Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort

Molecular Neurobiology - Tập 60 - Trang 6826-6839 - 2023
Toyanji Joseph Punchaichira1, Prachi Kukshal1,2, Triptish Bhatia3, Smita Neelkanth Deshpande3, B. K. Thelma1
1Department of Genetics, University of Delhi South Campus, New Delhi, India
2Sri Sathya Sai Sanjeevani International Centre for Child Heart Care & Research, Palwal, India
3Department of Psychiatry, Postgraduate Institute of Medical Education and Research-Dr. Ram Manohar Lohia Hospital, New Delhi, India

Tóm tắt

Genetic perturbations in dopamine neurotransmission and calcium signaling pathways are implicated in the etiology of schizophrenia. We aimed to test the association of a functional splice variant each in Dopamine β-Hydroxylase (DBH; rs1108580) and Calcium voltage-gated channel subunit alpha1 C (CACNA1C; rs1006737) genes in these pathways with schizophrenia (506 cases, 443 controls); Abnormal Involuntary Movement Scale (AIMS) scores in subjects assessed for tardive dyskinesia (76 TD-positive, 95 TD-negative) and Penn Computerized Neurocognitive Battery (PennCNB) scores (334 cases, 234 controls). The effect of smoking status and SNP genotypes on AIMS scores were assessed using ANOVA; health status and SNP genotypes on three performance functions of PennCNB cognitive domains were assessed by ANCOVA with age and sex as covariates. Association with Positive and Negative Syndrome Scale (PANSS) scores in the TD cohort and cognitive scores in healthy controls of the cognition cohort were tested by linear regression. None of the markers were associated with schizophrenia. Smoking status [F(2, 139) = 10.6; p = 5 × 10−5], rs1006737 [F(2, 139) = 7.1; p = 0.001], TD status*smoking [F(2, 139) = 8.0; p = 5.0 × 10−4] and smoking status*rs1006737 [F(4, 139) = 2.7; p = 0.03] had an effect on AIMS score. Furthermore, rs1006737 was associated with orofacial [F(2, 139) = 4.6; p = 0.01] and limb-truncal TD [(F(2, 139) = 3.8; p = 0.02]. Main effect of rs1108580 on working memoryprocessing speed [F(2, 544) = 3.8; p = 0.03] and rs1006737 on spatial abilityefficiency [F(1, 550) = 9.4; p = 0.02] was identified. Health status*rs1006737 interaction had an effect on spatial memoryprocessing speed [F(1, 550) = 6.9; p = 0.01]. Allelic/genotypic association (p = 0.01/0.03) of rs1006737 with disorganized/concrete factor and allelic association of rs1108580 (p = 0.04) with a depressive factor of PANSS was observed in the TD-negative subcohort. Allelic association of rs1006737 with sensorimotor dexterityaccuracy (p = 0.03), attentionefficiency (p = 0.05), and spatial abilityefficiency (p = 0.02); allelic association of rs1108580 with face memoryaccuracy (p = 0.05) and emotionefficiency (p = 0.05); and allelic/genotypic association with emotionaccuracy (p = 0.003/0.009) were observed in healthy controls of the cognition cohort. These association findings may have direct implications for personalized medicine and cognitive remediation.

Tài liệu tham khảo

Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull 35(3):549–562. https://doi.org/10.1093/schbul/sbp006

Berridge MJ (2014) Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res 357(2):477–492. https://doi.org/10.1007/s00441-014-1806-z

Cubells JF, Zabetian CP (2004) Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology. Psychopharmacology (Berl) 174(4):463–476. https://doi.org/10.1007/s00213-004-1840-8

Gonzalez-Lopez E, Vrana KE (2019) Dopamine beta-hydroxylase and its genetic variants in human health and disease. J Neurochem. https://doi.org/10.1111/jnc.14893

Punchaichira TJ, Prasad S, Deshpande SN, Thelma BK (2016) Deep sequencing identifies novel regulatory variants in the distal promoter region of the dopamine-beta-hydroxylase gene. Pharmacogenet Genomics 26(7):311–323. https://doi.org/10.1097/FPC.0000000000000214

