Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.     

Evidence of an interaction between FXR1 and GSK3β polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

BackgroundGenome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication.MethodsTo test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3β expression.ResultsWe found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex.DiscussionOur findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ.     

Neural Correlates of Variation in Personal Space and Social Functioning in Schizophrenia and Healthy Individuals

BackgroundChanges in the regulation of interpersonal distance, or “personal space” (PS), have been repeatedly observed in schizophrenia and, in some studies, linked to negative symptoms. However, the neurobiological basis of these impairments is poorly understood.MethodsPersonal space measurements, functional connectivity of a brain network sensitive to intrusions into PS, and symptoms of social withdrawal and anhedonia were assessed, and associations among these outcomes measured, in 33 individuals with a psychotic disorder (primarily schizophrenia [SCZ]) and 36 control subjects (CON).ResultsPersonal space size was significantly higher (P = .002) and PS permeability (reflecting the capacity to tolerate intrusions into PS) was significantly lower (P = .021) in the SCZ relative to the CON group, and both measures were significantly correlated with social anhedonia and withdrawal in the full sample (all P < .007). Moreover, functional connectivity between the PS and default mode (DM) networks was significantly correlated with the permeability, but not the size, of PS in the full sample and in the SCZ and CON groups separately, and with social withdrawal in the SCZ group. Lastly, the association between PS-DM network connectivity and social withdrawal in the SCZ group was fully mediated by PS permeability.DiscussionNeural and behavioral aspects of PS regulation are linked to social motivation in both healthy individuals and those with psychotic disorders, suggesting that measurements of PS could serve as transdiagnostic markers of social functioning.     

Exploratory analysis of the genetics of impulse control disorders in Parkinson's disease using genetic risk scores

ObjectiveTo study the association between impulse control disorders (ICDs) in Parkinson's disease (PD) and genetic risk scores (GRS) for 40 known or putative risk factors (e.g. depression, personality traits).BackgroundIn absence of published genome-wide association studies (GWAS), little is known about the genetics of ICDs in PD. GRS of related phenotypes, for which large GWAS are available, may help shed light on the genetic contributors of ICDs in PD.MethodsWe searched for GWAS on European ancestry populations with summary statistics publicly available for a broad range of phenotypes, including other psychiatric disorders, personality traits, and simple phenotypes. We separately tested their predictive ability in two of the largest PD cohorts with clinical and genetic available: the Parkinson's Progression Markers Initiative database (N = 368, 33% female, age range = [33–84]) and the Drug Interaction With Genes in Parkinson's Disease study (N = 373, 40% female, age range = [29–85]).ResultsWe considered 40 known or putative risk factors for ICDs in PD for which large GWAS had been published. After Bonferroni correction for multiple comparisons, no GRS or the combination of the 40 GRS were significantly associated with ICDs from the analyses in each cohort separately and from the meta-analysis.ConclusionAlbeit unsuccessful, our approach will gain power in the coming years with increasing availability of genotypes in clinical cohorts of PD, but also from future increase in GWAS sample sizes of the phenotypes we considered. Our approach may be applied to other complex disorders, for which GWAS are not available or limited.     

Polygenic risk for schizophrenia and associated brain structural changes: A systematic review

BackgroundGenome wide association studies (GWAS) of schizophrenia allow the generation of Polygenic Risk Scores (PRS). PRS can be used to determine the contribution to altered brain structures in this disorder, which have been well described. However, findings from studies using PRS to predict brain structural changes in schizophrenia have been inconsistent. We therefore performed a systematic review to determine the association between schizophrenia PRS and brain structure.MethodsFollowing PRISMA systematic review guidelines, databases were searched for literature using key search terms. Inclusion criteria for the discovery sample required case-control schizophrenia GWAS summary statistics from European populations. The target sample was required to be of European ancestry, and have brain structure and genotype information. Quality assessment of the publications was conducted using the Mixed Methods Appraisal Tool for quantitative non-randomised studies.Main findingsA total of seven studies were found to be eligible for review. Five studies found no significant association and two studies found a significant association of schizophrenia PRS with total brain, reduced white matter volume, and globus pallidus volume. However, the latter studies were conducted using smaller discovery (n_cases = 9394 n_controls = 12,462) and target samples compared to the studies with substantially larger discovery (n_cases = 33,636 n_controls = 43,008) and target samples where no association was observed. Taken together, the results suggest that schizophrenia PRS are not significantly associated with brain structural changes in this disorder.ConclusionsThe lack of significant association between schizophrenia PRS and brain structural changes may indicate that intermediate phenotypes other than brain structure should be the focus of future work. Alternatively, however, the lack of association found here may point to limitations of the current evidence-base, and so point to the need for future better powered studies.     

