Exploration of cell type-specific somatic mutations in schizophrenia and the impact of maternal immune activation on the somatic mutation profile in the brain.

AIM: Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ. METHODS: We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations. RESULTS: We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes. CONCLUSION: Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.

LINE-1 hypomethylation, increased retrotransposition and tumor-specific insertion in upper gastrointestinal cancer.

The long interspersed nuclear element-1 (LINE-1) retrotransposons are a major family of mobile genetic elements, comprising approximately 17% of the human genome. The methylation state of LINE-1 is often used as an indicator of global DNA methylation levels and it regulates the retrotransposition and somatic insertion of the genetic element. We have previously reported the significant relationship between LINE-1 hypomethylation and poor prognosis in upper gastrointestinal (GI) cancers. However, the causal relationships between LINE-1 hypomethylation, retrotransposition, and tumor-specific insertion in upper GI cancers remain unknown. We used bisulfite-pyrosequencing and quantitative real-time PCR to verify LINE-1 methylation and copy number in tissue samples of 101 patients with esophageal and 103 patients with gastric cancer. Furthermore, we analyzed the LINE-1 retrotransposition profile with an originally developed L1Hs-seq. In tumor samples, LINE-1 methylation levels were significantly lower than non-tumor controls, while LINE-1 copy numbers were markedly increased. As such, there was a significant inverse correlation between the LINE-1 methylation level and copy number in tumor tissues, with lower LINE-1 methylation levels corresponding to higher LINE-1 copy numbers. Of particular importance is that somatic LINE-1 insertions were more numerous in tumor than normal tissues. Furthermore, we observed that LINE-1 was inserted evenly across all chromosomes, and most often within genomic regions associated with tumor-suppressive genes. LINE-1 hypomethylation in upper GI cancers is related to increased LINE-1 retrotransposition and tumor-specific insertion events, which may collectively contribute to the acquisition of aggressive tumor features through the inactivation of tumor-suppressive genes.

G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression.

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on ß-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.

Quantification of cytosine modifications in the aged mouse brain.

Quantifying cytosine modifications in various brain regions provides important insights into the gene expression regulation and pathophysiology of neuropsychiatric disorders. In this study, we quantified 5-methylcytosine (5-mC), 5-hydroxymethylation (5-hmC), and 5-formylcytosine (5-fC) levels in five brain regions (the frontal lobe, cerebral cortical region without frontal lobe, hippocampus, basal ganglia, and the cerebellum) and the heart at three developmental periods (12, 48, and 101 weeks). We observed significant regional variations in cytosine modification. Notably, regional variations were generally maintained throughout development, suggesting that epigenetic regulation is unique to each brain region and remains relatively stable with age. The 5-mC and 5-hmC levels were positively correlated, although the extent of the correlations seemed to differ in different brain regions. On the contrary, 5-fC levels did not correlate with 5-mC or 5-hmC levels. Additionally, we observed an age-dependent decrease in 5-fC levels in the basal ganglia, suggesting a unique epigenetic regulation mechanism. Further high-resolution studies using animal models of neuropsychiatric disorders as well as postmortem brain evaluation are warranted.

Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion.

Background & Aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. Conclusions: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. Impact and implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.

Sex-dependent behavioral alterations in a poly(I:C)-induced maternal immune activation mouse model without segment filamentous bacteria.

Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen, polyinosinic-polycytidylic acid (poly(I:C)), is used to induce maternal immune activation in animal models of psychiatric disorders. In the mouse poly(I:C) model, the existence of segment filamentous bacteria (SFB) in the maternal intestine has been reported to be important for the induction of ASD-related behavioral alterations as well as atypical cortical development called cortical patches. This study aimed to elucidate the effect of a single poly(I:C) injection during embryonic day (E) 9 to E16 on offspring's behavior in the ensured absence of maternal SFB by vancomycin drinking in C57BL/6N mice. The cortical patches were not found at either injection timings with poly(I:C) or PBS vehicle, tested in male or female offspring at postnatal day 0 or 1. Prepulse inhibition was decreased in male adult offspring most strongly at poly(I:C) injection timings later than E11, whereas a modest but significant decrease was observed in female offspring with an injection during E12 to E15. The decrease in social interaction was observed in female offspring most conspicuously at injection timings later than E11, whereas a significant decrease was observed in male offspring with an injection during E12 to E15. In conclusion, this study indicated that behavioral alterations could be induced without maternal SFB. The effect on behavior was substantially different between males and females.

Crohn's disease-related anal fistula cancer diagnosed by examination under anesthesia: a case report.

