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. Author manuscript; available in PMC: 2016 Sep 1.
Published in final edited form as: Bipolar Disord. 2015 Sep;17(6):645–652. doi: 10.1111/bdi.12323

Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder

Malik Nassan a, Paul E Croarkin a, Joan L Luby b, Marin Veldic a, Paramjit T Joshi c, Susan L McElroy d, Robert M Post e, John T Walkup f, Kelly Cercy g, Jennifer Geske g, Karen D Wagner h, Alfredo B Cuellar-Barboza i, Leah Casuto d, Catharina Lavebratt j,k, Martin Schalling j,k, Peter S Jensen l,*, Joanna M Biernacka a,g,*, Mark A Frye a,*
PMCID: PMC4672380  NIHMSID: NIHMS709891  PMID: 26528762

Abstract

Objectives

Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association.

Methods

DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset with the definition of first manic or depressive episode at age ≤ 19 years (versus adult-onset cases at age > 19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects.

Results

Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04).

Conclusions

These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder.

Keywords: association, BDNF, bipolar disorder, brain-derived neurotrophic factor, early onset, Val66Met

Early-onset bipolar disorder (EO-BD) has been associated with substantial morbidity characterized by rapid cycling, severe impairment, prolonged time to remission, poor treatment response, and increased psychiatric comorbidity (1–4). It has been estimated that the prevalence of bipolar disorder (BD) among children exceeds 1%, which calls for more research to enhance early identification, understanding, and management of this not-uncommon disease (5). Familial studies provide compelling evidence for a strong genetic contribution to BD (6), with heritability estimates, based on twin studies, of between 64% and 85% (7, 8). EO-BD has been shown to increase the familial risk rate substantially more than late-onset BD (LO-BD) (3). Despite the increased severity of EO-BD, as well as the strong evidence of heritability, the genetic basis of this disorder is undetermined.

BD is a heterogeneous disease that presents considerable challenges in the study of genetic risk factors (9). Investigators have proposed that classifying BD into subgroups with specific subphenotypes may facilitate the determination of associated genotypes (10). EO-BD may represent a clinically distinct BD subgroup with specific genetic risk factors (1). Consistent with this proposition, polymorphisms in at least 17 genes have been reported to be associated with EO-BD, including the brain-derived neurotrophic factor (BDNF) gene (2, 3, 11–21).

Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor in the central nervous system that has a role in growth, maintenance, and differentiation of neural cells (22). The BDNF gene is located in chromosome 11 at 11p13. BDNF rs6265 polymorphism is a common functional, nonsynonymous single nucleotide polymorphism (SNP) in which the amino acid valine (Val) is substituted with methionine (Met) (23). Because of its important neurologic functions, BDNF has been studied extensively as a candidate gene for BD, as well as other psychiatric illnesses (24).

The BDNF rs6265 (Val66Met) polymorphism has been evaluated in subphenotypes of BD. Two case-control candidate gene studies found an association between BDNF and EO-BD that was not identified in LO-BD (25, 26). Several studies have also reported an association of Val66Met with different age at onset among BD patients (27, 28). Non-DNA studies have further implicated reduced lymphocytic BDNF gene expression in EO-BD (29). Collectively, these studies are suggestive of a potential association between BDNF Val66Met polymorphism and EO-BD. Further studies in this area could elucidate the role of BDNF in EO-BD.

The aim of the present study was to further explore the association of BDNF Val66Met SNP with EO-BD through a case-control candidate gene study.

Methods

Ethics statement

Protocols and procedures were approved by the Mayo Clinic Institutional Review Board and the institutional review boards associated with the Treatment of Early Age Mania (TEAM) study. All participants provided informed consent.

Participants

The present study contained three participant groups: pediatric and adolescent BD patients from the TEAM study (n = 82), adult BD patients from the Mayo Clinic Bipolar Disorder Biobank (n = 855), and an adult healthy control group from the Mayo Clinic Biobank (n = 857) (30). The TEAM study was a randomized clinical trial comparing antimanic treatments (31). TEAM participants were outpatients [mean (standard deviation) age = 10.1 (2.8) years] with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) BD type I, manic, or mixed episodes. The inclusion and exclusion criteria are described elsewhere (31). Blood draw for future DNA studies was done before drug randomization.

