Tablet-Based Cognitive and Eye Movement Measures as Accessible Tools for Schizophrenia Assessment: Multisite Usability Study.

BACKGROUND: Schizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking. OBJECTIVE: This study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. METHODS: Forty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest. RESULTS: Cognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P<.001). The Codebreaker task showed the highest classification effectiveness in distinguishing schizophrenia with an area under the receiver operating characteristic curve of 0.90. Combining cognitive and eye movement measures further improved accuracy with a maximum area under the receiver operating characteristic curve of 0.94. Cognitive measures were more effective in differentiating patients with schizophrenia from healthy controls, whereas eye movement measures better differentiated schizophrenia from other psychiatric conditions. CONCLUSIONS: This multisite study demonstrates the feasibility and effectiveness of a tablet-based app for assessing cognitive functioning and eye movements in patients with schizophrenia. Our results suggest the potential of tablet-based assessments of cognitive function and eye movement as simple and accessible evaluation tools, which may be useful for future clinical implementation.

Epigenetic signatures of social anxiety, panic disorders and stress experiences: Insights from genome-wide DNA methylation risk scores.

Social anxiety disorder (SAD) and panic disorder (PD) are prevalent anxiety disorders characterized by a complex interplay of genetic and environmental factors. Both disorders share overlapping features and often coexist, despite displaying distinct characteristics. Childhood life adversity, overall stressful life events, and genetic factors contribute to the development of these disorders. DNA methylation, an epigenetic modification, has been implicated in the pathogenesis of these diseases. In this study, we investigated whether whole-genome DNA methylation risk scores (MRSs) for SAD risk, severity of social anxiety, childhood life adversity, PD risk, and overall stressful life events were associated with SAD or PD case‒control status. Preliminary epigenome-wide association studies (EWASs) for SAD risk, severity of social anxiety, and childhood life adversity were conducted in 66 SAD individuals and 77 healthy controls (HCs). Similarly, EWASs for PD risk and overall stressful life events were performed in 182 PD individuals and 81 HCs. MRSs were calculated from these EWASs. MRSs derived from the EWASs of SAD risk and severity of social anxiety were greater in PD patients than in HCs. Additionally, MRSs derived from the EWASs of overall stressful life events, particularly in PD individuals, were lower in SAD individuals than in HCs. In contrast, MRSs for childhood life adversity or PD risk were not significantly associated with PD or SAD case‒control status. These findings highlight the epigenetic features shared in both disorders and the distinctive epigenetic features related to social avoidance in SAD patients, helping to elucidate the epigenetic basis of these disorders.

Tissue-specific gene expression of genome-wide significant loci associated with major depressive disorder subtypes.

Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes-(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10-3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19-2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = -0.17--1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80-2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.

Genome-wide DNA methylation risk scores for schizophrenia derived from blood and brain tissues further explain the genetic risk in patients stratified by polygenic risk scores for schizophrenia and bipolar disorder.

BACKGROUND: Genetic and environmental factors contribute to the pathogenesis of schizophrenia (SZ) and bipolar disorder (BD). Among genetic risk groups stratified by combinations of Polygenic Risk Score (PRS) deciles for SZ, BD and SZ versus BD, genetic SZ risk groups had high SZ risk and prominent cognitive impairments. Furthermore, epigenetic alterations are implicated in these disorders. However, it was unclear whether DNA Methylation Risk Scores (MRSs) for SZ risk derived from blood and brain tissues were associated with SZ risk, particularly the PRS-stratified genetic SZ risk group. METHODS: Epigenome-wide association studies (EWASs) of SZ risk in whole blood were preliminarily conducted between 66 SZ patients and 30 healthy controls (HCs) and among genetic risk groups (individuals with low genetic risk for SZ and BD in HCs (n=30) and in SZ patients (n=11), genetic BD risk in SZ patients (n=25) and genetic SZ risk in SZ patients (n=30)) stratified by combinations of PRSs for SZ, BD and SZ versus BD. Next, differences in MRSs based on independent EWASs of SZ risk in whole blood, postmortem frontal cortex (FC) and superior temporal gyrus (STG) were investigated among our case‒control and PRS-stratified genetic risk status groups. RESULTS: Among case‒control and genetic risk status groups, 33 and 351 genome-wide significant differentially methylated positions (DMPs) associated with SZ were identified, respectively, many of which were hypermethylated. Compared with the low genetic risk in HCs group, the genetic SZ risk in SZ group had 39 genome-wide significant DMPs, while the genetic BD risk in SZ group had only six genome-wide significant DMPs. The MRSs for SZ risk derived from whole blood, FC and STG were higher in our SZ patients than in HCs in whole blood and were particularly higher in the genetic SZ risk in SZ group than in the low genetic risk in HCs and genetic BD risk in SZ groups. Conversely, the MRSs for SZ risk based on our whole-blood EWASs among genetic risk groups were also associated with SZ in the FC and STG. There were no correlations between the MRSs and PRSs. CONCLUSIONS: These findings suggest that the MRS is a potential genetic marker in understanding SZ, particularly in patients with a genetic SZ risk.

