Genetic association study of PDLIM5 and HTR2A variants in Malaysian subjects diagnosed with bipolar disorder; a genetic modelling approach

  • Mohd Aizat Zain Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Wilayah Persekutuan, Malaysia.
  • Nor Zuraida Zainal Department of Psychology Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Wilayah Persekutuan, Malaysia
  • Sharmilla Kanagasundram Department of Psychology Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Wilayah Persekutuan, Malaysia
  • Zahurin Mohamed Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Wilayah Persekutuan, Malaysia
Keywords: PDLIM5, HTR2A, polymorphism, Bipolar disorder

Abstract

Genetic hereditary has been implicated in bipolar disorder pathogenesis. The PDLIM5 and HTR2A genes have been investigated for its association with bipolar disorder in various populations, however, the results have been conflicting. In this study, we investigate the association between bipolar disorder and the two genes of interest, PDLIM5 and HTR2A genes. We recruited 253 bipolar disorder patients (75 Malays, 104 Chinese, and 74 Indians) and 505 control individuals (198 Malays, 155 Chinese, and 152 Indians) from three ethnic groups within Malaysian population. We genotyped for 3 SNPs of the PDLIM5 (rs2433320, rs2433322 and rs2438146) and 3 SNPs of the HTR2A (rs6313, rs2070040 and rs6311). Significant associations between bipolar disorder and each of the 3 SNPs of PDLIM5 in Malays, Indians and pooled samples. However, only rs2438146 remains significant in the Malays as co-dominant (T/T vs. C/C, p=0.004, OR=0.128, 95%CI=0.031-0.524) and recessive genetic models (T/T vs. C/T+C/C, p=0.003, OR=0.122, 95%CI=0.030-0.494) after applying conservative Bonferroni correction. Haplotype analysis of 3 SNPs of PDLIM5 also showed a significant association with bipolar disorder. No association was observed between bipolar disorder and each of the 3 SNPs of HTR2A in any of the ethnicities. We conclude that PDLIM5 polymorphisms are associated with bipolar disorder in the pooled analysis. After stratification to different ethnic groups, the association remains significant in the Malay and Indian groups. The association is also supported by the significant association in haplotype analysis of PDLIM5. We also conclude there is no association between the HTR2A polymorphisms in the Malaysian population.

References

Amidfar M., Kim Y.K., Colic L., Arbabi M., Mobaraki G., Hassanzadeh G., Walter M. Increased levels of 5HT2A receptor mRNA expression in peripheral blood mononuclear cells of patients with major depression: correlations with severity and duration of illness. Nord J Psychiatry. 2017,71, 282-288, https://doi.org/10.1080/08039488.2016.1276624

Camp N.J., Lowry M.R., Richards R.L., Plenk A.M., Carter C., Hensel C.H., et al. Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet. 2005, 135B, 85-93. https://doi.org/10.1002/ajmg.b.30177

Chee I.S., Lee S.W., Kim J.L., Wang S.K., Shin Y.O., Shin S.C., et al. 5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder. Psychiatr Genet. 2001, 11, 111-114. https://www.ncbi.nlm.nih.gov/pubmed/11702051

Detera-Wadleigh S.D., Badner J.A., Yoshikawa T., Sanders A.R., Goldin L.R., 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. https://doi.org/10.1002/(SICI)1096-8628(19970531)74:3%3C254::AID-AJMG4%3E3.0.CO;2-Q

Gordon D., Haynes C., Blumenfeld J., Finch S.J. PAWE-3D: visualizing power for association with error in case-control genetic studies of complex traits. Bioinformatics. 2005, 21, 3935-3937. https://doi.org/10.1093/bioinformatics/bti643

Gutierrez B., Bertranpetit J., Collier D., Arranz M.J., Valles V., Guillamat R., et al. Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder. Hum Genet. 1997, 100, 582-584. https://www.ncbi.nlm.nih.gov/pubmed/9341875

