Cargando…

A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia

As genetic and environmental influences on schizophrenia might converge on DNA methylation (DNAm) within loci which are both associated with the disease and implicated in response to environmental stress, we examined whether DNAm within CYP17A1, a hypothalamus–pituitary–adrenal axis gene which is si...

Descripción completa

Detalles Bibliográficos
Autores principales: Alfimova, Margarita, Kondratyev, Nikolay, Korovaitseva, Galina, Lezheiko, Tatyana, Plakunova, Victoria, Gabaeva, Marina, Golimbet, Vera
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604497/
https://www.ncbi.nlm.nih.gov/pubmed/36293479
http://dx.doi.org/10.3390/ijms232012629
_version_ 1784817828957782016
author Alfimova, Margarita
Kondratyev, Nikolay
Korovaitseva, Galina
Lezheiko, Tatyana
Plakunova, Victoria
Gabaeva, Marina
Golimbet, Vera
author_facet Alfimova, Margarita
Kondratyev, Nikolay
Korovaitseva, Galina
Lezheiko, Tatyana
Plakunova, Victoria
Gabaeva, Marina
Golimbet, Vera
author_sort Alfimova, Margarita
collection PubMed
description As genetic and environmental influences on schizophrenia might converge on DNA methylation (DNAm) within loci which are both associated with the disease and implicated in response to environmental stress, we examined whether DNAm within CYP17A1, a hypothalamus–pituitary–adrenal axis gene which is situated within the schizophrenia risk locus 10q24.32, would mediate genetic and environmental effects on stress-related schizophrenia symptoms. DNAm within an exonic–intronic fragment of CYP17A1 was assessed in the blood of 66 schizophrenia patients and 63 controls using single-molecule real-time bisulfite sequencing. Additionally, the VNTR polymorphism of the AS3MT gene, a plausible causal variant within the 10q24.32 locus, was genotyped in extended patient and control samples (n = 700). The effects of local haplotype, VNTR and a polyenviromic risk score (PERS) on DNAm, episodic verbal memory, executive functions, depression, and suicidality of patients were assessed. Haplotype and PERS differentially influenced DNAm at four variably methylated sites identified within the fragment, with stochastic, additive, and allele-specific effects being found. An allele-specific DNAm at CpG-SNP rs3781286 mediated the relationship between the local haplotype and verbal fluency. Our findings do not confirm that the interrogated DNA fragment is a place where genetic and environmental risk factors converge to influence schizophrenia symptoms through DNAm.
format Online
Article
Text
id pubmed-9604497
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96044972022-10-27 A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia Alfimova, Margarita Kondratyev, Nikolay Korovaitseva, Galina Lezheiko, Tatyana Plakunova, Victoria Gabaeva, Marina Golimbet, Vera Int J Mol Sci Article As genetic and environmental influences on schizophrenia might converge on DNA methylation (DNAm) within loci which are both associated with the disease and implicated in response to environmental stress, we examined whether DNAm within CYP17A1, a hypothalamus–pituitary–adrenal axis gene which is situated within the schizophrenia risk locus 10q24.32, would mediate genetic and environmental effects on stress-related schizophrenia symptoms. DNAm within an exonic–intronic fragment of CYP17A1 was assessed in the blood of 66 schizophrenia patients and 63 controls using single-molecule real-time bisulfite sequencing. Additionally, the VNTR polymorphism of the AS3MT gene, a plausible causal variant within the 10q24.32 locus, was genotyped in extended patient and control samples (n = 700). The effects of local haplotype, VNTR and a polyenviromic risk score (PERS) on DNAm, episodic verbal memory, executive functions, depression, and suicidality of patients were assessed. Haplotype and PERS differentially influenced DNAm at four variably methylated sites identified within the fragment, with stochastic, additive, and allele-specific effects being found. An allele-specific DNAm at CpG-SNP rs3781286 mediated the relationship between the local haplotype and verbal fluency. Our findings do not confirm that the interrogated DNA fragment is a place where genetic and environmental risk factors converge to influence schizophrenia symptoms through DNAm. MDPI 2022-10-20 /pmc/articles/PMC9604497/ /pubmed/36293479 http://dx.doi.org/10.3390/ijms232012629 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alfimova, Margarita
Kondratyev, Nikolay
Korovaitseva, Galina
Lezheiko, Tatyana
Plakunova, Victoria
Gabaeva, Marina
Golimbet, Vera
A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title_full A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title_fullStr A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title_full_unstemmed A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title_short A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia
title_sort role of dna methylation within the cyp17a1 gene in the association of genetic and environmental risk factors with stress-related manifestations of schizophrenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604497/
https://www.ncbi.nlm.nih.gov/pubmed/36293479
http://dx.doi.org/10.3390/ijms232012629
work_keys_str_mv AT alfimovamargarita aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT kondratyevnikolay aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT korovaitsevagalina aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT lezheikotatyana aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT plakunovavictoria aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT gabaevamarina aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT golimbetvera aroleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT alfimovamargarita roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT kondratyevnikolay roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT korovaitsevagalina roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT lezheikotatyana roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT plakunovavictoria roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT gabaevamarina roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia
AT golimbetvera roleofdnamethylationwithinthecyp17a1geneintheassociationofgeneticandenvironmentalriskfactorswithstressrelatedmanifestationsofschizophrenia