Punchaichira TJ, Dey SK, Mukhopadhyay A, Kundu S, Thelma BK (2017) Characterization of SNPs in the dopamine-beta-hydroxylase gene providing new insights into its structure-function relationship. Neurogenetics 18(3):155–168

Punchaichira TJ, Deshpande SN, Thelma BK (2018) Determination of dopamine-beta-hydroxylase activity in human serum using UHPLC-PDA detection. Neurochem Res 43(12):2324–2332. https://doi.org/10.1007/s11064-018-2653-1

Yamamoto K, Cubells JF, Gelernter J, Benkelfat C, Lalonde P, Bloom D, Lal S, Labelle A, Turecki G, Rouleau GA, Joober R (2003) Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study. Am J Med Genet B Neuropsychiatr Genet 117B(1):33–38. https://doi.org/10.1002/ajmg.b.10011

Barrie ES, Weinshenker D, Verma A, Pendergrass SA, Lange LA, Ritchie MD, Wilson JG, Kuivaniemi H, Tromp G, Carey DJ, Gerhard GS, Brilliant MH, Hebbring SJ, Cubells JF, Pinsonneault JK, Norman GJ, Sadee W (2014) Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circ Res 115(12):1017–1025. https://doi.org/10.1161/CIRCRESAHA.116.304398

Srivastava V, Deshpande SN, Thelma BK (2010) Dopaminergic pathway gene polymorphisms and genetic susceptibility to schizophrenia among north Indians. Neuropsychobiology 61(2):64–70. https://doi.org/10.1159/000265131

Kobayashi K, Kurosawa Y, Fujita K, Nagatsu T (1989) Human dopamine beta-hydroxylase gene: two mRNA types having different 3'-terminal regions are produced through alternative polyadenylation. Nucleic Acids Res 17(3):1089–1102

Sun Z, Ma Y, Li W, He J, Li J, Yang X, Mao P, Cubells JF, Tang YL (2018) Associations between the DBH gene, plasma dopamine beta-hydroxylase activity and cognitive measures in Han Chinese patients with schizophrenia. Schizophr Res 193:58–63. https://doi.org/10.1016/j.schres.2017.06.028

Chamberlain SR, Robbins TW (2013) Noradrenergic modulation of cognition: therapeutic implications. J Psychopharmacol 27(8):694–718. https://doi.org/10.1177/0269881113480988

Punchaichira TJ, Mukhopadhyay A, Kukshal P, Bhatia T, Deshpande SN, Thelma BK (2020) Association of regulatory variants of dopamine beta-hydroxylase with cognition and tardive dyskinesia in schizophrenia subjects. J Psychopharmacol 34(3):358–369. https://doi.org/10.1177/0269881119895539

Dolmetsch RE, Pajvani U, Fife K, Spotts JM, Greenberg ME (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294(5541):333–339. https://doi.org/10.1126/science.1063395

Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S, Alliey-Rodriguez N, Cooper J, Romanos B, Liu C (2014) A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain. Mol Psychiatry 19(8):890–894. https://doi.org/10.1038/mp.2013.107

Nyegaard M, Demontis D, Foldager L, Hedemand A, Flint TJ, Sorensen KM, Andersen PS, Nordentoft M, Werge T, Pedersen CB, Hougaard DM, Mortensen PB, Mors O, Borglum AD (2010) CACNA1C (rs1006737) is associated with schizophrenia. Mol Psychiatry 15(2):119–121. https://doi.org/10.1038/mp.2009.69

Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM, Gould TD (2012) CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 99(1):1–14. https://doi.org/10.1016/j.pneurobio.2012.06.001

Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, Bergen SE, Collins AL et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159. https://doi.org/10.1038/ng.2742

Erk S, Meyer-Lindenberg A, Linden DEJ, Lancaster T, Mohnke S, Grimm O, Degenhardt F, Holmans P et al (2014) Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. Neuroimage 94:147–154. https://doi.org/10.1016/j.neuroimage.2014.03.007

