Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.
Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Yongsheng
Y
Li
Center of Excellence in Neuroscience and Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Cynthia
C
Camarillo
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Juan
J
Xu
Department of Pediatrics, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Tania Bedard
TB
Arana
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Yun
Y
Xiao
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Zheng
Z
Zhao
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Hong
H
Chen
Center of Excellence in Neuroscience and Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Mercedes
M
Ramirez
Center of Excellence in Neuroscience and Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Juan
J
Zavala
Center of Excellence in Neuroscience and Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Michael A
MA
Escamilla
Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94103, USA.
Regina
R
Armas
Los Angeles Biomedical Research Center at Harbor, University of California Los Angeles Medical Center, Torrance, CA 90502, USA.
Ricardo
R
Mendoza
Instituto de Informacion de Investigacion en Salud Mental, 64710 Monterrey, NL, Mexico.
Alfonso
A
Ontiveros
Medical and Family Research Group, Carracci S.C., 03740 Mexico City, DF, Mexico.
Humberto
H
Nicolini
Centro Internacional de Trastornos Afectivos y de la Conducta Adictiva (CITACA), 01010 Guatemala City, Guatemala.
Alvaro Antonio Jerez
AA
Magaña
Department of Pediatrics, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Lewis P
LP
Rubin
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Xia
X
Li
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China ; Department of Pediatrics, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, USA.
Chun
C
Xu
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D002874:Chromosome Mapping; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult