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Novel Sequence Variations in the Brain-Derived Neurotrophic Factor Gene and Association with Major Depression and Antidepressant Treatment Response

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Novel Sequence Variations in the Brain-Derived Neurotrophic Factor Gene and Association with Major Depression and Antidepressant Treatment Response ORIGINAL ARTICLE Novel Sequence Variations in the Brain-Derived Neurotrophic Factor Gene and Association With Major Depression and Antidepressant Treatment Response Julio Licinio, MD; Chuanhui Dong, PhD; Ma-Li Wong, MD Context: Variations in the brain-derived neurotrophic Results: We identified 83 novel single-nucleotide poly- factor gene (BDNF) have been associated with psychiat- morphisms (SNPs): 30 in untranslated regions, 4 in cod- ric disorders. Deep sequencing of the BDNF gene may ing sequences, 37 in introns, and 12 in upstream regions; identify new variations and bring further insight into psy- 3 of 4 rare novel coding SNPs were nonsynonymous. As- chiatric genetics. sociation analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD Objective: To better characterize sequence variability (rs12273539, rs11030103, rs6265, rs28722151, in the BDNF gene by resequencing a genomic DNA re- rs41282918, and rs11030101) and 2 haplotypes in differ- gion of 22 kilobases that contained all BDNF exons and ent blocks (one including Val66, another near exon VIIIh) their flanking regions. were significantly associated with MDD. One recently re- ported 5Ј untranslated region SNP, rs61888800, was as- sociated with antidepressant response after adjusting for Design: Case-control study. age, sex, medication, and baseline score on the 21-item Hamilton Depression Rating Scale. Setting: University of California, Los Angeles, and Uni- versity of Miami. Conclusions: Our data support the concept that exten- sive resequencing of key candidate genes can lead to the Participants: Two hundred sixty-four controls and 272 discovery of substantial numbers of new variants. Fur- Mexican Americans with major depressive disorder ther studies using larger independent samples are needed (MDD) from Los Angeles who were assessed by the same to confirm the association of the rs61888800 SNP with bilingual clinical research team. antidepressant response. Main Outcome Measures: Identification of novel ge- Trial Registration: clinicaltrials.gov Identifier: netic polymorphisms in the BDNF gene and assessment NCT00265291 of their frequencies and associations with MDD or anti- depressant response. Arch Gen Psychiatry. 2009;66(5):488-497 HE NEUROTROPHINS ARE SE- phosphate–response element, which influ- creted peptides that are criti- ences the expression of BCL2, a pro- cally involved in differen- survival gene. It also has important roles tiation and survival of in excitatory synaptic transmission and neuronal populations.1-3 plasticity,10-13 memory processing and stor- Brain-derived neurotrophic factor age,13-18 and kindling and temporal lobe T4-7 19-22 (BDNF) is a neurotrophin that is abun- epilepsy. This relevance to crucial CNS dantly and widely expressed in the central functions has raised interest in its role nervous system (CNS).8,9 During the past in neurodegenerative and psychiatric decade, BDNF has emerged as a key factor disorders. implicated in complex behavioral pat- Allelic variations of the BDNF gene have terns in the developing CNS and in dis- been implicated in several conditions. Spe- ease. The BDNF modulates signaling path- cifically, the allelic variation Thr2Ile (sub- Author Affiliations: Center on Pharmacogenomics, ways that rapidly affect local synaptic stitution of isoleucine for threonine at Department of Psychiatry and function but also has long-term effects on amino acid position 2 in the coding se- Behavioral Sciences, University gene transcription. It promotes neuronal quence) has been implicated in congeni- of Miami Miller School of survival in the peripheral and CNS via the tal central hypoventilation syndrome.23 Medicine, Miami, Florida. transcription factor cyclic adenosine mono- Variations in BDNF have been exten- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 5), MAY 2009 WWW.ARCHGENPSYCHIATRY.COM 488 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 sively studied and implicated in the susceptibility to registered at http://clinical trials.gov (No. NCT00265291).44,45 The memory and hippocampal function impairments24 and demographic characteristics and the numbers of subjects in each several psychiatric disorders,25 such as obsessive- subgroup are presented in eTable 1 (http://www.archgenpsychiatry compulsive disorder,26 eating disorders,27,28 bipolar dis- .com) and a flowchart (eFigure 1). Briefly, all patients with MDD order,29-34 schizophrenia,35 major depression,36,37 and Alz- had a comprehensive psychiatric and medical assessment in their 38-40 primary language based on diagnostic and ratings instruments