Adult cases from the Mayo Clinic Bipolar Disorder Biobank included 855 participants with a diagnosis of BD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV-TR), aged 18 to 80 years at enrollment. Cases included participants with diagnoses of BD type I and BD type II. Exclusion criteria were the inability to speak English, inability or unwillingness to provide consent, and actively psychotic or suicidal state. From the Mayo Clinic Biobank, 857 participants were selected to be in the control group (30). Depending on self-report and electronic health records, the exclusion criteria were a current or prior psychiatric condition, including diagnosis of BD, clinical depression, schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism, and Down syndrome. Participants who reported having a first-degree relative with BD were also excluded. Controls were matched to adult cases from the Mayo Clinic BD Biobank for ethnicity/race, age, and gender.

Study assessment

The diagnosis of TEAM participants was confirmed by the Washington University in St. Louis (Missouri) Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) for DSM-IV. In the definition of a manic episode, severity level had to be ≥ 4 and a substantial impairment must be present. A score of ≤ 60 on the Children’s Global Assessment Scale was used to indicate serious impairment. To define a mixed episode, DSM-IV criteria had to be met for both mania and depressive disorders in coinciding time frames. Among the participants, 100% had elated mood or grandiosity; 82.6%, psychotic symptoms; and 95.7%, mixed episodes. Independent raters evaluated children and their primary caretakers. The results were combined through the highest scores from either the children or their primary caretaker ratings. Inter-rater reliability was 90% for psychiatric diagnoses, including mania, on the WASH-U-KSADS.

Adults with BD from the Mayo Clinic BD Biobank were assessed with the Structured Clinical Interview (SCID) for DSM-IV-TR. A patient questionnaire and clinical questionnaire were also used in the assessment, to obtain more information about the past medical and medication history of study participants. A subset of the adult BD cases were classified as early-onset BD, defined as first manic or depressive episode at age ≤ 19 years (n = 189), based on a review of the SCID and electronic medical record, when available. To produce a more homogeneous sample, we set the age threshold lower (≤ 19 years) than in earlier studies (1, 13, 14, 32). Demographics and main clinical characteristics of TEAM and adult BD cases are summarized in Table 1.

Table 1.

Demographics by bipolar disorder case, control, and age at onset status

Characteristic Controls TEAM BD Adults EO-BD only All adults BD
(n = 764) (n = 69) (n = 189) (n = 725)
Age at enrollment, years, mean (SD) 41.3 (14.6) 10.5 (2.9) 35.8 (12.7) 42.5 (15.1)
Gender, male, n (%) 312 (40.8) 30 (43.5) 64 (33.9) 299 (41.2)
BD type I, n (%) – 69 (100) 189 (100) 543 (74.9)
Rapid cycling, n (%) – 69 (100) 134 (70.9) 420 (58.4)
Psychosis, n (%) – 57 (82.6) 107 (58.2) 319 (44.9)
Mixed episodes, n (%) – 66 (95.7) 27 (14.3) 75 (10.5)
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TEAM BD = Treatment of Early Age Mania; EO-BD = early-onset bipolar disorder; BD = bipolar disorder; SD = standard deviation.

Genotyping and quality control

DNA specimens were isolated from blood samples. TEAM samples (n = 82) were genotyped with the TaqMan assay (Life Technologies) at Washington University; adult BD cases (n = 855) and controls (n = 857) from the Mayo Biobanks were genotyped using the same TaqMan assay on an ABI 7900 HT instrument (Applied Biosystems) the Karolinska Institutet. Ten adult BD cases from the Mayo biobank were genotyped at Washington University with the TEAM EO-BD samples for quality control, obtaining 100% concordant genotype calls at the Karolinska Institutet and Washington University for subjects genotyped in duplicate. To reduce the chances of confounding through population stratification, analyses were conducted only on Caucasian participants of European ancestry. After excluding nonwhite participants, as well as the participants whose genotyping had failed, 69 TEAM EO-BD cases, 725 adult Mayo Clinic Bipolar Disorder Biobank cases (189 of early onset), and 764 controls were included in the analyses. The genotype frequencies demonstrated no evidence of departures from Hardy–Weinberg Equilibrium within TEAM cases, adult cases, controls and overall (all p-value > 0.10)