BACKGROUND: As the number of patients with inflammatory bowel disease (IBD) increases, the incidence of IBD-related colorectal cancer (CRC) is also on the rise. Crohn's disease (CD)-related CRC has been reported to have a poorer prognosis than sporadic CRC, and the early detection of CD-related CRC is difficult. Japanese patients with CD are reported to have a higher frequency of anorectal cancer than the Western population; however, methods for early diagnosis have not yet been established because of perianal pain during the examination. CASE PRESENTATION: We report a case of CD-related anal fistula cancer that was detected early by surveillance examination under anesthesia (EUA). The patient was a 37-year-old man, diagnosed with CD at the age of 15 years and started medical treatment. However, due to poor disease control, the intestinal tract remained highly inflamed and the patient continued to have over 10 bowel movements per day. He was referred to our hospital for surgical treatment after a colonoscopy (CS), which revealed multiple active ulcers and stenoses. Since three perianal seton drainage tubes had been placed around his anus since the age of 33 years, we decided to perform an EUA to rule out cancer coexistence in the anorectal region. After a random biopsy of the rectum by CS under general anesthesia, we resected and curetted multiple perianal fistulas as much as possible and reinserted the seton drainage tubes. Pathological examination of the fistula tract revealed adenocarcinoma in one tract, indicating the coexistence of anal fistula cancer. Based on the diagnosis of multiple intestinal stenoses and anal fistula cancer due to CD, we performed hand-assisted laparoscopic total colectomy, rectal amputation, extensive perineal resection, and reconstruction using a left rectus abdominis flap. CONCLUSION: In a long-term CD patient with anorectal lesions, we performed an EUA to diagnose the coexistence of anal fistula cancer at an early stage, and surgical resection was achieved. EUA is effective for the early detection and treatment of CD-related CRC and may contribute to an improved prognosis.

Identification of epigenetically active L1 promoters in the human brain and their relationship with psychiatric disorders.

Long interspersed nuclear element-1 (LINE-1, L1) affects the transcriptome landscape in multiple ways. Promoter activity within its 5'UTR plays a critical role in regulating diverse L1 activities. However, the epigenetic status of L1 promoters in adult brain cells and their relationship with psychiatric disorders remain poorly understood. Here, we examined DNA methylation and hydroxymethylation of the full-length L1s in neurons and nonneurons and identified "epigenetically active" L1s. Notably, some of epigenetically active L1s were retrotransposition competent, which even had chimeric transcripts from the antisense promoters at their 5'UTRs. We also identified differentially methylated L1s in the prefrontal cortices of patients with psychiatric disorders. In nonneurons of bipolar disorder patients, one L1 was significantly hypomethylated and showed an inverse correlation with the expression level of the overlapping gene NREP. Finally, we observed that altered DNA methylation levels of L1 in patients with psychiatric disorders were not affected by the surrounding genomic regions but originated from the L1 sequences. These results suggested that altered epigenetic regulation of the L1 5'UTR in the brain was involved in the pathophysiology of psychiatric disorders.

[A Case Report-A Successful Case of Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer with an Aberrant Right Hepatic Artery].

In cases of pancreatic cancer with anatomical variations of the hepatic artery, it is important to evaluate the hemodynamics of each case for surgical indication. We report the case of a 68-year-old man with locally advanced pancreatic cancer and an aberrant right hepatic artery who underwent distal pancreatectomy with celiac axis resection(DP-CAR). He was admitted to our institute due to abdominal discomfort. A CT scan showed pancreatic cancer invading the common hepatic artery. He underwent chemoradiotherapy with a diagnosis of locally advanced pancreatic cancer. After the tumor downstaging, we performed DP-CAR, which included a gastroduodenal artery and a proper hepatic artery resection. Even though delayed gastric emptying was observed after the operation, he was discharged on postoperative day 36.

[FOLFIRI plus RAM Therapy in Later Line of Unresectable Colorectal Cancer].

FOLFIRI plus ramucirumab(RAM)therapy has been reported to be effective and safe in the RAISE trial as second-line treatment for unresectable colorectal cancer. It is hypothesized that RAM may be effective in patients with PD treated with FOLFIRI plus bevacizumab(Bev)due to different mechanism of action from that of Bev, which is also an angiogenesis inhibitor. From January 2017 to December 2021, we conducted a retrospective study of 6 patients who had PD with 5-FU, oxaliplatin, irinotecan, or Bev as first or second-line treatment at our institution and who received FOLFIRI plus RAM in later line treatment. The 6 cases consisted of 3 patients in the third-line treatment, 1 patient in the fourth-line treatment, and 2 patients in the sixth-line treatment. The anti-tumor effect was PD in all cases in the third-line and fourth-line treatment, but the 2 patients of sixth-line treatment were controlled diseases.

Clinical outcomes of single incision laparoscopic surgery for colorectal cancer: A propensity score-matched analysis between well-experienced and novice surgeons.

