Skip to main content
SpringerLink
Log in

Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder

  • Biological Psychiatry - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The vesicle-associated membrane protein-associated protein A (VAPA) gene maps to this region. VAPA interacts with presynaptic proteins and is necessary for vesicular neurotransmission. Dysregulation of synaptic neurotransmission might contribute to the pathophysiology of BPD. In this study, we hypothesize that genetic variations in the VAPA gene contribute to BPD. We tested this hypothesis by genotyping 6 SNPs (rs494015; rs29193; rs29162; rs29145; rs29067; rs29066) in BPD patients (n = 570) and healthy controls (n = 730). Genotype and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs29067 and rs29066 with BPD; however, after permutation correction, only rs29066 showed a trend towards an allelic association (P = 0.066). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide suggestive evidence of an association between SNPs in the 3′UTR of the VAPA gene and BPD. Interestingly, these SNPs are in close proximity to the microsatellite marker D18S464, which showed significant signals in previous linkage studies of BPD. Additional studies are necessary to confirm and elucidate the role of VAPA as a susceptibility gene for BPD on chromosome 18p.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Bacanu SA, Devlin B, Roeder K (2000) The power of genomic control. Am J Hum Genet 66:1933–1944

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, Schulze TG, Cichon S, Rietschel M, Nothen MM, Georgi A, Schumacher J, Schwarz M, Abou Jamra R, Hofels S, Propping P, Satagopan J, Detera-Wadleigh SD, Hardy J, McMahon FJ (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13:197–207

    Article  PubMed  CAS  Google Scholar 

  • Beasley CL, Honer WG, Bergmann K, Falkai P, Lutjohann D, Bayer TA (2005) Reductions in cholesterol and synaptic markers in association cortex in mood disorders. Bipolar Disord 7:449–455

    Article  PubMed  CAS  Google Scholar 

  • Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D, Heron J, Comerford C, Middle F, Corvin A, Pelios G, Kirov G, Larsen B, Mulcahy T, Williams N, O’Connell R, O’Mahony E, Payne A, Owen M, Holmans P, Craddock N, Gill M (2002) The wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry 7:189–200

    Article  PubMed  CAS  Google Scholar 

  • Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr, Gershon ES (1994) Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci USA 91:5918–5921

    Article  PubMed  CAS  Google Scholar 

  • Berrettini WH, Vuoristo J, Ferraro TN, Buono RJ, Wildenauer D, Ala-Kokko L (1998) Human G(olf) gene polymorphisms and vulnerability to bipolar disorder. Psychiatr Genet 8:235–238

    Article  PubMed  CAS  Google Scholar 

  • Bly M (2005) Mutation in the vesicular monoamine gene, SLC18A1, associated with schizophrenia. Schizophr Res 78:337–338

    Article  PubMed  Google Scholar 

  • Bowen T, Kirov G, Gill M, Spurlock G, Vallada HP, Murray RM, McGuffin P, Collier DA, Owen MJ, Craddock N (1999) Linkage studies of bipolar disorder with chromosome 18 markers. Am J Med Genet 88:503–509

    Article  PubMed  CAS  Google Scholar 

  • Chen K, Rajewsky N (2006) Natural selection on human microRNA binding sites inferred from SNP data. Nat Genet 38:1452–1456

    Article  PubMed  CAS  Google Scholar 

  • Chen SF, Chen CH, Chen JY, Wang YC, Lai IC, Liou YJ, Liao DL (2007) Support for association of the A277C single nucleotide polymorphism in human vesicular monoamine transporter 1 gene with schizophrenia. Schizophr Res 90:363–365

    Article  PubMed  Google Scholar 

  • Corradi JP, Ravyn V, Robbins AK, Hagan KW, Peters MF, Bostwick R, Buono RJ, Berrettini WH, Furlong ST (2005) Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. Mol Psychiatry 10:1017–1025

    Article  PubMed  CAS  Google Scholar 

  • Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G, Rollins DY, Moses T, Sanders AR, Karkera JD, Esterling LE, Zeng J, Ferraro TN, Guroff JJ, Kazuba D, Maxwell ME, Nurnberger JI Jr, Gershon ES (1999) 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 USA 96:5604–5609

    Article  PubMed  CAS  Google Scholar 

  • Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Eastwood SL, Harrison PJ (2000) Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 5:425–432

