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Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders

Published online by Cambridge University Press:  23 March 2020

G. Mezquida ,
R. Penadés ,
B. Cabrera ,
G. Savulich ,
A. Lobo ,
A. González-Pinto ,
M.J. Penzol ,
I. Corripio ,
E. Fernandez-Egea  and
P. Gassó
...Show all authors
G. Mezquida
Affiliation:
Barcelona clinic schizophrenia unit (BCSU), Institut clínic de neurociències (ICN), hospital clinic de Barcelona, Barcelona, Spain
R. Penadés
Affiliation:
Barcelona clinic schizophrenia unit (BCSU), Institut clínic de neurociències (ICN), hospital clinic de Barcelona, Barcelona, Spain Department of psychiatry and clinical psychobiology, university of Barcelona, Barcelona, Spain Institut d’investigacions biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain
B. Cabrera
Affiliation:
Barcelona clinic schizophrenia unit (BCSU), Institut clínic de neurociències (ICN), hospital clinic de Barcelona, Barcelona, Spain Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain
G. Savulich
Affiliation:
Department of psychiatry, university of Cambridge, Cambridge, UK
A. Lobo
Affiliation:
Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain Instituto de Investigación Sanitaria de Aragón (IIS Aragón), university of Zaragoza, Zaragoza, Spain
A. González-Pinto
Affiliation:
Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain Araba university hospital, Bioaraba research institute, Araba, Spain University of the Basque Country (UPV-EHU), Leioa, Spain
M.J. Penzol
Affiliation:
Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain Child and adolescent psychiatry department, hospital general universitario Gregorio Marañón, school of medicine, universidad Complutense, Madrid, Spain
I. Corripio
Affiliation:
Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain Department of psychiatry, institut d’investigació Biomèdica-Sant Pau (IIB-SANT PAU), hospital de la Santa Creu i Sant Pau, Barcelona, Spain Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
E. Fernandez-Egea
Affiliation:
Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain Behavioural and clinical neuroscience institute, university of Cambridge, Cambridge, UK
P. Gassó
Affiliation:
Institut d’investigacions biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of pathological anatomy, pharmacology and microbiology, university of Barcelona, Barcelona, Spain
M.J. Cuesta
Affiliation:
Department of psychiatry, Complejo Hospitalario de Navarra, Navarra, Spain IdiSNA, Navarra institute for health research, Navarra, Spain
M. Bernardo*
Affiliation:
Barcelona clinic schizophrenia unit (BCSU), Institut clínic de neurociències (ICN), hospital clinic de Barcelona, Barcelona, Spain Department of psychiatry and clinical psychobiology, university of Barcelona, Barcelona, Spain Institut d’investigacions biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Biomedical research networking centre in mental health (CIBERSAM), Barcelona, Spain
*
*Corresponding author. Barcelona clinic schizophrenia unit, hospital clinic of Barcelona, 170, Villarroel, 08036 Barcelona, Spain. Tel.: +34932275400x3142; fax: +34932275548. E-mail address:[email protected](M. Bernardo).
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Abstract

Objective

A functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients.

Methods

Using a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity.

Results

There was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele.

Conclusions

The results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum.

Keywords

Schizophrenia and psychosisGeneticsClinical symptomatologyNeurocognitionGenotype
Type
Original article
Information
European Psychiatry , Volume 38 , October 2016 , pp. 61 - 69
Copyright
Copyright © Elsevier Masson SAS 2016

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Footnotes

1

M. Bioque, C. García-Rizo, M. Parellada, C. Llorente, A. Alonso, M. Rabella, M. Martinez-Cengotitabengoa, I. Gonzalez-Ortega, F. Barcones, S. del Olmo, E.J. Aguilar, M.J. Escartí, D. Bergé, R. Cortizo, E. Vieta, C. Torrent, J. Castro-Fornieles, I. Baeza, F. Contreras, A. Albacete, J. Bobes, P. Portilla, A. Zabala, R. Segarra, I. Morales-Muñoz, R. Rodriguez-Jimenez, A. Butjosa, J. Usall, S. Sarró, R. Landín-Romero, Á. Ibáñez, A. Sánchez-Torres, V. Balanzá-Martínez.

