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Brief Report   |    
Linkage Disequilibrium of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism in Children With a Prepubertal and Early Adolescent Bipolar Disorder Phenotype
Barbara Geller, M.D.; Judith A. Badner, M.D., Ph.D.; Rebecca Tillman, M.S.; Susan L. Christian, Ph.D.; Kristine Bolhofner, B.S.; Edwin H. Cook, Jr., M.D.
Am J Psychiatry 2004;161:1698-1700. doi:10.1176/appi.ajp.161.9.1698
Abstract

OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands’ diagnoses. Genotyping was done with TaqMan Assay-on-Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: χ2=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele.

Abstract Teaser
Figures in this Article

Brain-derived neurotrophic factor (BDNF) is heavily expressed in human brain and has increased expression beginning in young adulthood (1). Relevance to child psychiatry of differential BDNF expression by age is not yet known. Preclinically, BDNF has been implicated in numerous mood-relevant neurobiological actions (e.g., antidepressant drug response [2] and the neuroprotective action of lithium [3]), and thus it was hypothesized to be a good candidate for investigation in bipolar disorders. Moreover, the Val66 allele is a functional variant in both human and preclinical studies (4).

Recently, two independent research groups, using family-based methods, reported that the Val66 allele (at amino acid position 66 in exon 1 of the BDNF gene on chromosome 11p13) was preferentially transmitted to predominantly Caucasian adult probands with bipolar disorder (5, 6). One Japanese case-control study had negative findings (7).

Based on functionality of the Val66Met single nucleotide polymorphism (SNP) (4) and on family-based findings in adult bipolar disorder (5, 6), preferential transmission of the Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was hypothesized.

Probands were a subset of subjects in the NIMH-funded Phenomenology and Longitudinal Course of Pediatric Bipolar Disorders study (8, 9) and were obtained by consecutive new case ascertainment from designated pediatric and child psychiatry venues, using methods described in detail elsewhere (9). In brief, research nurses screened every new child at multiple pediatric and child psychiatric sites. All children who were not excluded because of a priori exclusion criteria (e.g., major medical illness) were interviewed by phone, and, if they still were not excluded, they were given the complete research assessments.

Comprehensive assessment by research nurses who were blind to the probands’ diagnoses included the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (10) given separately to the probands’ parents about their children and to the children about themselves (11). The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one of the two cardinal criteria of mania (i.e., euphoria and/or grandiosity). Use of this cardinal symptom approach was analogous to the DSM-IV requirement of sad mood or anhedonia for a diagnosis of major depressive disorder. This definition of a prepubertal and early adolescent bipolar disorder phenotype ensured differentiation from attention deficit hyperactivity disorder. This differentiation was a major contentious issue in the field of child bipolar disorder, because of overlapping symptoms (e.g., hyperactivity, distractibility) between the two disorders (8, 9). Moreover, the cardinal symptom approach also facilitated differentiation of a prepubertal and early adolescent bipolar disorder phenotype from other child psychiatry disorders that have aggression/irritability as a symptom (e.g., references 12, 13). The Children’s Global Assessment Scale (14) score needed to be ≤60, which corresponds to definite clinical impairment (15). The prepubertal and early adolescent bipolar disorder phenotype has 4-year longitudinal validation (8).

After complete description of the study was provided to parents and children, written informed consent was obtained from parents and written assent from children.

DNA extraction was performed by using a PureGene DNA extraction kit by Gentra Systems Inc. (Minneapolis), and DNA quantitation was conducted with the PicoGreen dsDNA kit by Molecular Probes, Inc. (Eugene, Ore.). SNP genotyping was performed by using TaqMan Assay-on-Demand (Applied Biosystems, Foster City, Calif.). Data acquisition was performed on the Analyst AD (Molecular Devices, Sunnyvale, Calif.) by using the fluorescence intensity method.