Statistical analysis

To test the hypothesis of association between BDNF Val66Met SNP and EO-BD, we performed four genetic association analyses using logistic regression with log-additive allele effects (i.e., coding genotypes as 0, 1, and 2 representing the number of minor alleles). The first analysis assessed the association between BD in adult cases and the studied SNP, comparing the Mayo Clinic controls with the Mayo Clinic adult cases. The second analysis compared TEAM samples with controls to test the association of Val66Met with pediatric-onset BD specifically. In the third analysis, we tested for association of EO-BD with the BDNF SNP by comparing the subgroup of early-onset adult Mayo Clinic cases (≤ 19 years of age at disease onset) with the controls. In the fourth analysis, we compared the controls with the combined group of early-onset cases consisting of the TEAM samples and the early-onset subgroup of adult Mayo cases.

The comparison of all adult Mayo Clinic cases with controls had 80% power to detect effects with odds ratio (OR) ≥ 1.29. The comparison of TEAM sample and adult EO-BD Mayo sample with the controls had 80% power to detect effects with ORs of 1.78 and 1.47, respectively, while the combined EO-BD sample (TEAM + early onset adult Mayo) provided 80% power to detect ORs of 1.41 when compared with the controls.

Statistical analyses were completed with R statistical computing software. A p-value of 0.05 was predefined as threshold for statistical significance.

Results

Association of Val66Met with EO-BD

Comparison of adult BD cases with controls provided nonsignificant evidence of association of the minor Met allele of Val66Met with BD (OR = 1.19, p = 0.06). However, comparison of TEAM early-onset cases with controls showed a stronger association of the minor allele with EO-BD (OR = 1.55, p = 0.04). Although comparison of adult EO-BD cases from the Mayo Clinic BD Biobank with controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When early-onset adult BD cases from the Mayo BD Biobank and TEAM early-onset cases were together compared with the controls, the association of the minor allele of rs6265 with EO-BD was statistically significant (OR = 1.30, p = 0.04) (Table 2).

Table 2.

Case–control association of Val66Met variant with bipolar disorder

Cases Controls Cases Controls Genotype Cases Controls OR p-value
Case definition n n MAF MAF n (%) n (%)
Adult BD cases 725 764 0.207 0.179 Val/Val 459 (63.3) 513 (67.2) 1.19 0.06
Val/Met 232 (32) 228 (29.8)
Met/Met 34 (4.7) 23 (3)
TEAM cases 69 764 0.254 0.179 Val/Val 41 (59.4) 513 (67.2) 1.55 0.04
Val/Met 21 (30.4) 228 (29.8)
Met/Met 7 (10.1) 23 (3)
Early-onset adult BD cases 189 764 0.216 0.179 Val/Val 121 (64) 513 (67.2) 1.21 0.19
Val/Met 57 (30.2) 228 (29.8)
Met/Met 11 (5.8) 23 (3)
TEAM + early-onset adult BD cases 258 764 0.229 0.179 Val/Val 162 (62.8) 513 (67.2) 1.30 0.04
Val/Met 78 (30.2) 228 (29.8)
Met/Met 18 (7) 23 (3)
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BD = bipolar disorder; MAF = minor allele frequency; OR = odds ratio; TEAM, =Treatment of Early Age Mania.

Discussion

We performed a case-control candidate gene analysis studying the association of Val66Met in BDNF with EO-BD in the largest sample to date. Further, the TEAM cases were patients who were younger than in prior studies.