Causal associations of intelligence with schizophrenia and bipolar disorder: A Mendelian randomization analysis

BackgroundIntelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk.MethodsTo estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ + BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized.ResultsA strong bidirectional association between risks for SCZ and BD was observed (odds ratio; OR_SCZ → BD = 1.47, p = 2.89 × 10⁻⁴¹, OR_BD → SCZ = 1.44, p = 1.85 × 10⁻⁵²). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (OR_{lower intelligence → SCZ} = 1.62, p = 3.23 × 10⁻¹⁴) than the reverse (OR_{SCZ → lower intelligence} = 1.06, p = 3.70 × 10⁻²³). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR _{lower intelligence → SCZ + BD} = 1.23, p = 3.41 × 10⁻⁵) and SCZ-specific risk (OR_{lower intelligence → SCZvsBD} = 1.64, p = 9.72 × 10⁻¹⁰); the shared risk (OR_{SCZ + BD → lower intelligence} = 1.04, p = 3.09 × 10⁻¹⁴) but not SCZ-specific risk (OR_{SCZvsBD → lower intelligence} = 1.00, p = 0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p > 0.05).ConclusionsThese findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.     

Genome-Wide Association Studies of Alcohol Dependence and Substance Use Disorders

Genome-wide association studies (GWAS) currently represent the most systematic approach to genetic research into complex disorders. They can detect associations of common variants in genomic regions in the absence of an a priori assumption. Most of the GWAS of addiction performed to date have focused on alcohol dependence or smoking behavior. Four GWAS of alcohol dependence have been published thus far, and only two single nucleotide polymorphisms have received modest support of replication in a subsequent study. Many more GWAS have been conducted for smoking behavior. One large, single GWAS and meta-analyses of the phenotype “smoking quantity” have generated convincing evidence for the contribution of variants in genes for cholinergic nicotinic receptor subunits. This article focuses on GWAS of alcohol addiction and provides an overview of GWAS of other substance abuse disorders.     

Genome‐wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications

Recent advances in molecular genetics have enabled assessments of the associations among genetic variants (e.g., single‐nucleotide polymorphisms) and susceptibility for complex diseases, including psychiatric disorders. Specifically, genome‐wide association studies (GWAS), meta‐analyses of the GWAS summary statistics, and mega‐analyses (which use raw data, not summary statistics) of GWAS have provided revolutionary results and have identified numerous susceptibility genes or single‐nucleotide polymorphisms. By using several tens of thousands of subjects, >40 genes have been identified as being associated with susceptibility for bipolar disorder so far. The purpose of this systematic review was to summarize the recent findings of bipolar disorder GWAS and discuss their clinical implications.     

Phenome-wide Association Analysis of Substance Use Disorders in a Deeply Phenotyped Sample

BackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRSs) and phenome-wide association studies are useful in evaluating pleiotropic effects. However, the comparatively low prevalence of SUDs in population samples and the lack of detailed information available in electronic health records limit these data sets’ informativeness for such analyses.MethodsWe used the deeply phenotyped Yale-Penn sample (n = 10,610 with genetic data; 46.3% African ancestry, 53.7% European ancestry) to examine pleiotropy for 4 major substance-related traits: alcohol use disorder, opioid use disorder, smoking initiation, and lifetime cannabis use. The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism, a comprehensive psychiatric interview.ResultsIn African ancestry individuals, PRS for alcohol use disorder, and in European individuals, PRS for alcohol use disorder, opioid use disorder, and smoking initiation were associated with their respective primary DSM diagnoses. These PRSs were also associated with additional phenotypes involving the same substance. Phenome-wide association study analyses of PRS in European individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in phenome-wide association study analyses, such as family environment and early childhood experiences.ConclusionsSmaller, deeply phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.     