Genotype data were analyzed with the Family Based Association Test program (http://www.biostat.harvard.edu/~fbat/fbat. htm) and with the ASPEX/sib_tdt program (16). A one-tailed test was used for analysis because only preferential transmission of the Val66 allele would be considered significant, based on adult bipolar disorder studies (5, 6).

The probands’ mean age was 10.7 years (SD=2.7), the mean age at onset of baseline mania episodes was 7.6 years (SD=3.6), and the mean duration of baseline mania episodes was 3.2 years (SD=2.5). The mean Children’s Global Assessment Scale score was 44.3 (SD=8.5). The proportion of female subjects was 35.8%, of Caucasians was 88.7%, and of prepubertal subjects was 60.4%.

There were 53 complete, independent biological trios (probands and both biological parents), among which there were 27 informative trios. The frequency of parental Val66 alleles was 79.2%. Proband alleles were in Hardy-Weinberg equilibrium (χ2=0.05, df=2, p=0.98). Analyses showed preferential transmission of the BDNF Val66 allele (Family Based Association Test: χ2=6.0, df=1, p=0.014; sib_tdt: p=0.014). The Val66 allele was transmitted 21 times and not transmitted nine times (both parents in a trio may transmit the allele). Exploratory analyses by prepubertal status (16 informative trios) were significant (Family Based Association Test: χ2=6.8, df=1, p=0.009; sib_tdt: p=0.011). Analyses by gender and by postpubertal status were not significant, but the number of informative trios for postpubertal status was small (N=11).

These data suggest that the BDNF Val66 allele confers susceptibility to a prepubertal and early adolescent bipolar disorder phenotype. To our knowledge, this is the first significant molecular genetic finding in child bipolar disorder. Whether this finding has implications for continuities between child and adult bipolar disorder will be an important question for future research.

Specificity of preferential Val66 allele transmission for bipolar disorder is unclear, as this finding has also been reported in one family-based study of probands with childhood-onset obsessive-compulsive disorder (17).

Received Aug. 14, 2003; revision received Dec. 16, 2003; accepted March 9, 2004. From the Department of Psychiatry, Washington University School of Medicine; and the Department of Psychiatry, University of Chicago, Chicago. Address reprint requests to Dr. Geller, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110; gellerb@medicine.wustl.edu (e-mail). Supported by NIMH grants MH-53063 and MH-57451 to Dr. Geller and MH-01389 to Dr. Cook; the Theodore and Vada Stanley Foundation (Dr. Geller and Dr. Cook); and the Nathan Cummings Foundation (Dr. Geller). The authors thank Betsy Zimerman, B.S.N., M.A., and Marlene Williams, R.N., for help with administration and data collection; Jeanne Frazier, B.S.N., and Linda Beringer, R.N., for help with data collection; and Diane Dickel, Heather L. Fritz, and Zhi-Ying Yang for help with genotyping.

Webster MJ, Weickert CS, Herman MM, Kleinman JE: BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Dev Brain Res  2002; 139:139–150
[CrossRef]
 
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS: Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci  2002; 22:3251–3261
[PubMed]
 
Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang DM: Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology  2002; 43:1173–1179
[PubMed]
[CrossRef]
 
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell  2003; 112:257–269
[PubMed]
[CrossRef]
 
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL: The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet  2002; 71:651–655
[PubMed]
[CrossRef]
 
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES: Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus: brain-derived neutrophic factor. Mol Psychiatry  2002; 7:579–593
[PubMed]
[CrossRef]
 
Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, Katsu T, Tanaka Y, Hamamura T, Kuroda S: Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett  2003; 337:17–20
[PubMed]
[CrossRef]
 
Geller B, Tillman R, Craney JL, Bolhofner K: Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry  2004; 61:459–467
[PubMed]
[CrossRef]
 
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, Frazier J, Beringer L: DSM-IV mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype compared to attention-deficit hyperactive and normal controls. J Child Adolesc Psychopharmacol  2002; 12:11–25
[PubMed]
[CrossRef]
 
