Abstract
Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3′. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Clayton D . A generalization of the transmission/disequilibrium test for uncertain- haplotype transmission Am J Hum Genet 1999 65: 1170–1177
MacKinnon DF, Jamison KR, DePaulo JR . Genetics of manic depressive illness Annu Rev Neurosci 1997 20: 355–373
Mendlewicz J, Linkowski P, Wilmotte J . Relationship between schizoaffective illness and affective disorders or schizophrenia. Morbidity risk and genetic transmission J Affect Disord 1980 2: 289–302
Baron M, Risch N, Hamburger R, Mandel B, Kushner S, Newman M et al. Genetic linkage between X-chromosome markers and bipolar affective illness Nature 1987 326: 289–292
Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR et al. Bipolar affective disorders linked to DNA markers on chromosome 11 Nature 1987 325: 783–787
Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nat Genet 1996 12: 427–430
Asherson P, Mant R, Williams N, Cardno A, Jones L, Murphy K et al. A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder Mol Psychiatry 1998 3: 310–320
Craddock N, Owen M, Burge S, Kurian B, Thomas P, McGuffin P . Familial cosegregation of major affective disorder and Darier's disease (keratosis follicularis) Br J Psychiatry 1994 164: 355–358
Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P et al. Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23–24.1 Am J Med Genet 1995 60: 94–102
Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagn B et al. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24 Am J Med Genet 1999 88: 567–587
Ewald H, Degn B, Mors O, Kruse TA . Significant linkage between bipolar affective disorder and chromosome 12q24 Psychiatr Genet 1998 8: 131–140
Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3 Nat Genet 1994 8: 291–296
Detera-Wadleigh SD, Badner JA, Goldin LR, Berrettini WH, Sanders AR, Rollins DY et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q Am J Hum Genet 1996 58: 1279–1285
Detera-Wadleigh SD, Badner JA, Yoshikawa T, Sanders AR, Goldin LR, Turner G et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q Am J Med Genet 1997 74: 254–262
Smyth C, Kalsi G, Curtis D, Brynjolfsson J, Rifkin ONJL, Moloney E et al. Two-locus admixture linkage analysis of bipolar and unipolar affective disorder supports the presence of susceptibility loci on chromosomes 11p15 and 21q22 Genomics 1997 39: 271–278
Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent- of-origin effect Am J Hum Genet 1995 57: 1384–1394
McMahon FJ, Hopkins PJ, Xu J, McInnis MG, Shaw S, Cardon L et al. Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series Am J Hum Genet 1997 61: 1397–1404
Freimer NB, Reus VI, Escamilla M, Spesny M, Smith L, Service S et al. An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees Am J Med Genet 1996 67: 254–263
Escamilla MA, Spesny M, Reus VI, Gallegos A, Meza L, Molina J et al. Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population Am J Med Genet 1996 67: 244–253
Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr, Gershon ES . Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene Proc Natl Acad Sci U S A 1994 91: 5918–5921
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity Nat Genet 1998 20: 284–287
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes Nat Genet 2000 26: 76–80
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD . Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease Proc Natl Acad Sci U S A 1993 90: 1977–1981
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families Science 1993 261: 921–923
Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H et al. Mutation in blood coagulation factor V associated with resistance to activated protein C Nature 1994 369: 64–67
Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus Nat Genet 2000 26: 163–175
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease Nature 2001 411: 603–606
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease Nature 2001 411: 599–603
Simpson SG, Folstein SE, Meyers DA, DePaulo JR . Assessment of lineality in bipolar I linkage studies Am J Psychiatry 1992 149: 1660–1665
Friddle C, Koskela R, Ranade K, Hebert J, Cargill M, Clark CD et al. Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype Am J Hum Genet 2000 66: 205–215