References

Schizophrenia working group of the psychiatric genomics consortium Nature 2014;511:421–427CrossRefGoogle Scholar
Sullivan, PFKendler, KSNeale, MCSchizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–1192CrossRefGoogle ScholarPubMed
Kheirollahi, MKazemi, EAshouri, SBrain-derived neurotrophic factor gene Val66Met polymorphism and risk of schizophrenia: a meta-analysis of case-control studies. Cell Mol Neurobiol. 2016;36:1–10CrossRefGoogle ScholarPubMed
Bernardo, MBioque, MSchizophrenia: from neurobiology to nosology of mental disorders. Actas Esp Psiquiatr. 2010;38(3): 15–17Google Scholar
Andreasen, NCWilcox, MAHo, BCEpping, EZiebell, SZeien, Eet al.Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes. Mol Psychiatry. 2012;17(11): 1093–1102CrossRefGoogle ScholarPubMed
Ursini, GCavalleri, TFazio, LAngrisano, TIacovelli, LPorcelli, Aet al.BDNF rs6265 methylation and genotype interact on risk for schizophrenia. Epigenetics. 2016;11(1): 11–23CrossRefGoogle ScholarPubMed
Ohi, KHashimoto, RIkeda, MYamamori, HYasuda, YFujimoto, Met al.Glutamate networks implicate cognitive impairments in schizophrenia: genome-wide association studies of 52 cognitive phenotypes. Schizophr Bull. 2015;41:909–918CrossRefGoogle ScholarPubMed
Insel, TRRethinking schizophrenia. Nature. 2010;468:187–193CrossRefGoogle ScholarPubMed
Bernardo, MMezquida, GBioque, MNuevos planteamientos clínicos en esquizofrenia: los síntomas negativos. Madrid: Ediveramerica; 2014Google Scholar
Chue, PLalonde, JKAddressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options. Neuropsychiatr Dis Treat. 2014;10:777–789CrossRefGoogle ScholarPubMed
Bernardo, MFernadez-Egea, ETorras, AGutierrez, FAhuir, MArango, CAdaptación y validación en castellano del Inventario para la Esquizofrenia Deficitaria. Med Clin (Barc). 2007;129(3): 91–93CrossRefGoogle Scholar
Buchanan, RWPersistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33:1013–1022CrossRefGoogle ScholarPubMed
Kirkpatrick, BBuchanan, RWMcKenney, PDAlphs, LDCarpenter, WT Jr.The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 1989;30:119–123CrossRefGoogle Scholar
Kirkpatrick, BGalderisi, SDeficit schizophrenia: an update. World Psychiatry. 2008;7:143–147CrossRefGoogle ScholarPubMed
Bernardo, MMezquida, GDisease burden. Schizophrenia: a costly illness. Insights in the management of schizophrenia. 2014 www.hospitalpharmacyeurope.comGoogle Scholar
Kirkpatrick, BMiller, BGarcia-Rizo, CFernandez-Egea, ESchizophrenia: a systemic disorder. Clin Schizophr Relat Psychoses. 2014;8:73–79CrossRefGoogle ScholarPubMed
Tsapakis, EMDimopoulou, TTarazi, FIClinical management of negative symptoms of schizophrenia: an update. Pharmacol Ther. 2015;153:135–147CrossRefGoogle ScholarPubMed
American psychiatric association Diagnostic and statistical manual of mental disorders (DSM5). 5th ed.Washington, DC:American Psychiatric Press; 2013Google Scholar
Bernardo, MBioque, MDSM-5 ¿quo vadis?. Madrid: Evideramerica; 2013Google Scholar
Green, MFKern, RSHeaton, RKLongitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72:41–51CrossRefGoogle ScholarPubMed
Keefe, RSFenton, WSHow should DSM-V criteria for schizophrenia include cognitive impairment?. Schizophr Bull. 2007;33:912–920CrossRefGoogle ScholarPubMed
Harvey, PDAssessment of everyday functioning in schizophrenia: implications for treatments aimed at negative symptoms. Schizophr Res. 2013;150:353–355CrossRefGoogle ScholarPubMed
Penades, RGasto, CBoget, TCatalan, RSalamero, MDeficit in schizophrenia: the relationship between negative symptoms and neurocognition. Compr Psychiatry. 2001;42:64–69CrossRefGoogle ScholarPubMed
Vilalta-Gil, VVilaplana, MOchoa, SHaro, JMDolz, MUsall, Jet al.Neurocognitive performance and negative symptoms: are they equal in explaining disability in schizophrenia outpatients?. Schizophr Res. 2006;87:246–253CrossRefGoogle Scholar
Dominguez, MDWichers, MLieb, RWittchen, HUvan Os, JEvidence that onset of clinical psychosis is an outcome of progressively more persistent subclinical psychotic experiences: an 8-year cohort study. Schizophr Bull. 2009;37:84–93CrossRefGoogle Scholar
Pickard, BSSchizophrenia biomarkers: translating the descriptive into the diagnostic. J Psychopharmacol. 2015;29:138–143CrossRefGoogle ScholarPubMed
Galderisi, SMerlotti, EMucci, ANeurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci. 2015;265:543–558CrossRefGoogle ScholarPubMed