    Article  PubMed  CAS  Google Scholar 

  • Esterling LE, Cox Matise T, Sanders AR, Yoshikawa T, Overhauser J, Gershon ES, Moskowitz MT, Detera-Wadleigh SD (1997) An integrated physical map of 18p11.2: a susceptibility region for bipolar disorder. Mol Psychiatry 2:501–504

    Article  PubMed  CAS  Google Scholar 

  • Fatemi SH, Earle JA, Stary JM, Lee S, Sedgewick J (2001) Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia. Neuroreport 12:3257–3262

    Article  PubMed  CAS  Google Scholar 

  • Frayling TM (2007) Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 8:657–662

    Article  PubMed  CAS  Google Scholar 

  • Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D (2004) Assessing the impact of population stratification on genetic association studies. Nat Genet 36:388–393

    Article  PubMed  CAS  Google Scholar 

  • Gutiérrez B, Rosa A, Papiol S, Arrufat F, Catalán R, Salgado P, Peralta V, Cuesta M, Fañanás L (2007) Identification of two risk haplotypes for schizophrenia and bipolar disorder in the synaptic vesicle monoamine transporter gene (SVMT). Am J Med Genet B Neuropsychiatr Genet 144B:502–507

    Article  PubMed  CAS  Google Scholar 

  • Heslop KE, Curzon G (1999) Effect of reserpine on behavioural responses to agonists at 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor subtypes. Neuropharmacology 38:883–891

    Article  PubMed  CAS  Google Scholar 

  • Hieronymus H, Silver PA (2004) A systems view of mRNP biology. Genes Dev 18:2845–2860

    Article  PubMed  CAS  Google Scholar 

  • Hirschfeld RM (2000) History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 61 Suppl 6:4–6

    PubMed  CAS  Google Scholar 

  • Honer WG, Falkai P, Bayer TA, Xie J, Hu L, Li H-Y, Arango V, Mann JJ, Dwork AJ, Trimble WS (2002) Abnormalities of SNARE mechanism proteins in anterior frontal cortex in severe mental illness. Cereb Cortex 12:349–356

    Article  PubMed  Google Scholar 

  • Ilardi JM, Mochida S, Sheng Z-H (1999) Snapin: a SNARE-associated protein implicated in synaptic transmission. Nat Neurosci 2:119–124

    Google Scholar 

  • Ishiguro H, Ohtsuki T, Okubo Y, Kurumaji A, Arinami T (2001) Association analysis of the pituitary adenyl cyclase activating peptide gene (PACAP) on chromosome 18p11 with schizophrenia and bipolar disorders. J Neural Transm 108:849–854

    Article  PubMed  CAS  Google Scholar 

  • Jayanthi LD, Ramamoorthy S (2005) Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. Aaps J 7:E728–E738

    Article  PubMed  CAS  Google Scholar 

  • John I Nurnberger JRD Jr, Gershon Elliot S, Reich Theodore, Blehar Mary C, Edenberg Howard J, Foroud Tatiana, Miller Marvin, Bowman Elizabeth, Aimee Mayeda N, Rau Leela, Carrie Smiley P, Conneally Michael, McMahon Francis, Meyers Deborah, Simpson Sylvia, Melvin McInnis O, Stine Colin, Detera-Wadleigh Sevilla, Goldin Lynn, Guroff Juliet, Maxwell Elizabeth, Kazuba Diane, Gejman Pablo V, Badner Judith, Sanders Alan, Rice John, Bierut Laura, Goate Alison (1997) Genomic survey of bipolar illness in the NIMH genetics initiative pedigrees: a preliminary report. Am J Med Genet 74:227–237

  • Kessler RC, Andrews G, Mroczek D, Ustun B, Wittchen H (1998) The World Health Organization composite international diagnostic interview short-form (CIDI-SF). Int J Methods Psychiatr Res 7:171–185

    Article  Google Scholar 

  • Lohoff FW, Berrettini WH (2005) Lack of association between variations in the melanocortin 5 receptor gene and bipolar disorder. Psychiatr Genet 15:255–258

    Article  PubMed  Google Scholar 

  • Lohoff FW, Dahl JP, Ferraro TN, Arnold SE, Gallinat J, Sander T, Berrettini WH (2006) Variations in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) are associated with bipolar I disorder. Neuropsychopharmacology 31:2739–2747

    Article  PubMed  CAS  Google Scholar 

  • McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, Rojas E, Spesny M, Baharloo S, Blankenship K, Peterson A, Tyler D, Shimayoshi N, Tobey C, Batki S, Vinogradov S, Meza L, Gallegos A, Fournier E, Smith LB, Barondes SH, Sandkuijl LA, Freimer NB (1996) A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci USA 93:13060–13065