Spitzer RL, Endicott J, Robins E . Clinical criteria for psychiatric diagnosis and DSM-III Am J Psychiatry 1975 132: 1187–1192
Foroud T, Castelluccio PF, Koller DL, Edenberg HJ, Miller M, Bowman E et al. Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees Am J Med Genet 2000 96: 18–23
Kirov G, Rees M, Jones I, MacCandless F, Owen MJ, Craddock N . Bipolar disorder and the serotonin transporter gene: a family-based association study Psychol Med 1999 29: 1249–1254
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes Nat Genet 1999 22: 231–238
DeAngelis MM, Wang DG, Hawkins TL . Solid-phase reversible immobilization for the isolation of PCR products Nucleic Acids Res 1995 23: 4742–4743
Chen X, Zehnbauer B, Gnirke A, Kwok PY . Fluorescence energy transfer detection as a homogeneous DNA diagnostic method Proc Natl Acad Sci U S A 1997 94: 10756–10761
Chen X, Kwok PY . Template-directed dye-terminator incorporation (TDI) assay: a homogeneous DNA diagnostic method based on fluorescence resonance energy transfer Nucleic Acids Res 1997 25: 347–353
Lindblad-Toh K, Winchester E, Daly MJ, Wang DG, Hirschhorn JN, Laviolette JP et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse Nat Genet 2000 24: 381–386
Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J et al. High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip- based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry Proc Natl Acad Sci U S A 2001 98: 581–584
Devlin B, Risch N . A comparison of linkage disequilibrium measures for fine-scale mapping Genomics 1995 29: 311–322
Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 Proc Natl Acad Sci U S A 1999 96: 5604–5609
Inayama Y, Yoneda H, Sakai T, Ishida T, Kobayashi S, Nonomura Y et al. Lack of association between bipolar affective disorder and tyrosine hydroxylase DNA marker Am J Med Genet 1993 48: 87–89
Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven C . Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients Am J Med Genet 1997 74: 176–178
Turecki G, Rouleau GA, Mari J, Joober R, Morgan K . Lack of association between bipolar disorder and tyrosine hydroxylase: a meta-analysis Am J Med Genet 1997 74: 348–352
Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC . No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder Am J Med Genet 1998 81: 245–247
Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D et al. Association between the tryptophan hydroxylase gene and manic- depressive illness Arch Gen Psychiatry 1998 55: 33–37
Kirov G, Owen MJ, Jones I, McCandless F, Craddock N . Tryptophan hydroxylase gene and manic-depressive illness Arch Gen Psychiatry 1999 56: 98–99
Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T, Nanko S . No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients Am J Psychiatry 1999 156: 774–776
Vincent JB, Masellis M, Lawrence J, Choi V, Gurling HM, Parikh SV, Kennedy JL . Genetic association analysis of serotonin system genes in bipolar affective disorder Am J Psychiatry 1999 156: 136–138
Serretti A, Lilli R, Lorenzi C, Lattuada E, Cusin C, Smeraldi E . Lack of association between tryptophan hydroxylase gene and psychotic symptomatology in schizophrenia [letter] Schizophr Res 1999 40: 171–172
Tsai SJ, Hong CJ, Wang YC . Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors Neuroreport 1999 10: 3773–3775
Stine OC, McMahon FJ, Chen L, Xu J, Meyers DA, MacKinnon DF et al. Initial genome screen for bipolar disorder in the NIMH genetics initiative pedigrees: chromosomes 2, 11, 13, 14, and X Am J Med Genet 1997 74: 263–269
Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C et al. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor Cell 1991 65: 885–893
Maisonpierre PC, Le Beau MM, Espinosa Rd, Ip NY, Belluscio L, de la Monte SM et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations Genomics 1991 10: 558–568
Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA . Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor J Biol Chem 2001 276: 12660–12666
Liu X, Ernfors P, Wu H, Jaenisch R . Sensory but not motor neuron deficits in mice lacking NT4 and BDNF Nature 1995 375: 238–241
Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex Cell 1999 98: 739–755
Altar CA . Neurotrophins and depression Trends Pharmacol Sci 1999 20: 59–61
Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF) Pharmacol Biochem Behav 1997 56: 131–137