The present data show statistically significant evidence of association between EO-BD and Val66Met, yet show no significant evidence of association of the SNP with BD when comparing adult cases with controls. Evidence of association of the SNP with EO-BD was statistically significant in the comparison of TEAM cases (age: 6–15 years) vs controls and TEAM plus Mayo adult early-onset cases vs controls, but not in the comparison of controls with only the Mayo adult early-onset adult cases (≤ 19 years of age at disease onset). These findings could be explained by differences between participants in the TEAM study and adult patients from the Mayo Clinic Bipolar Disorder Biobank who were identified retrospectively as having had EO-BD. Differences between the groups may include age at onset and inclusion criteria, differential diagnosis, and diagnosis confirmation method. Specifically, TEAM cases had earlier onset of BD and thus might include cases with a more severe type of disease, which may be more genetically influenced than the Mayo Clinic BD Biobank early-onset adult cases. Thus, the early-onset adult cases may be an intermediate group that combines patients with pediatric onset, as well as those with early adult onset. On the other hand, knowing the earlier onset of TEAM cases, the evolution of this younger cohort diagnoses were not followed.

Other differences between the TEAM sample and the Mayo Clinic BD Biobank sample may have contributed to the observed difference in BDNF association with EO-BD. For example, ADHD was a common comorbidity in the TEAM sample. Knowing the similarity of the clinical presentation of ADHD and EO-BD, the TEAM sample BD diagnosis was differentiated from ADHD on the basis that 100% had elated mood or grandiosity and 82.6 had psychosis, accounting for symptoms that do not present in patients with ADHD solely. However, because one-third of the TEAM participants had ADHD, the possibility of Val66Met being associated with EO-BD comorbidity in ADHD cannot be ruled out.

Furthermore, TEAM study participants had the diagnosis of BD type I or mixed-episode BD, whereas the adult BD sample held a larger number of diagnoses, including BD type I and BD type II. Of note, the TEAM and early onset BD samples only contain subjects with BD type I, making the early onset group a more homogenous group. In addition, different structured clinical interviews were used to confirm the diagnosis in the two samples, which were WASH-U-KSADS and SCID for TEAM participants and early-onset adults from the Mayo Clinic BD Biobank, respectively. The heterogeneity in the set of diagnoses could further explain the difference in the genetic association results.

Our case–control study results agree with some previous reports in the literature. Skibinska and colleagues (26) found no association between adult LO-BD and Val66Met but reported a significant association when a subgroup of EO-BD cases was compared with the control group. Similar findings were reported by Tang and colleagues (25), where the association was present in the early-onset subgroup and absent in the LO-BD group. However, the studies were inconsistent with respect to the genotype associated with the EO-BD. In the study by Tang et al, the Val/Val genotype was associated with higher risk of EO-BD; however, the data of Skibinska et al indicated lower risk in heterozygotes, with higher risk in both types of homozygotes. When we reanalyzed these data, assuming log-additive allele effects, the association was not statistically significant. This inconsistency could be explained by limitations of the previous studies, including small sample size. The inconsistent results also may reflect different genetic effects in groups with different race/ethnicity.

To our knowledge, four meta-analyses of the BDNF Val66Met association with BD have been completed. Although 1 meta-analysis found a significant association (33), the other three indicated a lack of association (24, 34, 35). Most prior studies did not account for BD subphenotypes, such as EO-BD, which may have contributed to the lack of consistent findings. Moreover, most previous studies found association (although inconsistent) between the Val allele with BD, with stronger evidence in rapid cycling subgroup (36, 37). However, the Met allele appears deleterious and more functionally relevant. For example, Met carriers have been shown to have a smaller hippocampus with poorer functioning, impaired BDNF cellular trafficking and lower BDNF secretion (38–40). These observations are in line with our finding of the Met allele being associated with EO-BD. One possible explanation for this is epigenetic modifications. In one of the first epi-genome wide association studies, BD subjects with Val/Val genotype were found to have increased methylation of BDNF promotor IX in the prefrontal cortex (41). The authors suggested that the possible association of epigenetic changes with DNA variation is relevant to the inconsistency in genetic association studies of BD. Another explanation might be the possible implication of gene–environment interaction (e.g., childhood adversity) (42).