Hahn C.G., Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord. 1999, 1, 81-86. https://doi.org/10.1034/j.1399-5618.1999.010204.x

Herrick S., Evers D.M., Lee J.Y., Udagawa N., Pak D.T. Postsynaptic PDLIM5/Enigma Homolog binds SPAR and causes dendritic spine shrinkage. Mol Cell Neurosci. 2010, 43, 188-200. https://doi.org/10.1016/j.mcn.2009.10.009

Horiuchi Y., Arai M., Niizato K., Iritani S., Noguchi E., Ohtsuki T., et al. A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia. Biol Psychiatry. 2006, 59, 434-439. https://doi.org/10.1016/j.biopsych.2005.07.041

Horiuchi Y., Ishikawa M., Kaito N., Iijima Y., Tanabe Y., Ishiguro H., et al. Experimental evidence for the involvement of PDLIM5 in mood disorders in hetero knockout mice. PLoS One. 2013, 8, e59320. https://doi.org/10.1371/journal.pone.0059320

Iga J., Ueno S., Yamauchi K., Numata S., Motoki I., Tayoshi S., et al. Gene expression and association analysis of LIM (PDLIM5) in major depression. Neurosci Lett. 2006, 400, 203-207. https://doi.org/10.1016/j.neulet.2006.02.044

Iwamoto K., Kakiuchi C., Bundo M., Ikeda K., Kato T. Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry. 2004, 9, 406-416. https://doi.org/10.1038/sj.mp.4001437

Kato T. Molecular genetics of bipolar disorder and depression. Psychiatry Clin Neurosci. 2007, 61, 3-19. https://doi.org/10.1111/j.1440-1819.2007.01604.x

Kato T., Iwayama Y., Kakiuchi C., Iwamoto K., Yamada K., Minabe Y., et al. Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia. Mol Psychiatry. 2005, 10, 1045-1055. https://doi.org/10.1038/sj.mp.4001719

Kishi T., Kitajima T., Tsunoka T., Ikeda M., Yamanouchi Y., Kinoshita Y., et al. Genetic association analysis of serotonin 2A receptor gene (HTR2A) with bipolar disorder and major depressive disorder in the Japanese population. Neurosci Res. 2009, 64, 231-234. https://doi.org/10.1016/j.neures.2009.03.003

Kuroda S., Tokunaga C., Kiyohara Y., Higuchi O., Konishi H., Mizuno K., et al. Protein-protein interaction of zinc finger LIM domains with protein kinase C. J Biol Chem. 1996, 271, 31029-31032. https://doi.org/10.1074/jbc.271.49.31029

Lewis C.M. Genetic association studies: design, analysis and interpretation. Brief Bioinform. 2002, 3, 146-153. https://www.ncbi.nlm.nih.gov/pubmed/12139434

Lewis C.M., Knight J. Introduction to genetic association studies. Cold Spring Harb Protoc. 2012, 3, 297-306. https://doi.org/10.1101/pdb.top068163

Li Z., Zhang Z., He Z., Tang W., Li T., Zeng Z., et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers. Cell Res. 2009, 19, 519–523. https://doi.org/10.1038/cr.2009.33

Liu Z., Liu W., Xiao Z., Wang G., Yin S., Zhu F., et al. A major single nucleotide polymorphism of the PDLIM5 gene associated with recurrent major depressive disorder. J Psychiatry Neurosci. 2008, 33, 43-46. https://www.ncbi.nlm.nih.gov/pubmed/18197271

Maeno-Hikichi Y., Chang S., Matsumura K., Lai M., Lin H., Nakagawa N., et al. A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels. Nat Neurosci. 2003, 6, 468-475. https://doi.org/10.1038/nn1041