Background: Single incision laparoscopic surgery (SILS) is a recent advancement in minimally invasive techniques for colorectal cancer (CRC). However, SILS is a technically challenging procedure for novice surgeons. The aim of this study was to evaluate clinical outcomes of SILS for CRC performed by novice surgeons compared with those performed by well-experienced surgeons. Methods: We retrospectively analyzed 1004 consecutive patients with stage I-IV CRC who underwent SILS between May 2009 and December 2018, using propensity score-matched analysis. Results: After propensity score-matching, we enrolled 344 patients (n = 172 in each group). Before matching, significant group-dependent differences were observed in terms of age (P = 0.034) and tumor location (P < 0.001). After matching, preoperative clinical factors were similar between groups, but operative time was longer in the Novice group (213 vs 171 min, P < 0.001). Other operative factors and morbidity rates did not differ significantly between groups. The number of harvested lymph nodes was smaller in the Novice group (23 vs 25, P = 0.040), and the number of patients with lymph node metastases was smaller in the Novice group (57 vs 86, P = 0.002). The 3-year disease-free survival rate was 85.8% in the Novice group and 89.9% in the Experienced group (P = 0.512). Three-year overall survival rate was 92.2% in the Novice group and 90.0% in the Experienced group (P = 0.899). Conclusion: SILS for CRC was safely performed by novice surgeons under the guidance of well-experienced surgeons, and could provide satisfactory oncological outcomes.

A Method for Detection of Somatic LINE-1 Insertions at the Single-Cell Level from Postmortem Human Brain.

Long Interspersed Element-1 (LINE-1, L1) is a retrotransposon that has the ability to amplify its copy in the genome autonomously. L1Hs is a human-specific active subtype of L1 reported to amplify its copy in neural progenitor cells causing genomic mosaicism. This chapter describes a new method named NECO-seq (Novel Elements Concentrated-sequence) to identify the genomic locus of L1Hs insertions at the single-cell level. This protocol contains the steps of (1) preparation of neuronal cell nuclei from a postmortem human brain, (2) whole genome amplification from single neural nuclei (snWGA), (3) single nucleotide polymorphisms (SNPs) genotyping for quality control of snWGA products, (4) library preparation for next-generation sequencing to enrich the genomic locus of L1Hs insertions, and (5) bioinformatic analysis to detect novel somatic L1Hs insertions. This method can detect approximately 97% of L1Hs originally existing in reference human genome and approximately 10-20 newly inserted L1Hs copies in a neuronal cell of a postmortem human brain.

Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia.

Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for descending colon cancer: a propensity score-matched analysis.

BACKGROUND: The clinical impact of single-incision laparoscopic surgery (SILS) for descending colon cancer (DCC) is unclear. The aim of this study was to evaluate the clinical outcomes of SILS for DCC compared with multi-port laparoscopic surgery (MPLS). METHODS: We retrospectively analyzed 137 consecutive patients with stage I-III DCC who underwent SILS or MPLS at two high-volume multidisciplinary tertiary hospitals between April 2008 and December 2018, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 88 patients (n = 44 in each group). SILS was successful in 97.7% of the matched cohort. Compared with the MPLS group, the SILS group showed significantly less blood loss and a greater number of harvested lymph nodes. Morbidity rates were similar between groups. Recurrence pattern did not differ between groups. No significant differences were found between groups in terms of 3-year disease-free and overall survivals. CONCLUSION: SILS appears safe and feasible and can provide satisfactory oncological outcomes for patients with DCC.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for rectosigmoid or upper rectal cancer.

BACKGROUND: Single-incision laparoscopic surgery (SILS) for rectal cancer is technically challenging, and its clinical impact is unclear. The aim of this study was to evaluate clinical outcomes of SILS for rectal cancer compared with multi-port laparoscopic surgery (MPLS). PATIENTS AND METHODS: We retrospectively analyzed 357 consecutive patients with stage I-III rectal cancer located in the rectosigmoid or upper rectum who underwent SILS or MPLS between January 2012 and December 2016, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 204 patients (n = 102 per group). Before matching, significant group-dependent differences were observed in tumor location (p < 0.001). After matching, preoperative clinical factors were similar between groups. SILS was successful in 73.5% of cases, an additional port was required in 23.5%, and 2.9% were converted to open surgery. Compared to the MPLS group, the SILS group showed shorter operative time (192 vs. 211 min, p = 0.015) and shorter postoperative hospital stay (9 vs. 11 days, p = 0.038). Other operative factors and morbidity rates did not differ significantly between groups. The number of harvested lymph nodes was smaller in the SILS group (24) than in the MPLS group (27, p = 0.008). Postoperative recurrence did not differ between groups, either before or after matching. No significant differences in 3-year disease-free, 3-year local recurrence-free, or 5-year overall survival were found between groups. CONCLUSIONS: SILS is safe, is feasible, and offers satisfactory oncological outcomes in selected patients with rectosigmoid or upper rectal cancer.

Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by repeated conflicting manic and depressive states. In addition to genetic factors, complex gene-environment interactions, which alter the epigenetic status in the brain, contribute to the etiology and pathophysiology of BD. Here, we performed a promoter-wide DNA methylation analysis of neurons and nonneurons derived from the frontal cortices of mutant Polg1 transgenic (n = 6) and wild-type mice (n = 6). The mutant mice expressed a proofreading-deficient mitochondrial DNA (mtDNA) polymerase under the neuron-specific CamK2a promoter and showed BD-like behavioral abnormalities, such as activity changes and altered circadian rhythms. We identified a total of 469 differentially methylated regions (DMRs), consisting of 267 neuronal and 202 nonneuronal DMRs. Gene ontology analysis of DMR-associated genes showed that cell cycle-, cell division-, and inhibition of peptide activity-related genes were enriched in neurons, whereas synapse- and GABA-related genes were enriched in nonneurons. Among the DMR-associated genes, Trim2 and Lrpprc showed an inverse relationship between DNA methylation and gene expression status. In addition, we observed that mutant Polg1 transgenic mice shared several features of DNA methylation changes in postmortem brains of patients with BD, such as dominant hypomethylation changes in neurons, which include hypomethylation of the molecular motor gene and altered DNA methylation of synapse-related genes in nonneurons. Taken together, the DMRs identified in this study will contribute to understanding the pathophysiology of BD from an epigenetic perspective.

Laparoscopic mesh removal for mesh infection related to pararectal incision of previous appendectomy after laparoscopic total extraperitoneal inguinal hernia repair: A case report.

A 67-year-old man with a history of appendectomy 40 years ago underwent single-incision laparoscopic surgery for total extraperitoneal inguinal hernia repair. Postoperatively, the pararectal incisional scar obtained from the appendectomy was infected; thus, antibiotic therapy and drainage were performed. However, the infection persisted. After 5 postoperative months, the mesh was laparoscopically removed at a sufficient distance from the infected site. No enterocutaneous fistula was observed. After 1 year and 10 months, no recurrence of hernia or infection was observed. Thus, laparoscopic mesh removal is feasible. Infection of a 40-year-old incision rarely results in mesh infection. Therefore, in pararectal incision, the extent of mesh coverage should be considered; if the overlap is large, changing the technique by not covering the incision may be necessary.

Single-Incision Laparoscopic Cholecystectomy: a Single-Centre Experience of 1469 Cases.

BACKGROUND: Despite having once been extensively used for cosmetics or pain reduction, the use of single-incision laparoscopic cholecystectomy (SILC) has declined in recent years due to technical difficulties and a reported increase in complications. Since the introduction of SILC in 2009, our hospital has been actively involved with this technique. Our experience suggests that SILC is not a difficult procedure and can be safe and useful, with particularly excellent cosmetic outcomes. This study retrospectively details the outcomes of SILC at our hospital. METHOD: Data on 1469 cases of SILC performed on a waitlist basis at Osaka Police Hospital from May 2009 to December 2020 were collected and retrospectively analysed. RESULTS: The median operative time and blood loss were 96 min and 0 mL, respectively. A total of 46 patients (3.1%) required conversion surgery, including 36 needing additional ports and 10 requiring laparotomy. Intraoperative complications included common bile duct injury in 1 patient (0.07%) and right hepatic artery injury in 1 patient (0.07%), with no other organ injury. Postoperative Clavien-Dindo 3 or higher complications were observed in 18 patients (1.2%). Incisional hernias occurred in 15 patients (1.0%). The median postoperative hospital stay was 3 days. CONCLUSION: This study showed that SILC can be performed safely without any increase in complications, as reported previously. Granted that it is performed safely, SILC may be a useful technique due to its superior cosmetic outcomes or pain reduction.

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone.

Accumulating evidence suggests that the epigenetic alterations induced by antipsychotics contribute to the therapeutic efficacy. However, global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics remain poorly understood. We conducted a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with antipsychotics. The cells were cultured with low and high concentrations of haloperidol or risperidone for 8 days. DNA methylation assay was performed with the Illumina HumanMethylation450 BeadChip. We found that both haloperidol and risperidone tended to cause hypermethylation changes and showed similar DNA methylation changes closely related to neuronal functions. A total of 294 differentially methylated probes (DMPs), including 197 hypermethylated and 97 hypomethylated DMPs, were identified with both haloperidol and risperidone treatment. Gene ontology analysis of the hypermethylated probe-associated genes showed enrichment of genes related to the regulation of neurotransmitter receptor activity and lipoprotein lipase activity. Pathway analysis identified that among the DMP-associated genes, SHANK1 and SHANK2 were the major genes in the neuropsychiatric disorder-related pathways. Our data would be valuable for understanding the mechanisms of action of antipsychotics from an epigenetic viewpoint.