Yoshimizu T, Pan JQ, Mungenast AE, Madison JM, Su S, Ketterman J, Ongur D, McPhie D et al (2015) Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry 20(2):284. https://doi.org/10.1038/mp.2014.181

Mallas E, Carletti F, Chaddock CA, Shergill S, Woolley J, Picchioni MM, McDonald C, Toulopoulou T, Kravariti E, Kalidindi S, Bramon E, Murray R, Barker GJ, Prata DP (2017) The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder(1). Genes Brain Behav 16(4):479–488. https://doi.org/10.1111/gbb.12355

Tecelao D, Mendes A, Martins D, Fu C, Chaddock CA, Picchioni MM, McDonald C, Kalidindi S, Murray R, Prata DP (2019) The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function. Genes Brain Behav 18(4):e12510. https://doi.org/10.1111/gbb.12510

Zhu D, Yin J, Liang C, Luo X, Lv D, Dai Z, Xiong S, Fu J, Li Y, Lin J, Lin Z, Wang Y, Ma G (2019) CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia: an updated meta-analysis. Brain Behav 9(6):e01292. https://doi.org/10.1002/brb3.1292

Stilo SA, Murray RM (2019) Non-genetic factors in schizophrenia. Curr Psychiatry Rep 21(10):100. https://doi.org/10.1007/s11920-019-1091-3

Quigley H, MacCabe JH (2019) The relationship between nicotine and psychosis. Ther Adv Psychopharmacol 9:2045125319859969. https://doi.org/10.1177/2045125319859969

Peterson RE, Bigdeli TB, Ripke S, Bacanu SA, Gejman PV, Levinson DF, Li QS, Rujescu D et al (2021) Genome-wide analyses of smoking behaviors in schizophrenia: findings from the psychiatric genomics consortium. J Psychiatr Res 137:215–224. https://doi.org/10.1016/j.jpsychires.2021.02.027

Tiwari AK, Deshpande SN, Rao AR, Bhatia T, Lerer B, Nimgaonkar VL, Thelma BK (2005) Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms. Schizophr Res 75(1):21–26. https://doi.org/10.1016/j.schres.2004.12.011

Deshpande SN, Mathur MN, Das SK, Bhatia T, Sharma S, Nimgaonkar VL (1998) A Hindi version of the diagnostic interview for genetic studies. Schizophr Bull 24(3):489–493

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(11):849–859 discussion 863-844

Schooler NR, Kane JM (1982) Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39(4):486–487

Guy W (1976) National institute of mental health (U.S.). Psychopharmacology research branch early clinical drug evaluation program. Ecdeu assessment manual for psychopharmacology. Rev ed. Rockville Md: U.S. Dept. of health education and welfare public health service alcohol drug abuse and mental health administration national institute of mental health psychopharmacology research branch division of extramural research programs 534–537

Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2):261–276. https://doi.org/10.1093/schbul/13.2.261

Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D (2012) Searching for a consensus five-factor model of the positive and negative syndrome scale for schizophrenia. Schizophr Res 137(1-3):246–250. https://doi.org/10.1016/j.schres.2012.01.031

Fervaha G, Foussias G, Agid O, Remington G (2014) Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia. Acta Psychiatr Scand 130(4):290–299. https://doi.org/10.1111/acps.12289

Kaliuzhna M, Kirschner M, Carruzzo F, Hartmann-Riemer MN, Bischof M, Seifritz E, Tobler PN, Kaiser S (2020) Clinical, behavioural and neural validation of the PANSS amotivation factor. Schizophr Res 220:38–45. https://doi.org/10.1016/j.schres.2020.04.018

Liemburg E, Castelein S, Stewart R, van der Gaag M, Aleman A, Knegtering H, Genetic R (2013) Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts. J Psychiatr Res 47(6):718–725. https://doi.org/10.1016/j.jpsychires.2013.01.024