Genetic correlations between suicide attempts and psychiatric and intermediate phenotypes adjusting for mental disorders.

BACKGROUND: Suicide attempts are a moderately heritable trait, and genetic correlations with psychiatric and related intermediate phenotypes have been reported. However, as several mental disorders as well as major depressive disorder (MDD) are strongly associated with suicide attempts, these genetic correlations could be mediated by psychiatric disorders. Here, we investigated genetic correlations of suicide attempts with psychiatric and related intermediate phenotypes, with and without adjusting for mental disorders. METHODS: To investigate the genetic correlations, we utilized large-scale genome-wide association study summary statistics for suicide attempts (with and without adjusting for mental disorders), nine psychiatric disorders, and 15 intermediate phenotypes. RESULTS: Without adjusting for mental disorders, suicide attempts had significant positive genetic correlations with risks of attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, MDD, anxiety disorders and posttraumatic stress disorder; higher risk tolerance; earlier age at first sexual intercourse, at first birth and at menopause; higher parity; lower childhood IQ, educational attainment and cognitive ability; and lower smoking cessation. After adjusting for mental disorders, suicide attempts had significant positive genetic correlations with the risk of MDD; earlier age at first sexual intercourse, at first birth and at menopause; and lower educational attainment. After adjusting for mental disorders, most of the genetic correlations with psychiatric disorders were decreased, while several genetic correlations with intermediate phenotypes were increased. CONCLUSIONS: These findings highlight the importance of considering mental disorders in the analysis of genetic correlations related to suicide attempts and suggest that susceptibility to MDD, reproductive behaviors, and lower educational levels share a genetic basis with suicide attempts after adjusting for mental disorders.

Is adjustment disorder genetically correlated with depression, anxiety, or risk-tolerant personality trait?

Adjustment disorder has three main subtypes: adjustment disorder with depressed mood, adjustment disorder with anxiety, and adjustment disorder with disturbance of conduct. The disorder is moderately heritable and has lifetime comorbidities with major depressive disorder (MDD), anxiety disorders, or risk-tolerant personality. However, it remains unclear whether the degrees of genetic correlations between adjustment disorder and other psychiatric disorders and intermediate phenotypes are similar or different to those between MDD, anxiety disorders or risk-tolerant personality and these other psychiatric disorders and intermediate phenotypes. To compare patterns of genetic correlations, we utilized large-scale genome-wide association study summary statistics for adjustment disorder-related disorders and personality trait, eleven other psychiatric disorders and fifteen intermediate phenotypes. Adjustment disorder had highly positive genetic correlations with MDD, anxiety disorders, and risk-tolerant personality. Among other psychiatric disorders, adjustment disorder, MDD, anxiety disorders and risk-tolerant personality were positively correlated with risks for schizophrenia (SCZ), bipolar disorder (BD), SCZ + BD, attention-deficit/hyperactivity disorder, and cross disorders. In contrast, adjustment disorder was not significantly correlated with risks for obsessive-compulsive disorder, Tourette syndrome, or posttraumatic stress disorder despite significant genetic correlations of MDD or anxiety disorders with these disorders. Among intermediate phenotypes, adjustment disorder, MDD, anxiety disorders, and risk-tolerant personality commonly had a younger age at first sexual intercourse, first birth, and menopause, lower cognitive ability, and higher rate of smoking initiation. Adjustment disorder was not genetically correlated with extraversion, although the related disorder and personality were correlated with extraversion. Only adjustment disorder was correlated with a higher smoking quantity. These findings suggest that adjustment disorder could share a genetic etiology with MDD, anxiety disorders and risk-tolerant personality trait, as well as have a disorder-specific genetic etiology.

Mitochondrial genetic variants associated with bipolar disorder and Schizophrenia in a Japanese population.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are complex psychotic disorders (PSY), with both environmental and genetic factors including possible maternal inheritance playing a role. Some studies have investigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However, the genetic variants identified as being associated are not identical among studies, and the participants were limited to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population. METHODS: After performing quality control for individuals and genetic variants, we investigated whether mitochondrial genetic variants [minor allele frequency (MAF) > 0.01, n = 45 variants) are associated with BD, SZ, and PSY in 420 Japanese individuals consisting of patients with BD (n = 51), patients with SZ (n = 172), and healthy controls (HCs, n = 197). RESULTS: Of mitochondrial genetic variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after correcting for multiple comparisons (PGC=0.045-4.9 × 10- 3). In particular, individuals with the minor G-allele of rs200044200, a missense variant, were only observed among patients with BD (MAF = 0.059) but not HCs (MAF = 0) (odds ratio=∞). Three patients commonly had neuropsychiatric family histories. CONCLUSIONS: We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contribute to the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production.

