Interaction between Methylation and CpG Single-Nucleotide Polymorphisms in the HTR2A Gene: Association Analysis with Suicide Attempt in Schizophrenia

Abstract

Dysfunctional mechanisms in the serotonergic system have been implicated in suicidal behavior among patients with schizophrenia. However, previous association analyses of major serotonin genes have provided inconsistent findings regarding their role in suicidal behavior. The goal of the current study was to identify single-nucleotide polymorphisms (SNP) within HTR2A that directly affect CpG methylation sites in schizophrenic patients with suicidal behavior. Furthermore, direct methylation analysis was performed using genomic DNA from peripheral leukocytes employing bisulfite pyrosequencing to assess the contributions of six CpG sites in HTR2A exon I in 67 schizophrenia patients assessed for lifetime suicide attempt. Potential methylation in 25 CpG SNPs across the entire HTR2A gene was analyzed considering their direct contribution to methylation. When we compared direct methylation between attempters and nonattempters, we found that only the polymorphic T102C (rs6313) was significantly different between the two groups (p = 0.02). Furthermore, in the potential methylation analysis, we found a nominal association with suicide attempt for six of the 25 SNPs analyzed, i.e. rs2770293 (p = 0.045), rs6313 (p = 0.033), rs17068986 (p = 0.029), rs4942578 (p = 0.024), rs1728872 (p = 0.014), and rs9534511 (p = 0.003). The results of this investigation provide preliminary evidence that the combined analysis of CpG SNPs and methylation may be useful for investigating the genetic and epigenetic factors involved in suicidal behavior.

Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment

“…Although many of these SNPs overlapped with pre‐mRNA processing sites, Piva et al () suggested that they do not affect transcript processing due to redundancy of signal sites that complement each other. Furthermore, experimental data shows that SNPs, methylation, and expression changes of HTR2A are associated with risk for SZ, suicidal behavior in patients with SZ, and tardive dyskinesia, a common side effect of treatment (Bani‐Fatemi et al, ; Castensson et al, ; Zhang et al, ).…”

Understanding epigenetic architecture of suicide neurobiology: A critical perspective

“…However, in a recent report Bani-Fatemi and group attempted to find out a functional link between hyposerotonergic neurotransmission and 25 methylated polymorphic loci of HTR2A gene in blood genomic DNA of 32 suicide attempters with major psychosis (Bani-Fatemi et al, 2016). Though the study was unable to establish a possible connection between the 5HT based epigenetic changes and suicide risk in schizophrenia patients but was able to determine significant hypermethylation at a genetically variable locus (rs6313) in the exon I of HTR2A gene.…”

Gene-methylation epistatic analyses via the W-test identifies enriched signals of neuronal genes in patients undergoing lipid-control treatment

“…There are an increasing number of laboratory experiments that provide evidence of DNA methylation and gene expression regulation [ 3 – 5 ]. Only a few studies, however, have evaluated the genome–epigenome interactions through statistical means, which may potentially provide novel findings for the joint effects of SNPs and cytosine-phosphate-guanine (CpG) sites [ 6 – 9 ]. The search for SNP-CpG epistasis is usually conducted through multistage or integrated analyses, where the genome and methylation data are first analyzed separately and the results then combined [ 10 , 11 ].…”