Gur RC, Ragland JD, Moberg PJ, Turner TH, Bilker WB, Kohler C, Siegel SJ, Gur RE (2001) Computerized neurocognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology 25(5):766–776. https://doi.org/10.1016/S0893-133X(01)00278-0

Gur RC, Ragland JD, Moberg PJ, Bilker WB, Kohler C, Siegel SJ, Gur RE (2001) Computerized neurocognitive scanning: II. The profile of schizophrenia. Neuropsychopharmacology 25(5):777–788. https://doi.org/10.1016/S0893-133X(01)00279-2

Bhatia T, Agarwal A, Shah G, Wood J, Richard J, Gur RE, Gur RC, Nimgaonkar VL, Mazumdar S, Deshpande SN (2012) Adjunctive cognitive remediation for schizophrenia using yoga: an open, non-randomized trial. Acta Neuropsychiatr 24(2):91–100. https://doi.org/10.1111/j.1601-5215.2011.00587.x

Kassambara A (2019) Ggcorrplot: visualization of a correlation matrix using 'ggplot2'. R package version 0.1.3

Kassambara A (2017) R Graphics essentials for great data visualization: statistical tools for high-throughput data analysis. Available from: https://goo.gl/oT8Ra6

Kassambara A, Mundt F (2020) Factoextra: extract and visualize the results of multivariate data analyses R package version 1.0.7

Kassambara A (2017) Practical guide to cluster analysis in r unsupervised machine learning: statistical tools for high-throughput data analysis. Available from: https://goo.gl/DmJ5y5

Schloerke B, Cook D, Larmarange J, Briatte F, Marbach M, Thoen E, Elberg A, Crowley J (2021) GGally: extension to 'ggplot2'. R package version 2.1.2

Andreasen NC, Olsen S (1982) Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry 39(7):789–794. https://doi.org/10.1001/archpsyc.1982.04290070025006

Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976) The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33(6):766–771. https://doi.org/10.1001/archpsyc.1976.01770060086012

Wang J, Lin M, Crenshaw A, Hutchinson A, Hicks B, Yeager M, Berndt S, Huang WY, Hayes RB, Chanock SJ, Jones RC, Ramakrishnan R (2009) High-throughput single nucleotide polymorphism genotyping using nanofluidic dynamic arrays. BMC Genomics 10:561. https://doi.org/10.1186/1471-2164-10-561

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. https://doi.org/10.1086/519795

Gauderman WJ, Morrison JM (2006) QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies http://biostats.usc.edu/Quanto.html. Accessed 13 Sept 2019

Wobbrock JO, Findlater L, Gergle D, Higgins JJ (2011) The aligned rank transform for nonparametric factorial analyses using only ANOVA procedures. Proceedings of the ACM Conference on Human Factors in ComputingSystems (CHI ’11); 7–12. Vancouver, BC, Canada; 143–146

Benjamini Y, Krieger AM, Yekutieli D (2006) Adaptive linear step-up procedures that control the false discovery rate. Biometrika 93(3):491–507. https://doi.org/10.1093/biomet/93.3.491

Josse J, Fo H (2016) missMDA: a package for handling missing values in multivariate data analysis. J Statistic Softw 70(1):1–31. https://doi.org/10.18637/jss.v070.i01

Hawkins DM, Weisberg S (2017) Combining the box-cox power and generalised log transformations to accommodate nonpositive responses in linear and mixed-effects linear models. South African Statistic J 51(2):317–328

Fox J, Weisberg S (2011) An R companion to applied regression. SAGE Publications, Los Angeles, Calif London

Lê S, Josse J, Husson F (2008) FactoMineR: an R package for multivariate analysis. J Statisti Softw 25(1):1–18. https://doi.org/10.18637/jss.v025.i01

Kassambara A (2017) Practical guide to principal component methods. In R: statistical tools for high-throughput data analysis. Available from: http://goo.gl/d4Doz9

Cubells JF, van Kammen DP, Kelley ME, Anderson GM, O'Connor DT, Price LH, Malison R, Rao PA, Kobayashi K, Nagatsu T, Gelernter J (1998) Dopamine beta-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation. Hum Genet 102(5):533–540