Kremeyer, BGarcia, JKymalainen, HWratten, NRestrepo, GPalacio, Cet al.Evidence for a role of the NOS1AP (CAPON) gene in schizophrenia and its clinical dimensions: an association study in a South American population isolate. Hum Hered. 2009;67:163–173CrossRefGoogle Scholar
Notaras, MHill, Rvan den Buuse, MA role for the BDNF gene Val66Met polymorphism in schizophrenia?. A comprehensive review. Neurosci Biobehav Rev. 2015;51:15–30CrossRefGoogle ScholarPubMed
Penadés, RGarcia-Rizo, CBioque, MGonzález-Rodríguez, ACabrera, BMezquida, Get al.The search for new biomarkers for cognition in schizophrenia. Schizophr Res Cogn. 2015;2:172–178CrossRefGoogle ScholarPubMed
Bueller, JAAftab, MSen, SGomez-Hassan, DBurmeister, MZubieta, JKBDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59:812–815CrossRefGoogle ScholarPubMed
Ibarra, PAlemany, SFatjo-Vilas, MCordova-Palomera, AGoldberg, XArias, Bet al.The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study. Eur Psychiatry. 2014;29:293–300CrossRefGoogle ScholarPubMed
Buckley, PFPillai, AHowell, KRBrain-derived neurotrophic factor: findings in schizophrenia. Curr Opin Psychiatry. 2011;24:122–127CrossRefGoogle Scholar
Gratacos, MGonzalez, JRMercader, JMde Cid, RUrretavizcaya, MEstivill, XBrain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61:911–922CrossRefGoogle Scholar
Rybakowski, JKBorkowska, ACzerski, PMSkibinska, MHauser, JPolymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord. 2003;5:468–472CrossRefGoogle ScholarPubMed
Martinowich, KLu, BInteraction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:73–83CrossRefGoogle ScholarPubMed
Zhai, JYu, QChen, MGao, YZhang, QLi, Jet al.Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Int J Clin Exp Pathol. 2013;6:1617–1623Google ScholarPubMed
Kanazawa, TGlatt, SJKia-Keating, BYoneda, HTsuang, MTMeta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet. 2007;17:165–170CrossRefGoogle ScholarPubMed
Ahmed, AOMantini, AMFridberg, DJBuckley, PFBrain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis. Psychiatry Res. 2015;226:1–13CrossRefGoogle ScholarPubMed
Chang, HALu, RBShy, MJChang, CCLee, MSHuang, SYBrain-derived neurotrophic factor Val66Met polymorphism: association with psychopathological symptoms of schizophrenia?. J Neuropsychiatry Clin Neurosci. 2009;21:30–37CrossRefGoogle ScholarPubMed
Zhang, XYChen da, CXiu, MHHaile, CNLuo, XXu, Ket al.Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet. 2012;131:1187–1195CrossRefGoogle ScholarPubMed
Miyajima, FOllier, WMayes, AJackson, AThacker, NRabbitt, Pet al.Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav. 2008;7:411–417CrossRefGoogle ScholarPubMed
Martinho, E Jr.Michelon, LAyres, AMScazufca, MMenezes, PRSchaufelberger, MSet al.BDNF gene polymorphism, cognition and symptom severity in a Brazilian population-based sample of first-episode psychosis subjects. Rev Bras Psiquiatr. 2012;34(2): 219–225Google Scholar
Papaleo, FLipska, BKWeinberger, DRMouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology. 2012;62(3): 1204–1220CrossRefGoogle Scholar
Buchanan, RWWeiner, EKelly, DLGold, JMKeller, WRWaltz, JAet al.Rasagiline in the treatment of the persistent negative symptoms of schizophrenia. Schizophr Bull. 2015;41:900–908CrossRefGoogle ScholarPubMed
Bernardo, MBioque, MParellada, MSaiz Ruiz, JCuesta, MJLlerena, Aet al.Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs). Rev Psiquiatr Salud Ment. 2013;6:4–16CrossRefGoogle Scholar
Williams, JBGibbon, MFirst, MBSpitzer, RLDavies, MBorus, Jet al.The structured clinical interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry. 1992;49:630–636CrossRefGoogle ScholarPubMed
American psychiatric association DSM-IV: diagnostic and statistical manual of mental disorders. 4th ed.Washington;American psychiatric association:1994.Google Scholar
Hollingshead, ABRedlich, FC.Class and mental illness.. 1955/09/01 ed. New York 1958.CrossRefGoogle Scholar
Kay, SRFiszbein, AOpler, LAThe positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–276CrossRefGoogle Scholar
Peralta, VCuesta, MJValidación de la escala de los síndromes positivo y negativo (PANSS) en una muestra de esquizofrénicos españoles. Actas Luso-Español Neurol Psiquiatría. 1994;22:171–177Google Scholar