Although our sample provided statistically significant evidence for the association between Val66Met and EO-BD, these results must be interpreted with caution, given the study limitations. The present study contained a large sample for the control group; however, the EO-BD group still had a relatively modest size (n = 258), despite being the largest sample of early-onset cases analyzed to date for association with BDNF. Furthermore, a potential retrospective assessment bias might be present in classifying our early-onset adult cases. In addition, methods requiring genome-wide SNP data to control for population stratification (e.g., principal components) were not used in these analyses. However, all subjects were of self-reported European ancestry reducing the chance of confounding by population structure. Nevertheless, the study also had important strengths, including a well-characterized (albeit small) sample of EO-BD cases from the TEAM study.

Our finding of a significant association between a subgroup of BD with early onset and a candidate SNP adds to previous successful studies with similar design based on defining more homogeneous disease subgroups (10). The present study provides further evidence that BD is a heterogeneous disease, and identification of the contributing genetic risk factors may require a more careful approach to phenotyping.

In conclusion, these preliminary analyses are suggestive of association between Val66Met and risk of EO-BD. Future studies need to evaluate this association in larger samples to increase statistical power and allow investigation of secondary phenotypes related to EO-BD. Utilizing enriched EO-BD samples, studying BDNF (i.e., Val66Met variant) gene–environment interactions, as well as the correlation with BDNF methylation patterns is warranted.

Acknowledgements

This study was funded by the Marriott Foundation and Mayo Clinic Center for Individualized Medicine, as well as the Swedish Research Council (Grant nos. 2010–3631 and 2011–4807), the Karolinska Institutet’s Faculty Funds, and the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet. The original TEAM study described herein received funding from National Institute of Mental Health (NIMH) cooperative grants U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, and R01 MH051481. We gratefully acknowledge the pivotal contributions of Barbara Geller, MD, to designing and overseeing this project from its inception through the main publication. We acknowledge the TEAM investigators for the design, oversight, and execution of the original TEAM study.

The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US Department of Health and Human Services, the National Institutes of Health, or the NIMH.