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee O, Meera P, Ghosh S, Kubendran S, Kiran K, Manjunath KR, Subhash MN, Benegal V, Brahmachari SK, Majumder PP, Jain S (2006) Evidence of linkage and association on 18p11.2 for psychosis. Am J Med Genet B Neuropsychiatr Genet 141B:868–873

    Article  PubMed  CAS  Google Scholar 

  • Nothen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J, Albus M, Borrmann-Hassenbach M, Kreiner R, Weigelt B, Minges J, Lichtermann D, Maier W, Craddock N, Fimmers R, Holler T, Baur MP, Rietschel M, Propping P (1999) Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families. Mol Psychiatry 4:76–84

    Article  PubMed  CAS  Google Scholar 

  • Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T (1994) Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51:849–859; discussion 844–863.

    PubMed  Google Scholar 

  • Pritchard JK, Donnelly P (2001) Case-control studies of association in structured or admixed populations. Theor Popul Biol 60:227–237

    Article  PubMed  CAS  Google Scholar 

  • Reyes GD, Esterling LE, Corona W, Ferraren D, Rollins DY, Padigaru M, Yoshikawa T, Monje VD, Detera-Wadleigh SD (2002) Map of candidate genes and STSs on 18p11.2, a bipolar disorder and schizophrenia susceptibility region. Mol Psychiatry 7:337–339

    Article  PubMed  CAS  Google Scholar 

  • Richards M, Iijima Y, Kondo H, Shizuno T, Hori H, Arima K, Saitoh O, Kunugi H (2006) Association study of the vesicular monoamine transporter 1 (VMAT1) gene with schizophrenia in a Japanese population. Behav Brain Funct 2:39

    Article  PubMed  CAS  Google Scholar 

  • Rojas K, Liang L, Johnson EI, Berrettini WH, Overhauser J (2000) Identification of candidate genes for psychiatric disorders on 18p11. Mol Psychiatry 5:389–395

    Article  PubMed  CAS  Google Scholar 

  • Saunders MA, Liang H, Li WH (2007) Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104:3300–3305

    Article  PubMed  CAS  Google Scholar 

  • Scarr E, Gray L, Keriakous D, Robinson PJ, Dean B (2006) Increased levels of SNAP–25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder. Bipolar Disord 8:133–143

    Article  PubMed  CAS  Google Scholar 

  • Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–676

    Article  PubMed  CAS  Google Scholar 

  • Skehel PA, Martin KC, Kandel ER, Bartsch D (1995) A VAMP-binding protein from Aplysia required for neurotransmitter release. Science 269:1580–1583

    Article  PubMed  CAS  Google Scholar 

  • Slattery DA, Hudson AL, Nutt DJ (2004) Invited review: the evolution of antidepressant mechanisms. Fundam Clin Pharmacol 18:1–21

    Article  PubMed  CAS  Google Scholar 

  • Spielman RS, Ewens WJ (1996) The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 59:983–989

    PubMed  CAS  Google Scholar 

  • Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C, Clark CD, McInnis MG, Simpson SG, Breschel TS et al (1995) Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet 57:1384–1394

    PubMed  CAS  Google Scholar 

  • Sullivan PF (2007) Spurious genetic associations. Biol Psychiatry 61:1121–1126

    Article  PubMed  CAS  Google Scholar 

  • The Welcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  CAS  Google Scholar 

  • Tsiouris SJ, Breschel TS, Xu J, McInnis MG, McMahon FJ (1996) Linkage disequilibrium analysis of G-olf alpha (GNAL) in bipolar affective disorder. Am J Med Genet 67:491–494

    Article  PubMed  CAS  Google Scholar 

  • Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ (2002) Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol Psychiatry 7:571–578

    Article  PubMed  CAS  Google Scholar 

  • Washizuka S, Kakiuchi C, Mori K, Kunugi H, Tajima O, Akiyama T, Nanko S, Kato T (2003) Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 120:72–78

    Article  Google Scholar 

  • Washizuka S, Iwamoto K, Kazuno AA, Kakiuchi C, Mori K, Kametani M, Yamada K, Kunugi H, Tajima O, Akiyama T, Nanko S, Yoshikawa T, Kato T (2004) Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees. Biol Psychiatry 56:483–489