Goncalves PP, Meireles SM, Neves P, Vale MG (2001) Ca2+ sensitivity of synaptic vesicle dopamine, gamma-aminobutyric acid, and glutamate transport systems. Neurochem Res 26(1):75–81

Lidow MS (2003) Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Brain Res Rev 43(1):70–84

Sczekan SR, Strumwasser F (1996) Antipsychotic drugs block IP3-dependent Ca(2+)-release from rat brain microsomes. Biol Psychiatry 40(6):497–502. https://doi.org/10.1016/0006-3223(95)00657-5

Eckart N, Song Q, Yang R, Wang R, Zhu H, McCallion AS, Avramopoulos D (2016) Functional characterization of schizophrenia-associated variation in CACNA1C. PLoS One 11(6):e0157086. https://doi.org/10.1371/journal.pone.0157086

Zheng F, Zhang Y, Xie W, Li W, Jin C, Mi W, Wang F, Ma W, Ma C, Yang Y, Du B, Li K, Liu C, Wang L, Lu T, Zhang H, Wang Y, Lu L, Lv L et al (2014) Further evidence for genetic association of CACNA1C and schizophrenia: new risk loci in a Han Chinese population and a meta-analysis. Schizophr Res 152(1):105–110. https://doi.org/10.1016/j.schres.2013.12.003

Zhang J, Cai J, Zhang X, Ni J, Guo Z, Zhang Y, Lu W, Zhang C (2013) Does the bipolar disorder-associated CACNA1C gene confer susceptibility to schizophrenia in Han Chinese? J Mol Neurosci 51(2):474–477. https://doi.org/10.1007/s12031-013-0079-4

Song JHT, Lowe CB, Kingsley DM (2018) Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia. Am J Hum Genet 103(3):421–430. https://doi.org/10.1016/j.ajhg.2018.07.011

Harrison PJ, Tunbridge EM, Dolphin AC, Hall J (2019) Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal. Br J Psychiatry:1–4. https://doi.org/10.1192/bjp.2019.157

Hall NAL, Tunbridge EM (2022) Brain-enriched CACNA1C isoforms as novel, selective targets for psychiatric indications. Neuropsychopharmacology 47(1):393–394. https://doi.org/10.1038/s41386-021-01114-2

Bhaduri N, Sarkar K, Sinha S, Chattopadhyay A, Mukhopadhyay K (2010) Study on DBH genetic polymorphisms and plasma activity in attention deficit hyperactivity disorder patients from Eastern India. Cell Mol Neurobiol 30(2):265–274. https://doi.org/10.1007/s10571-009-9448-5

Chamberlain SR, Muller U, Blackwell AD, Robbins TW, Sahakian BJ (2006) Noradrenergic modulation of working memory and emotional memory in humans. Psychopharmacology (Berl) 188(4):397–407. https://doi.org/10.1007/s00213-006-0391-6

Zhang Q, Shen Q, Xu Z, Chen M, Cheng L, Zhai J, Gu H, Bao X, Chen X, Wang K, Deng X, Ji F, Liu C, Li J, Dong Q, Chen C (2012) The effects of CACNA1C gene polymorphism on spatial working memory in both healthy controls and patients with schizophrenia or bipolar disorder. Neuropsychopharmacology 37(3):677–684. https://doi.org/10.1038/npp.2011.242

Essali A, Soares-Weiser K, Bergman H, Adams CE (2018) Calcium channel blockers for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 3(3):CD000206. https://doi.org/10.1002/14651858.CD000206.pub4

Diehl A, Reinhard I, Schmitt A, Mann K, Gattaz WF (2009) Does the degree of smoking effect the severity of tardive dyskinesia? A longitudinal clinical trial. Eur Psychiatry 24(1):33–40. https://doi.org/10.1016/j.eurpsy.2008.07.007

Thông tin
Thông tin xuất bản

Molecular Neurobiology

Tập 60

6826-6839

Thông tin tác giả