Parkinson's disease polygenic risk score is not associated with impulse control disorders: A longitudinal study

ObjectiveTo examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD.BackgroundGenome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility.MethodsWe used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs.ResultsOf 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99).ConclusionDespite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs.     

Perceived Purpose in Life,Mental Health,and Suicidality in Older U.S. Military Veterans: Results From the National Health and Resilience in Veterans Study

ObjectiveTo determine the current prevalence of perceived purpose in life (PIL) and its association with screening positive for mental disorders and suicidality in a nationally representative sample of predominantly older U.S. veterans.MethodsData were analyzed from the 2019–2020 National Health and Resilience in Veterans Study (N = 4,069; M_age = 62.2). Veterans were classified into three groups based on perceived PIL level (i.e., low, average, and high). Self-report assessments were administered to screen for mental disorders and suicidality.ResultsMost veterans endorsed average PIL (71.7%), while 16.0% endorsed low PIL and 12.4% endorsed high PIL. A “dose-response” association was observed between PIL and outcomes. High PIL was associated with 42%–94% reduced odds of screening positive for major depressive, generalized anxiety, posttraumatic stress, and substance use disorders, as well as suicide attempts, ideation, and future intent.ConclusionHigher PIL is associated with lower odds of mental disorders and suicidality in U.S. veterans, underscoring the potential importance of interventions to bolster PIL in this population.     

Genome-wide association studies in non-anxiety individuals identified novel risk loci for depression

BackgroundDepression is a debilitating mental disorder that often coexists with anxiety. The genetic mechanisms of depression and anxiety have considerable overlap, and studying depression in non-anxiety samples could help to discover novel gene. We assess the genetic variation of depression in non-anxiety samples, using genome-wide association studies (GWAS) and linkage disequilibrium score regression (LDSC).MethodsThe GWAS of depression score and self-reported depression were conducted using the UK Biobank samples, comprising 99,178 non-anxiety participants with anxiety score <5 and 86,503 non-anxiety participants without self-reported anxiety, respectively. Replication analysis was then performed using two large-scale GWAS summary data of depression from Psychiatric Genomics Consortium (PGC). LDSC was finally used to evaluate genetic correlations with 855 health-related traits based on the primary GWAS.ResultsTwo genome-wide significant loci for non-anxiety depression were identified: rs139702470 (p = 1.54 × 10⁻⁸, OR = 0.29) locate in PIEZO2, and rs6046722 (p = 2.52 × 10⁻⁸, OR = 1.09) locate in CFAP61. These associated genes were replicated in two GWAS of depression from PGC, such as rs1040582 (p_{replication GWAS1} = 0.02, p_{replication GWAS2} = 2.71 × 10⁻³) in CFAP61, and rs11661122 (p_{replication GWAS1} = 8.16 × 10⁻³, p_{replication GWAS2} = 8.08 × 10⁻³) in PIEZO2. LDSC identified 19 traits genetically associated with non-anxiety depression (p < 0.001), such as marital separation/divorce (rg = 0.45, SE = 0.15).ConclusionsOur findings provide novel clues for understanding of the complex genetic architecture of depression.     

Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders – Findings from a Danish population-based study

BackgroundPrevious studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease.MethodsWe used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort.ResultsOf 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P = 2.67 × 10⁻⁷, OR = 1.38, 95%CI = 1.22–1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR = 1.13, 95%CI: 1.07–1.21, P = 7.95 × 10⁻⁵) and vice versa (HR = 1.27, 95%CI = 1.16–1.39, P = 8.77 × 10⁻¹⁵). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00–1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10⁻³⁶, OR = 1.80, 95% CI: 1.64–1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10⁻⁸, OR = 10.65, 95%CI = 3.21–35.36).ConclusionsOur findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.     