    Article  PubMed  CAS  Google Scholar 

  • Weir ML, Klip A, Trimble WS (1998) Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP–33): a broadly expressed protein that binds to VAMP. Biochem J 333(Pt 2):247–251

    PubMed  CAS  Google Scholar 

  • Weir ML, Xie H, Klip A, Trimble WS (2001) VAP-A binds promiscuously to both v- and tSNAREs. Biochem Biophys Res Commun 286:616–621

    Article  PubMed  CAS  Google Scholar 

  • Weller AE, Dahl JP, Lohoff FW, Ferraro TN, Berrettini WH (2006) Analysis of variations in the NAPG gene on chromosome 18p11 in bipolar disorder. Psychiatr Genet 16:3–8

    Article  PubMed  Google Scholar 

  • Yoshikawa T, Turner G, Esterling LE, Sanders AR, Detera-Wadleigh SD (1997) A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder. Mol Psychiatry 2:393–397

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE, Detera-Wadleigh SD (2000) Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2). Mol Psychiatry 5:165–171

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania. Financial support is gratefully acknowledged from National Institutes of Health grants MH59553, MH63876 (to W H.B.) and K08 MH080372 (to F W.L.), grants from the National Alliance for Research on Schizophrenia and Depression (to W H.B. and F W.L.), a grant from the Tzedakah Foundation (to W H.B.), the Daland Fellowship Award by the American Philosophical Society (to F W.L.), a grant from Philip and Marcia Cohen (to W H.B.), the McCabe Foundation (to F W.L) and the APIRE/AstraZeneca Young Minds in Psychiatry Award (to F W.L.). We thank Candice Schwebel for technical assistance. Most importantly, we thank the families who have participated in and contributed to these studies. Data and biomaterials utilized in this study were collected as part of ten projects that participated in the national institute of mental health (NIMH) Bipolar Disorder Genetics Initiative. From 1999 to 2003, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M.D., Ph.D., Marvin Miller, M.D., Elizabeth Bowman, M.D., N. Leela Rau, M.D, P. Ryan Moe, M.D., Nalini Samavedy, M.D., Rif El-Mallakh, M.D, (at University of Louisville), Husseini Manji, M.D. (at Wayne State University), Debra A. Blitz, M.D (at Wayne State University), Eric T. Meyer, M.S., Carrie Smiley, R.N., Tatiana Foroud, Ph.D., Leah Flury, M.S., Danielle M. Dick, Ph.D., Howard Edenberg, Ph.D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph.D., Theodore Reich, M.D., Allison Goate, Ph.D., Laura Bierut, M.D.; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis, M.D., J. Raymond DePaulo, Jr., M.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., James B. Potash, M.D., Peter P. Zandi, Ph.D, Dimitrios Avramopoulos, Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini, M.D., Ph.D.; University of California at Irvine, CA, R01 MH60068, William Byerley, M.D. and Mark Vawter, M.D.; University of Iowa, IA, R01 MH059548, William Coryell, M.D., Raymond Crowe, M.D.; University of Chicago, IL, R01 MH059535, Elliot Gershon, M.D., Judith Badner, Ph.D., Francis McMahon, M.D., Chunyu Liu, Ph.D., Alan Sanders, M.D., Maria Caserta, Steven Dinwiddie, M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M.D., Rebecca McKinney, B.A.; Rush University, IL, R01 MH059556, William Scheftner, M.D., Howard M. Kravitz, D.O., M.P H., Diana Marta, B S., Annette Vaughn-Brown, M.S N., R.N., Laurie Bederow, M.A.; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH02810-01, Francis J. McMahon, M.D., Layla Kassem, PsyD., Sevilla Derta-Wadleigh, Ph.D., Lisa Austin, Ph.D., Dennis L. Murphy, M.D.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Translational Research Laboratories, University of Pennsylvania School of Medicine, Center for Neurobiology and Behavior, 125 South 31st Street, Room 2213, Philadelphia, PA, 19104, USA

    Falk W. Lohoff, Andrew E. Weller, Paul J. Bloch, Aleksandra H. Nall, Thomas N. Ferraro & Wade H. Berrettini

Authors
  1. Falk W. Lohoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew E. Weller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul J. Bloch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aleksandra H. Nall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas N. Ferraro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wade H. Berrettini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Falk W. Lohoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lohoff, F.W., Weller, A.E., Bloch, P.J. et al. Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder. J Neural Transm 115, 1339–1345 (2008). https://doi.org/10.1007/s00702-008-0093-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-008-0093-9

Keywords

Search

Navigation