Maturana A.D., Nakagawa N., Yoshimoto N., Tatematsu K., Hoshijima M., Tanizawa K., et al. LIM domains regulate protein kinase C activity: a novel molecular function. Cell Signal. 2011, 23, 928-934. https://doi.org/10.1016/j.cellsig.2011.01.021

Mowry B.J., Ewen K.R., Nancarrow D.J., Lennon D.P., Nertney D.A., Jones H.L., et al. Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample. Am J Med Genet. 2000, 96, 864-869. https://doi.org/10.1002/1096-8628(20001204)96:6%3C864::AID-AJMG35%3E3.0.CO;2-D

Nichols C.D. Serotonin 5-HT(2A) Receptor function as a contributing factor to both neuropsychiatric and cardiovascular diseases. Cardiovasc Psychiatry Neurol. 2009, 2009, 475108. https://doi.org/10.1155/2009/475108

Nichols D.E., Nichols C.D. Serotonin receptors. Chem Rev. 2008, 108, 1614-1641. https://doi.org/10.1021/cr078224o

Numata S., Ueno S., Iga J., Yamauchi K., Hongwei S., Hashimoto R., et al. Gene expression in the peripheral leukocytes and association analysis of PDLIM5 gene in schizophrenia. Neurosci Lett. 2007, 415, 28-33. https://doi.org/10.1016/j.neulet.2007.01.018

Shen J., Li Z., Chen J., Song Z., Zhou Z., Shi Y. SHEsisPlus, a toolset for genetic studies on polyploid species. Sci. Rep. 2016, 6, 24095. https://doi.org/10.1038/srep24095

Sherry S.T., Ward M.H., Kholodov M., Baker J., Phan L., Smigielski E.M., et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001, 29, 308-311. https://www.ncbi.nlm.nih.gov/pubmed/11125122

Shi J., Badner J.A., Liu C. PDLIM5 and susceptibility to bipolar disorder: a family-based association study and meta-analysis. Psychiatr Genet. 2008, 18, 116-121. https://doi.org/10.1097/YPG.0b013e3282fa184b

Shi Y.Y., He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Research. 2006, 15, 97-98. https://doi.org/10.1038/sj.cr.7290272

Smoller J.W., Finn C.T. Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet. 2003, 123C, 48-58. https://doi.org/10.1002/ajmg.c.20013

Vallenius T., Luukko K., Makela T.P. CLP-36 PDZ-LIM protein associates with nonmuscle alpha-actinin-1 and alpha-actinin-4. J Biol Chem. 2000, 275, 11100-11105. https://doi.org/10.1074/jbc.275.15.11100

Wang H.Y., Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry. 1996, 40, 568-575. https://doi.org/10.1016/0006-3223(95)00611-7

Zain M.A., Roffeei S.N., Zainal N.Z., Kanagasundram S., Mohamed Z. Nonsynonymous polymorphisms of the PDLIM5 gene association with the occurrence of both bipolar disorder and schizophrenia. Psychiatr Genet. 2013, 23, 258-261. https://doi.org/10.1097/YPG.0000000000000015

Zhao T., Liu Y., Wang P., Li S., Zhou D., Zhang D., et al. Positive association between the PDLIM5 gene and bipolar disorder in the Chinese Han population. J Psychiatry Neurosci. 2009, 34, 199-204. https://www.ncbi.nlm.nih.gov/pubmed/19448850

Zhou Q., Ruiz-Lozano P., Martone M.E., Chen J. Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C. J Biol Chem. 1999, 274, 19807-19813. https://doi.org/10.1074/jbc.274.28.19807

Published
2018-08-08
How to Cite
Zain, M. A., Zainal, N. Z., Kanagasundram, S. and Mohamed, Z. (2018) “Genetic association study of PDLIM5 and HTR2A variants in Malaysian subjects diagnosed with bipolar disorder; a genetic modelling approach”, Neuroscience Research Notes, 1(1), pp. 11-20. doi: 10.31117/neuroscirn.v1i1.9.
Section
Research Notes