TY - JOUR
T1 - Integrative DNA Methylation and Gene Expression Analysis in the Prefrontal Cortex of Mexicans Who Died by Suicide
AU - Romero-Pimentel, Ana L.
AU - Almeida, Daniel
AU - Munõz-Montero, Said
AU - Rangel, Claudia
AU - Mendoza-Morales, Roberto
AU - Gonzalez-Saenz, Eli E.
AU - Nagy, Corina
AU - Chen, Gary
AU - Aouabed, Zahia
AU - Theroux, Jean Francois
AU - Turecki, Gustavo
AU - Martinez-Levy, Gabriela
AU - Walss-Bass, Consuelo
AU - Monroy-Jaramillo, Nancy
AU - Fernández-Figueroa, Edith A.
AU - Gómez-Cotero, Amalia
AU - Garciá-Dolores, Fernando
AU - Morales-Marin, Mirna E.
AU - Nicolini, Humberto
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of CINP.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Background: Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. Methods: In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. Results: We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing. Conclusion: Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.
AB - Background: Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. Methods: In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. Results: We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing. Conclusion: Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.
KW - Epigenomics/transcriptomics
KW - Mexico
KW - postmortem human brain
KW - suicide
UR - http://www.scopus.com/inward/record.url?scp=85118343004&partnerID=8YFLogxK
U2 - 10.1093/ijnp/pyab042
DO - 10.1093/ijnp/pyab042
M3 - Artículo
C2 - 34214149
AN - SCOPUS:85118343004
SN - 1461-1457
VL - 24
SP - 935
EP - 947
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
IS - 12
ER -