PEC has received grant support from Pfizer, NIMH (K23 MH100266), the Brain and Behavior Research Foundation, and the Mayo Foundation; and has received in-kind support for equipment and supplies from Neuronetics, Inc, and AssureRx Health, Inc. JLL has received grant or research support from NIMH, the Communities Healing Adolescent Depression and Suicide Coalition, and the Sidney R. Baer, Jr Foundation. SLM is employed by the University of Cincinnati College of Medicine, University of Cincinnati Physicians/UC Health, and the Lindner Center of HOPE; is or has been a consultant to, or a member of the scientific advisory boards of, in the past year, Bracket, F. Hoffmann-La Roche Ltd, MedAvante Inc, Naurex Inc, Novo Nordisk A/S, Shire PLC, and Sunovion Pharmaceuticals Inc.; is, or has been in the past year, a principal investigator or a co-investigator on research studies sponsored by the Agency for Healthcare Research and Quality in the Department of Health and Human Services, Alkermes, Cephalon Inc., Forest Laboratories, Inc., the J. Willard and Alice S. Marriott Foundation, NIMH, Naurex Inc., Orexigen Therapeutics, Inc., Shire PLC, and Takeda Pharmaceutical Co Ltd.; and is also an inventor on US Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and, along with the patent’s assignee University of Cincinnati, Cincinnati, OH, has received payments from Johnson & Johnson Pharmaceutical Research and Development, LLC, which has exclusive rights under the patent. JTW has received grant funding from The Hartwell Foundation and the Tourette Syndrome Association; has received free medication/placebo from the following pharmaceutical companies for NIMH-funded studies: Eli Lilly & Co (2003), Abbott (2005), and Pfizer Inc. (2007); was paid for a one-time consultation with Shire PLC (2011); is a paid speaker for the Tourette Syndrome National Education and Outreach Program of the National Center on Birth Defects and Developmental Disabilities at the US Centers for Disease Control and Prevention; receives royalties for books on Tourette syndrome from Guilford Press and Oxford University Press, the American Academy of Child and Adolescent Psychiatry, and the American Psychiatric Association; and is an unpaid adviser to the Anxiety Disorders Association of America, Consumer Reports of US Inc., and the Trichotillomania Learning Center. KDW has received honoraria from UBM LLC, CME LLC, the American Psychiatric Association, the Las Vegas Psychiatric Society, the American Academy of Child and Adolescent Psychiatry, North American Center for Continuing Medical Education LLC, and Oxford University Press; and has been an unpaid consultant for Lundbeck. LC is employed by the University of Cincinnati College of Medicine and the University of Cincinnati Physicians/UC Health at the Lindner Center of HOPE; and is currently, or has been in the past year, a co-investigator on research studies sponsored by Cephalon, Inc., Forest Laboratories, the J. Willard and Alice S. Marriott Foundation, Naurex Inc., Shire PLC, and Takeda Pharmaceutical Co Ltd. PSJ is employed by The REACH Institute, New York, NY; in the past 12 months has received charitable gift support from Shire PLC and grant support from the J. Willard and Alice S. Marriott Foundation and the Klingenstein Third Generation Foundation; is a part owner of the psychiatric consulting organization CATCH Services Inc, New York, NY; and receives book royalties from American Psychiatric Publishing, Civic Research Institute Inc, Ballantine Books, and Guilford Press. JMB has received research funding from the National Institute on Drug Abuse (principal investigator), National Institute on Alcohol Abuse and Alcoholism (principal investigator), NIMH (as co-investigator), National Institute of General Medical Sciences (co-investigator), and the Marriott family, which supported the Mayo Clinic Bipolar Disorder Biobank (co-principal investigator). MAF has received grant support from AssureRx Health Inc., Myriad, Pfizer Inc., NIMH (R01 MH079261), the National Institute on Alcohol Abuse and Alcoholism (P20AA017830) in the National Institutes of Health at the US Department of Health and Human Services, and the Mayo Foundation; has been a consultant to Janssen Global Services, LLC, Mitsubishi Tanabe Pharma Corp., Myriad Genetics, Inc., Sunovion Pharmaceuticals, Inc., and Teva Pharmaceutical Industries Ltd.; and has received continuing medical education, travel, and presentation support from CME Outfitters, LLC, and Sunovion Pharmaceuticals, Inc.

Footnotes

Disclosures

MN, MV, PTJ, RMP, KC, JG, ABC, CL, and MS do have any conflicts of interest to disclose.

