original languageEnglish
Pages (from-to)488-497
Number of pages10
JournalArchives of General Psychiatry
Volume66
Issue number5
DOIs
StatePublished - May 1 2009

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Brain-Derived Neurotrophic Factor
Antidepressive Agents
Depression
Major Depressive Disorder
Single Nucleotide Polymorphism
Genes
Therapeutics
Los Angeles
Psychiatry
Untranslated Regions
High-Throughput Nucleotide Sequencing
5' Untranslated Regions
Genetic Polymorphisms
Introns
Haplotypes
Case-Control Studies
Exons
Outcome Assessment (Health Care)
DNA

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

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title = "Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response",
abstract = "Context: 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. Design: Case-control study. Setting: University of California, Los Angeles, and University of Miami. Participants: 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. Main Outcome Measures: Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or anti- depressant 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 differ- entblocks(one includingVal66, anothernearexonVIIIh) 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.",
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N2 - Context: 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. Design: Case-control study. Setting: University of California, Los Angeles, and University of Miami. Participants: 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. Main Outcome Measures: Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or anti- depressant 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 differ- entblocks(one includingVal66, anothernearexonVIIIh) 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.

AB - Context: 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. Design: Case-control study. Setting: University of California, Los Angeles, and University of Miami. Participants: 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. Main Outcome Measures: Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or anti- depressant 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 differ- entblocks(one includingVal66, anothernearexonVIIIh) 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.

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