Marder, SRDavis, JMChouinard, GThe effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538–546CrossRefGoogle ScholarPubMed
Cuesta, MJSanchez-Torres, AMCabrera, BBioque, MMerchan-Naranjo, JCorripio, Iet al.Premorbid adjustment and clinical correlates of cognitive impairment in first-episode psychosis. The PEPsCog study. Schizophr Res. 2015;164:65–73CrossRefGoogle ScholarPubMed
Conners, CConner’s continuous performance test II: computer program for Windows. Technical guide and software manual. Systems MH: North Tonawanda. 2000Google Scholar
Wechsler, DWAIS-III: Escala de inteligencia de Wechsler para Adultos. Tercera versión (WAIS-III: Wechsler Adult Intelligence Scale. Third Version). Madrid: TEA, SA; 1999Google Scholar
Heaton, RKWisconsin card sorting test manuel. Odessa (FL): Psychological Assessment Resource Inc; 1981Google Scholar
Benedet, MJTest de Aprendizaje Verbal España-Complutense (TAVEC). Madrid 1988Google Scholar
Baron, RKenny, DThe moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51:1173–1182CrossRefGoogle ScholarPubMed
Govindarajan, ARao, BSNair, DTrinh, MMawjee, NTonegawa, Set al.Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A. 2006;103(35): 13208–13213CrossRefGoogle ScholarPubMed
Kawashima, KIkeda, MKishi, TKitajima, TYamanouchi, YKinoshita, Yet al.BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophr Res. 2009;112(1–3):72–79CrossRefGoogle Scholar
Nanko, SKunugi, HHirasawa, HKato, NNabika, TKobayashi, SBrain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res. 2003;62:281–283Google ScholarPubMed
Niitsu, TIshima, TYoshida, THashimoto, TMatsuzawa, DShirayama, Yet al.A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia. Psychiatry Res. 2014;215:268–273CrossRefGoogle Scholar
Nurjono, MLee, JChong, SAA review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci. 2012;10:61–70CrossRefGoogle Scholar
Dincheva, IGlatt, CELee, FSImpact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics. Neuroscientist. 2012;18:439–451CrossRefGoogle ScholarPubMed
Ho, BCMilev, PO’Leary, DSLibrant, AAndreasen, NCWassink, THCognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry. 2006;63:731–740CrossRefGoogle ScholarPubMed
Egan, MFKojima, MCallicott, JHGoldberg, TEKolachana, BSBertolino, Aet al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–269CrossRefGoogle ScholarPubMed
Dempster, EToulopoulou, TMcDonald, CBramon, EWalshe, MFilbey, Fet al.Association between BDNF val66 met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet.134B 2005 73–75CrossRefGoogle ScholarPubMed
Tabares-Seisdedos, RBalanza-Martinez, VSanchez-Moreno, JMartinez-Aran, ASalazar-Fraile, JSelva-Vera, Get al.Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at 1-year follow-up. J Affect Disord. 2008;109:286–299CrossRefGoogle Scholar
Lu, WZhang, CYi, ZLi, ZWu, ZFang, YAssociation between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naive patients with schizophrenia. J Mol Neurosci. 2012;47:505–510CrossRefGoogle ScholarPubMed
Marques-Iturria, IGarolera, MPueyo, RSegura, BHernan, IGarcia-Garcia, Iet al.The interaction effect between BDNF val66met polymorphism and obesity on executive functions and frontal structure. Am J Med Genet B Neuropsychiatr Genet.165B 2014 245–253CrossRefGoogle ScholarPubMed
Rybakowski, JKBorkowska, ASkibinska, MSzczepankiewicz, AKapelski, PLeszczynska-Rodziewicz, Aet al.Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. Psychiatry Clin Neurosci. 2006;60:70–76CrossRefGoogle ScholarPubMed
Kirkpatrick, BStrauss, GPNguyen, LFischer, BADaniel, DGCienfuegos, Aet al.The brief negative symptom scale: psychometric properties. Schizophr Bull. 2011;37:300–305CrossRefGoogle ScholarPubMed
Mane, AGarcia-Rizo, CGarcia-Portilla, MPBerge, DSugranyes, GGarcia-Alvarez, Let al.Spanish adaptation and validation of the Brief negative symptoms scale. Compr Psychiatry. 2014;55:1726–1729CrossRefGoogle ScholarPubMed
Kring, AMGur, REBlanchard, JJHoran, WPReise, SPThe Clinical assessment interview for negative symptoms (CAINS): final development and validation. Am J Psychiatry. 2013;170:165–172CrossRefGoogle ScholarPubMed
Valiente-Gomez, AMezquida, GRomaguera, AVilardebo, IAndres, HGranados, Bet al.Validation of the Spanish version of the Clinical assessment for negative symptoms (CAINS). Schizophr Res. 2015;166:104–109CrossRefGoogle Scholar
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