Relationship of Major Depressive Disorder and Schizophrenia Polygenic Risk Scores to Suicide: A Comparison Between European and Asian Ancestry Populations.

Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the East Asian data set for MDD/SCZ, resulting in less statistical power to detect robust difference between the two ancestries.

Psychiatric diagnosis in suicides appears more common in Europeans than in East Asians.This is the first comparison of suicide genome-wide association studies between Europeans and East Asians.Major depressive disorder/schizophrenia polygenic risk scores for suicide were more significant for Europeans than for East Asians.

Pharmacokinetics of Brexpiprazole, Quetiapine, Risperidone, and Its Active Metabolite Paliperidone in a Postpartum Woman and Her Baby.

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

Epigenome-wide association study on methamphetamine dependence.

Repeated abuse of methamphetamine (METH) can cause dependence, repeated relapse of psychotic symptoms, compulsive drug-seeking behaviour, and various neurological symptoms. These long-term biological changes may be associated with epigenetic mechanisms; however, the association between METH use and epigenetic mechanisms has been poorly investigated. Thus, we performed an epigenome-wide association study of METH dependence using genomic DNA extracted from the blood samples of 24 patients with METH dependence and 24 normal controls. All participants were of Japanese descent. We tested the association between METH dependence and DNA methylation using linear regression analysis. We found epigenome-wide significant associations at four CpG sites, one of which occurred in the CNOT1 gene and another in the PUM1 gene. We especially noted the CNOT1 and PUM1 genes as well as several other genes that indicated some degree of association with METH dependence. Among the relatively enriched Gene Ontology terms, we were interested in terms of mRNA metabolism, respirasome, and excitatory extracellular ligand-gated ion channel activity. Among the relatively enriched Kyoto Encyclopedia of Genes and Genome pathways, we noted pathways of several neurological diseases. Our results indicate that genetic changes akin to those in other psychiatric or neurodegenerative disorders may also occur via epigenetic mechanisms in patients with METH dependence.

Accelerated epigenetic aging in alcohol dependence.

Alcohol dependence poses a global health threat associated with aging and reduced life expectancy. Recently, aging research through deoxyribonucleic acid (DNA) methylation has gained attention. New epigenetic clocks have been developed; however, no study has investigated GrimAge components, GrimAge2 components and DunedinPACE in patients with alcohol dependence. In this study, we aimed to perform epigenetic clock analysis to evaluate epigenetic age acceleration and DNA methylation-based age-predictive components in patients with alcohol dependence and controls. We utilized publicly available DNA methylation data (GSE98876) for our analysis. Additionally, we compared the values of the same items before and after the patients underwent a treatment program. The dataset comprised 23 controls and 24 patients. We observed that DunedinPACE accelerated more in patients with alcohol dependence. AgeAccelGrim and AgeAccelGrim2 decelerated more after the treatment program than before, and beta-2-microglobulin and Cystatin C decreased after the treatment program than before. These findings are crucial as they affect the cranial nerve area, potentially contributing to cognitive dysfunction and psychiatric symptoms in patients with alcohol dependence.

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population.

BACKGROUND: More than 800 000 people die by suicide annually. The heritability of suicide is 30%-50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia-inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single-nucleotide polymorphism (SNP), in suicide completers and controls. METHODS: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). RESULTS: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. CONCLUSION: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF-related genetic studies, including those of rs17004038, are necessary with larger sample sizes.

Accelerated epigenetic aging and decreased natural killer cells based on DNA methylation in patients with untreated major depressive disorder.

Major depressive disorder (MDD) is known to cause significant disability. Genome-wide DNA methylation (DNAm) profiles can be used to estimate biological aging and as epigenetic clocks. However, information on epigenetic clocks reported in MDD patients is inconsistent. Since antidepressants are likely confounders, we evaluated biological aging using various DNAm-based predictors in patients with MDD who had never received depression medication. A publicly available dataset consisting of whole blood samples from untreated MDD patients (n = 40) and controls (n = 40) was used. We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAm-based telomere length (DNAmTL), and DNAm-based age-related plasma proteins (GrimAge components), as well as DNAm-based white blood cell composition. The results indicate that patients with untreated MDD were significantly associated with epigenetic aging acceleration in HannumAge and GrimAge. Furthermore, a decrease in natural killer cells, based on DNAm, was observed in patients with untreated MDD.

Mapping the genetic architecture of suicide attempt and suicide death using polygenic risk scores for clinically-related psychiatric disorders and traits.

BACKGROUND: Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death. METHODS: We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis. RESULTS: PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10-4). The polygenic effects of all 22 psychiatric disorders/traits had the same direction (p for binomial tests = 4.8 × 10-7) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents. CONCLUSIONS: We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.

Association of two variable number of tandem repeats in the monoamine oxidase A gene promoter with suicide completion: The present study and meta-analysis.