heimer disease. Despite conflicting findings in that had been fully validated in English and in Spanish. Exclu- replication studies for several of these associations, it is sion criteria included active medical illnesses that could be etio- interesting that the less frequent variation, Met66, which logically related to the ongoing depressive episode, current or ac- is associated with poorer episodic memory and abnor- tive suicidal ideation with a plan and strong intent, pregnancy, mal hippocampal activation on functional magnetic reso- lactation, current use of medications with significant CNS activ- nance imaging, generally confers a protective effect for ity that interfere with activity on an electroencephalogram (eg, neuropsychiatric conditions. benzodiazepines) or any other antidepressant treatment within The genetic factors that contribute to human disease the 2 weeks before enrollment, illicit drug use and/or alcohol abuse show enormous variation in the allelic spectra in num- in the preceding 3 months, or current enrollment in psycho- ber and population frequency of disease-predisposing therapy. Control individuals for our genomic studies were in gen- eral good health but were not screened for medical or psychiat- alleles. Common and complex disorders are multifacto- ric illness; they were age- and sex-matched and recruited from rial and probably composed of both common genetic vari- the same Mexican American community in Los Angeles by the ants (common disease/common allele model) with small same bilingual clinical research team. effect and rare sequence variants (rare variant/common disease model) with larger effect.41 Although the com- ANTIDEPRESSANT TREATMENT mon allele is the prevalent view of these 2 competing mod- els regarding the genetic basis of common and complex All patients had an initial comprehensive psychiatric and medi- diseases, it has been predicted that resequencing studies cal assessment and, if enrolled, had weekly structured fol- may identify many rarer variants (Ͼ5%) of intermediate low-up assessments for 9 weeks. The study consisted of 2 phases: effect associated with common disorders; such efforts may a 1-week single-blind placebo lead-in phase to minimize the also identify structural variations in genomic DNA, such impact of placebo responders, followed (if subjects continued as duplication and deletions of DNA sequences.42,43 to meet the inclusion criteria after phase 1) by random assign- Given the functional importance of BDNF in the CNS, ment to 1 of the 2 treatment groups: fluoxetine hydrochlo- the discovery of new BDNF allelic variants may be rel- ride, 10 to 40 mg/d, or desipramine hydrochloride, 50 to 200 evant to understanding the role of this gene in neurologic mg/d, administered in a double-blind manner for 8 weeks. Our primary clinical outcome measure was HAM-D21 score, and and psychiatric disorders. A number of studies have been clinical remission with antidepressants was defined as having conducted to examine the association of BDNF variants, a final (week 8) HAM-D21 score less than 8.44 In addition, the but most of them have been focused on genotyping tag relative response change was also computed as the difference single-nucleotide polymorphisms (SNPs) or the func- in HAM-D21 score between pretreatment and posttreatment tional coding SNP rs6265. To our knowledge, no study has divided by the pretreatment HAM-D21 score. comprehensively surveyed the entire BDNF exonic se- quence variation through direct sequencing and corre- GENOMIC DNA COLLECTION lated the identified genetic variants with disease suscepti- AND SEQUENCING bility. To discover new BDNF genetic variants and detect rare variants, we sequenced a total 22-kilobase (kb) ge- At the initial visit, blood samples were collected under in- nomic DNA including all BDNF exons and their flanking formed consent from the participating individuals into EDTA regions in 536 DNA samples from 264 control subjects and (K2EDTA BD Vacutainer EDTA tubes; Becton Dickinson, Frank- 272 Mexican American individuals with major depressive lin Lakes, New Jersey), and genomic DNA was isolated by using disorder (MDD). We further investigated all of the iden- DNA purification kits (Puregene; Gentra Systems, Indianapo- tified genetic variants for association with risk for major lis, Indiana). BDNF (OMIM 113505) DNA sequencing was com- depression and antidepressant treatment response. pleted to identify genetic polymorphisms in exonic or flank- ing exons by the Wellcome Trust Sanger Institute following their ExoSeq protocol (http://www.sanger.ac.uk/humgen/exoseq/). METHODS A 22-kb genomic DNA region, containing the entire BDNF ex- ons and their flanking regions, was sequenced. Briefly, DNA sequences were extracted from the Vega database (http://vega PARTICIPANTS .sanger.ac.uk/index.html). Primers were designed automati- cally by means of Primer3 (http://frodo.wi.mit.edu/)
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