Analysis of KCNH2 and CACNA1C schizophrenia risk genes on EEG functional network modulation during an auditory odd-ball task
A deficit in task-related functional connectivity modulation from electroencephalogram (EEG) has been described in schizophrenia. The use of measures of neuronal connectivity as an intermediate phenotype may allow identifying genetic factors involved in these deficits, and therefore, establishing underlying pathophysiological mechanisms. Genes involved in neuronal excitability and previously associated with the risk for schizophrenia may be adequate candidates in relation to functional connectivity alterations in schizophrenia. The objective was to study the association of two genes of voltage-gated ion channels (CACNA1C and KCNH2) with the functional modulation of the cortical networks measured with EEG and graph-theory parameter during a cognitive task, both in individuals with schizophrenia and healthy controls. Both CACNA1C (rs1006737) and KCNH2 (rs3800779) were genotyped in 101 controls and 50 schizophrenia patients. Small-world index (SW) was calculated from EEG recorded during an odd-ball task in two different temporal windows (pre-stimulus and response). Modulation was defined as the difference in SW between both windows. Genetic, group and their interaction effects on SW in the pre-stimulus window and in modulation were evaluated using ANOVA. The CACNA1C genotype was not associated with SW properties. KCNH2 was significantly associated with SW modulation. Healthy subjects showed a positive SW modulation irrespective of the KCNH2 genotype, whereas within patients allele-related differences were observed. Patients carrying the KCNH2 risk allele (A) presented a negative SW modulation and non-carriers showed SW modulation similar to the healthy subjects. Our data suggest that KCNH2 genotype contributes to the efficient modulation of brain electrophysiological activity during a cognitive task in schizophrenia patients.
KeywordsSchizophrenia Electroencephalography Small-world CACNA1C KCNH2
This work was supported by: (1) the Instituto Carlos III through the projects PI11/02708, PI11/02203, PI15/00299 and PI15/01420 (co-funded by the European Regional Development Fund/European Social Fund “Investing in your future”); (2) the Gerencia Regional de Salud de Castilla y León (GRS 932/A/14 and GRS 1134/A/15) grants; (3) Consejería de Educación de la Junta de Castilla y León (VA059U13, VA037U16); (4) European Commission and FEDER under Project “Análisis y correlación entre genoma completo y la actividad cerebral para la ayuda en el diagnóstico de la enfermedad de Alzheimer” (Cooperation Program Interreg V-A Spain-Portugal POCTEP 2014–2020); (5) predoctoral fellowships to A. Lubeiro (Consejería de Educación Junta de Castilla y León and European Social Fund’) and to J. Gomez-Pilar (University of Valladolid); (6) a Sara Borrell contract to M Fatjó-Vilas (CD16/00264); (7) the Comissionat per a Universitats i Recerca del DIUE, of the Generalitat de Catalunya regional authorities (2017SGR1271).
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
All participants provided written informed consent to participate in the study. It was approved by the ethical committee of the involved hospitals endorsed the study according to The Code of Ethics of the World Medical Association (Helsinki Declaration of 1975, as revised in 2008).
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