Causal assessment of sleep on coronary heart disease

ObjectiveSleep is an essential physiological process that protects our physical and mental health. However, the causality of the association between sleep and coronary heart disease (CHD) is unknown. Mendelian randomization (MR), using genetic variants as instrumental variables to test for causality, can infer credible causal associations. We applied a two-sample MR framework to determine the causal association between sleep (sleeplessness, sleep duration, and daytime dozing) and CHD by integrating summary-level genome-wide association study (GWAS) data.MethodsData included in this study were the GWAS summary statistics datasets from the C4D Consortium for CHD; Neale Lab UKB-a:13 Consortium for sleeplessness; Neale Lab UKB-a:9 Consortium for sleep duration and Neale Lab UKB-a:15 Consortium for daytime dozing. The conventional MR approach (inverse variance weighted, IVW) method and Egger method were used. Heterogeneity was calculated using each of the different MR methods where possible. Horizontal pleiotropy was evaluated by p-value of the MR–Egger intercept.ResultsThe IVW method estimate indicated that the odds ratio (OR) (95% confidence interval, CI) for CHD was 3.924 (1.345–11.447) per standard deviation increase in sleeplessness (p = 0.012). Results were consistent in MR–Egger method (OR, 4.654; 95% CI, 1.191–18.186; p = 0.009). The genetically predicted sleeplessness was positively casually associated with CHD. The causal association between sleep duration (or daytime dozing) and CHD was not established.ConclusionOur analysis provided evidence supporting a causal relationship between sleeplessness (not sleep duration or daytime dozing) and CHD.     

Imbalance Between Prefronto-Thalamic and Sensorimotor-Thalamic Circuitries Associated with Working Memory Deficit in Schizophrenia

BackgroundThalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia.MethodsBoth n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis.ResultsDuring both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d′ score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively.ConclusionsThe thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function.     

Investigation of inflammation related gene polymorphism of the mannose-binding lectin 2 in schizophrenia and bipolar disorder

Objectives:To investigate the association between mannose-binding lectin 2 (MBL2) codon 54 polymorphism and clinical features of patients diagnosed with schizophrenia (SCZ) or bipolar disorder (BD).Methods:One hundred and eighteen patients with SCZ, 100 patients with BD, and 100 healthy volunteers were included in the case-control study. The patients consecutively admitted to the outpatient clinic in December 2017-May 2018 and were evaluated with some scales for clinical parameters. Polymerase chain reaction and RFLP were used to determine MBL2 polymorphism in DNA material.Results:The MBL2 gene polymorphism distributions in SCZ or BD patients were significantly different from the control group. The heterozygous genotype percentages were significantly higher in the control group than in the SCZ or BD patients (OR: 0.450; 95% Cl: 0.243-0.830; p=0.010; OR: 0.532; 95%Cl: 0.284-0.995; p=0.047, respectively), and there were statistically significant differences in the MBL2 polymorphism distributions between treatment-responsive SCZ or BD patients and treatment-resistant patients diagnosed with SCZ or BD. The heterozygous genotype percentages were also significantly higher in the treatment-responsive group than in the treatment-resistant group in SCZ or BD patients (OR: 7.857; 95% Cl: 1.006-61.363; p=0.023; OR: 8.782; 95% Cl: 1.114-69.197; p=0.016, respectively).Conclusion:The presence of a heterozygous MBL2 genotype seems to be favorable both in terms of the absence of SCZ and BD in the healthy population and treatment response for Turkish patients.