BACKGROUND: One potential cause of suicide is serotonergic dysfunction. Sex differences have been reported to modulate the effects of serotonergic polymorphisms. Monoamine oxidase A (MAOA) is an enzyme that degrades serotonin and is located on the X chromosome. A previous study indicated that the upstream (u) variable number of tandem repeat (VNTR) in the MAOA gene promoter may be associated with suicide. However, a meta-analysis showed that this polymorphism may not be related to suicide. According to a recent study, compared with the uVNTR, the distal (d)VNTR and the haplotypes of the two VNTRs modulate MAOA expression. METHODS: We examined the two VNTRs in the MAOA gene promoter in 1007 subjects who committed suicide and 844 healthy controls. We analyzed the two VNTRs using fluorescence-based polymerase chain reaction assays. We conducted a meta-analysis for the two VNTRs to update it. RESULTS: Our results demonstrated that neither the genotype-based associations nor allele/haplotype frequencies of the two VNTRs were significantly associated with suicide. In the meta-analysis, we did not indicate relationships between uVNTR and suicide nor did we identify articles analyzing dVNTR in suicide. CONCLUSION: Overall, we did not find a relationship between the two VNTRs in the MAOA promoter and suicide completion; thus, warranting further studies are required.

Epigenetic clock analysis reveals increased plasma cystatin C levels based on DNA methylation in major depressive disorder.

Major depressive disorder (MDD) is a common mental illness and a major public health concern worldwide. Depression is associated with epigenetic changes that regulate gene expression, and analyzing these changes may help elucidate the pathophysiology of MDD. Genome-wide DNA methylation (DNAm) profiles can function as 'epigenetic clocks' that can help estimate biological aging. Here, we assessed biological aging in patients with MDD using various DNAm-based indicators of epigenetic aging. We used a publicly available dataset containing data obtained from the whole blood samples of MDD patients (n = 489) and controls (n = 210). We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and DNAm-based telomere length (DNAmTL). We also investigated seven DNAm-based age-predictive plasma proteins (including cystatin C) and smoking status, which are components of GrimAge. Following adjustment for confounding factors such as age and sex, patients with MDD showed no significant difference in epigenetic clocks and DNAmTL. However, DNAm-based plasma cystatin C levels were significantly higher in patients with MDD than controls. Our findings revealed specific DNAm changes predicting plasma cystatin C levels in MDD. These findings may help elucidate the pathophysiology of MDD, leading to the development of new biomarkers and medications.

Ribosomal DNA gene copies are increased in blood and brain of Japanese schizophrenia patients.

Past evidence has indicated increased ribosomal DNA (rDNA) content in the blood of patients with schizophrenia (SCZ) among European populations. Here, for the first time, we investigated the rDNA copy number (rDNAcn) of SCZ in East Asian populations as well as in blood and brain tissues. In this study, we measured 18S/28S rDNAcn in the peripheral blood of live participants (81 patients with SCZ and 98 healthy controls) and the dorsolateral prefrontal cortices (DLPFCs) of postmortem individuals (10 patients with SCZ and 23 non-psychiatric controls) in the Japanese population. Patients with SCZ had significantly increased 18S/28S rDNAcn in the blood compared to controls (p < 0.05). 18S rDNAcn was significantly increased in the brain of patients with SCZ compared to controls (p < 0.05). In conclusion, regarding the increased rDNAcn in the blood of patients with SCZ that was previously reported in Europeans, we successfully replicated this by using a different, ethnically East Asian, cohort. Additionally, we provide the first evidence of increased rDNAcn in the brain of patients with SCZ. These findings may help to elucidate the molecular underpinnings of SCZ pathophysiology related to ribosomal DNA abnormalities.

Physiologically-based pharmacokinetic model to investigate the effect of pregnancy on risperidone and paliperidone pharmacokinetics: Application to a pregnant woman and her neonate.

This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their "virtual twins." Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05-3.80 and 0.82-1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia.

Background: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. Patients and methods: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). Results: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. Conclusion: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

Epigenetic clock analysis in methamphetamine dependence.

Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.

Epigenetic aging in Williams syndrome.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder caused by a microdeletion at the 7q11.23 region and is characterized by diverse symptoms encompassing physical and cognitive features. WS was reported to be associated to altered DNA methylation (DNAm) patterns. However, due to the limited information from long-term studies, it remains unclear whether WS accelerates aging. Genome-wide DNAm profiles can serve as "epigenetic clocks" to help estimate biological aging along with age-related markers, such as plasma proteins and telomere length. METHODS: We investigated GrimAge, DNAm-based telomere length (DNAmTL), and other epigenetic clocks in blood samples of 32 patients with WS and 32 healthy controls. RESULTS: We observed a significant acceleration in GrimAge, DNAmTL, and other epigenetic clocks in patients with WS as compared with those of controls. In addition, several GrimAge components, such as adrenomedullin, growth differentiation factor-15, leptin and plasminogen activator inhibitor-1, were altered in patients with WS. CONCLUSIONS: This study provides novel evidence supporting the hypothesis that WS may be associated to accelerated biological aging. A better understanding of the overall underlying biological effects of WS can provide new foundations for improved patient care; thus, long-term follow-up studies are still warranted.

Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis.

SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.

Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as 'epigenetic clocks' that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. METHODS: We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. RESULTS: Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. CONCLUSION: Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.