References

  • 1.Geoffroy PA, Etain B, Scott J, et al. Reconsideration of bipolar disorder as a developmental disorder: importance of the time of onset. J Physiol Paris. 2013;107:278–285. doi: 10.1016/j.jphysparis.2013.03.006. [DOI] [PubMed] [Google Scholar]
  • 2.Oliveira J, Hamdani N, Busson M, et al. Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder. J Affect Disord. 2014;165:135–141. doi: 10.1016/j.jad.2014.04.059. [DOI] [PubMed] [Google Scholar]
  • 3.Mick E, Faraone SV. Family and genetic association studies of bipolar disorder in children. Child Adolesc Psychiatr Clin N Am. 2009;18:441–453. doi: 10.1016/j.chc.2008.11.008. [DOI] [PubMed] [Google Scholar]
  • 4.Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71:864–872. doi: 10.4088/JCP.08m04994yel. [DOI] [PubMed] [Google Scholar]
  • 5.Wozniak J, Faraone SV, Martelon M, McKillop HN, Biederman J. Further evidence for robust familiality of pediatric bipolar I disorder: results from a very large controlled family study of pediatric bipolar I disorder and a meta-analysis. J Clin Psychiatry. 2012;73:1328–1334. doi: 10.4088/JCP.12m07770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Belmonte Mahon P, Pirooznia M, Goes FS, et al. Bipolar Genome Study (BiGS) Consortium, The Wellcome Trust Case Control Consortium Bipolar Disorder Group. Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:370–378. doi: 10.1002/ajmg.b.31172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Lichtenstein P, Yip BH, Bjork C, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373:234–239. doi: 10.1016/S0140-6736(09)60072-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60:497–502. doi: 10.1001/archpsyc.60.5.497. [DOI] [PubMed] [Google Scholar]
  • 9.Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998;21:102–105. doi: 10.1016/s0166-2236(97)01187-9. [DOI] [PubMed] [Google Scholar]
  • 10.Winham SJ, Cuellar-Barboza AB, Oliveros A, et al. Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2. Mol Psychiatry. 2014;19:1010–1016. doi: 10.1038/mp.2013.159. [DOI] [PubMed] [Google Scholar]
  • 11.McGrath CL, Glatt SJ, Sklar P, et al. Evidence for genetic association of RORB with bipolar disorder. BMC Psychiatry. 2009;9:70. doi: 10.1186/1471-244X-9-70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Dizier MH, Etain B, Lajnef M, et al. Genetic heterogeneity according to age at onset in bipolar disorder: a combined positional cloning and candidate gene approach. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:653–659. doi: 10.1002/ajmg.b.32069. [DOI] [PubMed] [Google Scholar]
  • 13.Etain B, Dumaine A, Mathieu F, et al. A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain. Mol Psychiatry. 2010;15:748–755. doi: 10.1038/mp.2008.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Jamain S, Cichon S, Etain B, et al. Common and rare variant analysis in early-onset bipolar disorder vulnerability. PLoS One. 2014;9:e104326. doi: 10.1371/journal.pone.0104326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Bellivier F, Laplanche JL, Schurhoff F, et al. Apolipoprotein E gene polymorphism in early and late onset bipolar patients. Neurosci Lett. 1997;233:45–48. doi: 10.1016/s0304-3940(97)00624-1. [DOI] [PubMed] [Google Scholar]
  • 16.Ospina-Duque J, Duque C, Carvajal-Carmona L, et al. An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia. Neurosci Lett. 2000;292:199–202. doi: 10.1016/s0304-3940(00)01464-6. [DOI] [PubMed] [Google Scholar]
  • 17.Massat I, Kocabas NA, Crisafulli C, et al. COMT and age at onset in mood disorders: a replication and extension study. Neurosci Lett. 2011;498:218–221. doi: 10.1016/j.neulet.2011.05.012. [DOI] [PubMed] [Google Scholar]
  • 18.Benedetti F, Dallaspezia S, Colombo C, Pirovano A, Marino E, Smeraldi E. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett. 2008;445:184–187. doi: 10.1016/j.neulet.2008.09.002. [DOI] [PubMed] [Google Scholar]
  • 19.Squassina A, Manchia M, Costa M, et al. Age at onset in bipolar disorder: investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample. Eur Psychiatry. 2011;26:141–143. doi: 10.1016/j.eurpsy.2010.09.013. [DOI] [PubMed] [Google Scholar]
  • 20.Gomez L, Wigg K, Feng Y, et al. G72/G30 (DAOA) and juvenile-onset mood disorders. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:1007–1012. doi: 10.1002/ajmg.b.30904. [DOI] [PubMed] [Google Scholar]
  • 21.Massat I, Lerer B, Souery D, et al. HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study. Mol Psychiatry. 2007;12:797–798. doi: 10.1038/sj.mp.4002018. [DOI] [PubMed] [Google Scholar]