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities Proc Natl Acad Sci U S A 1999 96: 15239–15244
Jardine R, Martin NG, Henderson AS . Genetic covariation between neuroticism and the symptoms of anxiety and depression Genet Epidemiol 1984 1: 89–107
Bagby RM, Young LT, Schuller DR, Bindseil KD, Cooke RG, Dickens SE et al. Bipolar disorder, unipolar depression and the Five-Factor Model of personality J Affect Disord 1996 41: 25–32
Hawi Z, Straub RE, O'Neill A, Kendler KS, Walsh D, Gill M . No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families Psychiatry Res 1998 81: 111–116
Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF, Sokoloff P . Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia Mol Psychiatry 2000 5: 558–562
Wassink TH, Nelson JJ, Crowe RR, Andreasen NC . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia Am J Med Genet 1999 88: 724–728
Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW . Neuroimaging in bipolar disorder Bipolar Disord 2000 2: 148–164
Baumann B, Bogerts B . Neuroanatomical studies on bipolar disorder Br J Psychiatry 2001 178: S142–S147
Baumann B, Bogerts B . Neuroanatomical studies on bipolar disorder Br J Psychiatry Suppl 2001 41: s142–s147
Elkis H, Friedman L, Wise A, Meltzer HY . Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparisons with controls or patients with schizophrenia Arch Gen Psychiatry 1995 52: 735–746
Soares JC, Mann JJ . The anatomy of mood disorders—review of structural neuroimaging studies Biol Psychiatry 1997 41: 86–106
Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME . Subgenual prefrontal cortex abnormalities in mood disorders Nature 1997 386: 824–827
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW . Hippocampal atrophy in recurrent major depression Proc Natl Acad Sci U S A 1996 93: 3908–3913
Steffens DC, Krishnan KR . Structural neuroimaging and mood disorders: recent findings, implications for classification, and future directions Biol Psychiatry 1998 43: 705–712
Chen G, Zeng WZ, Yuan PX, Huang LD, Jiang YM, Zhao ZH, Manji HK . The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS J Neurochem 1999 72: 879–882
Pettmann B, Henderson CE . Neuronal cell death Neuron 1998 20: 633–647
Jo K, Derin R, Li M, Bredt DS . Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN- 7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex J Neurosci 1999 19: 4189–4199
Acknowledgements
We thank the patients and families for participation, Rose Kouyoumjian and Noel Burtt for technical assistance with genotyping, Michele Cargill and the high-throughput SNP detection team, David Altshuler and Leif Groop for DNAs. We thank the Stanley Foundation for brain RNA. For the NIMH samples, data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991–98, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD, and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, MD, Allison Goate, PhD, and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274, J Raymond DePaulo, Jr, MD, Sylvia Simpson, MD, MPH, and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA, and Elizabeth Maxwell, MSW. Collection and typing of the UK sample was supported by grants from the Wellcome Trust.
This study was supported by a NARSAD Young Investigator Award (PS), a research grant from Bristol-Myers Squibb, Millennium Pharmaceuticals, and Affymetrix (ESL). GK is a Wellcome Trust Advanced Fellow, IJ is a Wellcome Trust Training Fellow in Mental Health, and NC is a Wellcome Trust Research Fellow in Clinical Sciences.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sklar, P., Gabriel, S., McInnis, M. et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 7, 579–593 (2002). https://doi.org/10.1038/sj.mp.4001058
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001058
Keywords
This article is cited by
-
BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects
Brain Imaging and Behavior (2023)
-
Pedigree-based study to identify GOLGB1 as a risk gene for bipolar disorder
Translational Psychiatry (2022)
-
Lithium as a Neuroprotective Agent for Bipolar Disorder: An Overview
Cellular and Molecular Neurobiology (2022)
-
SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population
BMC Medical Genetics (2020)
-
Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia
Advances in Rheumatology (2020)