Schizophrenia (SCZ) and bipolar disorder (BD) are chronic psychiatric disorders that cause substantial disruptions in psychosocial capacity and occur in approximately 1% of the world population.¹ Genome-wide association studies (GWAS) of Psychiatric Genomics Consortium for SCZ recognized more than a hundred common single nucleotide polymorphisms (SNPs) with minor individual effects presenting susceptibility to the SCZ.² A similar mega-analysis for BD, although including a more moderate sample, identified common risk variants specific to BD.³ The long-lasting alterations in gene expression patterns after environmental exposures imply that epigenetic mechanisms might also play a critical role in chronic psychiatric disorders.⁴ Again, previous researches have constantly reported shared genetic etiology between SCZ and BD. Researches showing the genetic overlap between SCZ and BD have improved from studying family and twin inheritance to determine genetic correlation and performing polygenic risk score analysis from GWAS data in large case-control samples.⁵ Despite these researches with large sample size, the cause of both disorders is still relatively unknown; recent studies have shown that uncontrolled activity of microglia and excessive inflammatory responses caused by pro-inflammatory cytokines are among the factors that play a role in the development of SCZ and BD based on genetic susceptibility.^1,6 A relationship between SCZ and many autoimmune diseases and an increase in the prevalence of an autoimmune disease occurrence by about 45% have been found. Moreover, infections of embryonic and early childhood periods lead to delays in fetal brain development and excessive synaptic pruning during adolescence, are among the possible risk factors of psychosis.^7,8 Systemic inflammation and central inflammation are thought to be associated with episodes, remission, and prognosis of BD. Neuroendocrine irregularities, neurotransmitter abnormalities, and glial cell dysfunctions cause plastic alterations in the mood-regulating brain areas. The high rate of comorbid autoimmune diseases also supports this claim.⁹Mannose-binding lectin (MBL) has a vital function in the innate immune system by stimulating the complement system’s lectin pathway. Therefore, it is the only collectin that binds to microorganisms, serves as an opsonin, promotes phagocytosis, and stimulates macrophages. MBL2 gene, which consists of 4 exons in the q11.2-q21 region of the long arm of chromosome 10, encoded MBL. Mutation at codon 54 follows in a replacement of glycine to aspartic acid (allele B), and the normal MBL2 allele is defined by allele A.^10-12 In heterozygous mutants, serum MBL decreases almost 10-fold, whereas, in homozygous mutants, the level decreases to an undetectable level. MBL deficiency is the most common immune defect in humans, affecting approximately 5-7% of individuals.¹³ A decrease in serum MBL level can cause recurrent spontaneous miscarriage,¹⁴ premature birth,¹⁵ and exacerbation of chronic diseases such as ischemic heart disease,¹⁶ and severe infections such as sepsis and systemic inflammatory response syndrome (SIRS).¹⁷ Besides, previous studies suggested that MBL plays an essential role in the pathogenesis of autoimmune diseases.^12,18 We believe that this is the first case-control study comparing MBL2 genotype distributions in patients with SCZ or BD according to treatment resistance, clinical characteristics, and scale scores in detail.Aims of the studyWe aimed to examine whether MBL2 codon 54 polymorphism was involved in the etiopathogenesis and treatment response of SCZ and BD compared with healthy controls.     

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500?kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.     

Prevalence,Correlates, and Psychiatric Burden of Prolonged Grief Disorder in U.S. Military Veterans: Results From a Nationally Representative Study

ObjectivesTo examine the point prevalence and correlates of prolonged grief disorder (PGD) in a nationally-representative sample of United States (U.S.) veterans.MethodsData were analyzed from the National Health and Resilience in Veterans Study, a nationally representative study of 2,441 U.S. veterans.ResultsA total of 158 (weighted 7.3%) veterans screened positive for PGD. The strongest correlates of PGD were adverse childhood experiences, female sex, non-natural causes of death, knowing someone who died from coronavirus disease 2019, and number of close losses. After adjusting for sociodemographic, military, and trauma variables, veterans with PGD were 5-to-9 times more likely to screen positive for post-traumatic stress disorder, major depressive disorder, and generalized anxiety disorder. After additional adjustment for current psychiatric and substance use disorders, they were 2–3 times more likely to endorse suicidal thoughts and behaviors.ConclusionsResults underscore the importance of targeting PGD as an independent risk factor for psychiatric disorders and suicide risk.     

A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders

ObjectiveTo evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive–compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ).MethodsParadigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012.ResultsA significant Hedge’s g was found for decreased SICI (g = 0.572, 95% confidence interval [0.179, 0.966], p = 0.004), enhanced intracortical facilitation (g = 0.446, 95% confidence interval [0.042, 0.849], p = 0.030) and decreased CSP (g = ?0.466, 95% confidence interval [?0.881, ?0.052], p = 0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g = 0.641, 95% confidence interval [0.384, 0.898], p = 0.000) and shortened CSP (g = ?1.232, 95% confidence interval [?1.530, ?0.933], p = 0.000). In SCZ, a significant Hedge’s g was shown for decreased SICI (g = 0.476, 95% confidence interval [0.331, 0.620], p = 0.000).ConclusionInhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD.SignificanceProvides a clear platform from which diagnostic procedures can be developed.