  • 22.Carrard A, Salzmann A, Perroud N, Gafner J, Malafosse A, Karege F. Genetic association of the Phosphoinositide-3 kinase in schizophrenia and bipolar disorder and interaction with a BDNF gene polymorphism. Brain Behav. 2011;1:119–124. doi: 10.1002/brb3.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hong CJ, Liou YJ, Tsai SJ. Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull. 2011;86:287–297. doi: 10.1016/j.brainresbull.2011.08.019. [DOI] [PubMed] [Google Scholar]
  • 24.González-Castro TB, Nicolini H, Lanzagorta N, et al. The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects. Bipolar Disord. 2015;17:27–38. doi: 10.1111/bdi.12227. [DOI] [PubMed] [Google Scholar]
  • 25.Tang J, Xiao L, Shu C, et al. Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China. Neurosci Lett. 2008;433:98–102. doi: 10.1016/j.neulet.2008.01.001. [DOI] [PubMed] [Google Scholar]
  • 26.Skibinska M, Hauser J, Czerski PM, et al. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry. 2004;5:215–220. doi: 10.1080/15622970410029936. [DOI] [PubMed] [Google Scholar]
  • 27.Min HJ, Cho HS, Kim SJ, Seok JH, Lee E, Jon DI. Association of the brain-derived neurotrophic factor gene and clinical features of bipolar disorder in Korea. Clin Psychopharmacol Neurosci. 2012;10:163–167. doi: 10.9758/cpn.2012.10.3.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Rybakowski JK, Borkowska A, Czerski PM, Skibiska M, Hauser J. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord. 2003;5:468–472. doi: 10.1046/j.1399-5618.2003.00071.x. [DOI] [PubMed] [Google Scholar]
  • 29.Pandey GN, Rizavi HS, Dwivedi Y, Pavuluri MN. Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry. 2008;47:1077–1085. doi: 10.1097/CHI.0b013e31817eecd9. [DOI] [PubMed] [Google Scholar]
  • 30.Olson JE, Ryu E, Johnson KJ, et al. The Mayo Clinic Biobank: a building block for individualized medicine. Mayo Clin Proc. 2013;88:952–962. doi: 10.1016/j.mayocp.2013.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Geller B, Luby JL, Joshi P, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry. 2012;69:515–528. doi: 10.1001/archgenpsychiatry.2011.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Etain B, Mathieu F, Rietschel M, et al. Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14. Mol Psychiatry. 2006;11:685–694. doi: 10.1038/sj.mp.4001815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Fan J, Sklar P. Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism. Novartis Found Symp. 2008;289:60–72. doi: 10.1002/9780470751251.ch5. [DOI] [PubMed] [Google Scholar]
  • 34.Seifuddin F, Mahon PB, Judy J, et al. Meta-analysis of genetic association studies on bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:508–518. doi: 10.1002/ajmg.b.32057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kanazawa T, Glatt SJ, Kia-Keating B, Yoneda H, Tsuang MT. Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet. 2007;17:165–170. doi: 10.1097/YPG.0b013e32801da2e2. [DOI] [PubMed] [Google Scholar]
  • 36.Green EK, Raybould R, Macgregor S, et al. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. Br J Psychiatry. 2006;188:21–25. doi: 10.1192/bjp.bp.105.009969. [DOI] [PubMed] [Google Scholar]
  • 37.Muller DJ, de Luca V, Sicard T, King N, Strauss J, Kennedy JL. Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder: family-based association study. Br J Psychiatry. 2006;189:317–323. doi: 10.1192/bjp.bp.105.010587. [DOI] [PubMed] [Google Scholar]
  • 38.Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–269. doi: 10.1016/s0092-8674(03)00035-7. [DOI] [PubMed] [Google Scholar]
  • 39.Hariri AR, Goldberg TE, Mattay VS, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003;23:6690–6694. doi: 10.1523/JNEUROSCI.23-17-06690.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Szeszko PR, Lipsky R, Mentschel C, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10:631–636. doi: 10.1038/sj.mp.4001656. [DOI] [PubMed] [Google Scholar]
  • 41.Mill J, Tang T, Kaminsky Z, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82:696–711. doi: 10.1016/j.ajhg.2008.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Aguilera M, Arias B, Wichers M, et al. Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med. 2009;39:1425–1432. doi: 10.1017/S0033291709005248. [DOI] [PubMed] [Google Scholar]

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