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, DelBello MP, Soutullo C: Reliability of the Washington University in St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections. J Am Acad Child Adolesc Psychiatry  2001; 40:450–455
[PubMed]
[CrossRef]
 
Tillman R, Geller B, Craney JL, Bolhofner K, Williams M, Zimerman B: Relationship of parent and child informants to prevalence of mania symptoms in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry  2004; 161:1278–1284
[PubMed]
[CrossRef]
 
McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D: Risperidone in children with autism and serious behavioral problems. N Engl J Med  2002; 347:314–321
[PubMed]
[CrossRef]
 
Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poulton R: Prior juvenile diagnoses in adults with mental disorder. Arch Gen Psychiatry  2003; 60:709–717
[PubMed]
[CrossRef]
 
Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Aluwahlia S: A Children’s Global Assessment Scale (CGAS). Arch Gen Psychiatry  1983; 40:1228–1231
[PubMed]
 
Bird HR, Gould MS, Staghezza B: Aggregating data from multiple informants in child psychiatry epidemiological research. J Am Acad Child Adolesc Psychiatry  1992; 31:78–85
[PubMed]
[CrossRef]
 
Hinds DA, Risch N: The ASPEX package: affective sib-pair exclusion mapping, 1996.
 
Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M: Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet  2003; 73:370–376
[PubMed]
[CrossRef]
 
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References

Webster MJ, Weickert CS, Herman MM, Kleinman JE: BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Dev Brain Res  2002; 139:139–150
[CrossRef]
 
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS: Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci  2002; 22:3251–3261
[PubMed]
 
Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang DM: Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology  2002; 43:1173–1179
[PubMed]
[CrossRef]
 
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell  2003; 112:257–269
[PubMed]
[CrossRef]
 
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL: The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet  2002; 71:651–655
[PubMed]
[CrossRef]
 
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES: Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus: brain-derived neutrophic factor. Mol Psychiatry  2002; 7:579–593
[PubMed]
[CrossRef]
 
Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, Katsu T, Tanaka Y, Hamamura T, Kuroda S: Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett  2003; 337:17–20
[PubMed]
[CrossRef]
 
Geller B, Tillman R, Craney JL, Bolhofner K: Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry  2004; 61:459–467
[PubMed]
[CrossRef]
 
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, Frazier J, Beringer L: DSM-IV mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype compared to attention-deficit hyperactive and normal controls. J Child Adolesc Psychopharmacol  2002; 12:11–25
[PubMed]
[CrossRef]
 
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, DelBello MP, Soutullo C: Reliability of the Washington University in St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections. J Am Acad Child Adolesc Psychiatry  2001; 40:450–455
[PubMed]
[CrossRef]
 
Tillman R, Geller B, Craney JL, Bolhofner K, Williams M, Zimerman B: Relationship of parent and child informants to prevalence of mania symptoms in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry  2004; 161:1278–1284
[PubMed]
[CrossRef]
 
McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D: Risperidone in children with autism and serious behavioral problems. N Engl J Med  2002; 347:314–321
[PubMed]
[CrossRef]
 
Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poulton R: Prior juvenile diagnoses in adults with mental disorder. Arch Gen Psychiatry  2003; 60:709–717
[PubMed]
[CrossRef]
 
Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Aluwahlia S: A Children’s Global Assessment Scale (CGAS). Arch Gen Psychiatry  1983; 40:1228–1231
[PubMed]
 
Bird HR, Gould MS, Staghezza B: Aggregating data from multiple informants in child psychiatry epidemiological research. J Am Acad Child Adolesc Psychiatry  1992; 31:78–85
[PubMed]
[CrossRef]
 
Hinds DA, Risch N: The ASPEX package: affective sib-pair exclusion mapping, 1996.
 
Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M: Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet  2003; 73:370–376
[PubMed]
[CrossRef]
 
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