Sex differences in brainstem structure volumes in patients with schizophrenia.

Patients with schizophrenia (SZ) display moderate reductions in brainstem volumes, including the midbrain, pons, superior cerebellar peduncle, and medulla oblongata. Here, we investigated alterations in brainstem volumes between SZ patients and healthy controls (HCs) stratified by sex. T1-weighted MRI brain scans were processed with FreeSurfer v6.0 in 156 SZ patients (61 males/95 females) and 205 HCs (133/72). Of the brainstem structures, pons volumes were significantly reduced, particularly in male SZ patients. The decreased pons volumes were correlated with lower levels of education but not duration of illness in male patients. These findings suggest that the reduction in pons volume in male patients might be occurred before or around the onset of the disorder.

Olfactory identification ability among schizophrenia patients, their first-degree relatives and healthy subjects.

OBJECTIVE: Olfactory impairments, including identification, have been reported in patients with schizophrenia, while few studies have examined the olfactory function of unaffected first-degree relatives of patients with schizophrenia, and the sample sizes of first-degree relatives were relatively small. Here, we investigated olfactory identification ability among patients with schizophrenia, first-degree relatives and healthy controls (HCs) using relatively large sample sizes at a single institute. METHODS: To assess olfactory identification ability, the open essence odorant identification test was administered to 172 schizophrenia patients, 75 first-degree relatives and 158 healthy controls. Differences in olfactory identification and correlations between olfactory ability and clinical variables were examined among these participants. RESULTS: We found a significant difference in olfactory identification ability among the diagnostic groups (p = 7.65 × 10-16). Schizophrenia patients displayed lower olfactory identification ability than first-degree relatives (Cohen's d = -0.57, p = 3.13 × 10-6) and healthy controls (d = -1.00, p = 2.19 × 10-16). Furthermore, first-degree relatives had lower olfactory identification ability than healthy controls (d = -0.29, p = 0.039). Olfactory identification ability moderately and negatively correlated with the duration of illness (r = -0.41, p = 1.88 × 10-8) and negative symptoms (r = -0.28, p = 1.99 × 10-4) in schizophrenia patients, although the correlation with the duration of illness was affected by aging (r = -0.24). CONCLUSIONS: Our results demonstrated that schizophrenia patients have impaired olfactory identification ability compared with first-degree relatives and healthy controls, and the impaired olfactory identification ability of first-degree relatives was intermediate between those in schizophrenia patients and healthy controls. Olfactory identification ability was relatively independent of clinical variables. Therefore, olfactory identification ability might be an intermediate phenotype for schizophrenia.

Higher polygenic risk scores for anxiety disorders are associated with reduced area in the anterior cingulate gyrus.

Anxiety disorders are heterogeneous, show a moderate genetic contribution and are associated with inconsistent cortical structure alterations. Here, we investigated whether genetic factors for anxiety disorders contribute to cortical alterations by conducting polygenic risk score (PRS) analyses. We calculated PRSs for anxiety disorders at several P value thresholds (from PT ≤ 5.0 × 10-8 to PT ≤ 1.0) based on the latest large-scale genome-wide association study of anxiety disorders from the UK biobank (25,453 cases; 58,113 controls) in an independent sample of psychiatrically and physically healthy subjects (n = 174). Using regression after adjusting for confounding factors, we tested whether these PRSs were associated with the surface area and cortical thickness in 34 bilateral brain regions extracted using FreeSurfer. A higher PRS for anxiety disorders at PT ≤ 1.0 was significantly associated with a reduced right caudal anterior cingulate area (beta = -0.25, puncorrected = 9.51 × 10-4, pcorrected = 0.032). PRSs based on more common SNPs, especially from PT ≤ 0.01 to PT ≤ 1.0, were associated with the right caudal anterior cingulate area (a maximum at PT ≤ 0.5: R2 = 0.066, beta = -0.27, puncorr = 3.81 × 10-4, pcorr = 0.013). Furthermore, individuals in the highest quartile for anxiety disorder PRS had lower surface area and volume in the right anterior cingulate gyrus than those in the lowest quartile. We suggest a shared genetic etiology between anxiety disorders and structural features of the anterior cingulate gyrus, possibly contributing to the pathogenesis of anxiety disorders via emotional dysregulations. Our findings suggest the potential usefulness of PRS to reduce pathological heterogeneity among anxiety disorders.

Cognitive performances across individuals at high genetic risk for schizophrenia, high genetic risk for bipolar disorder, and low genetic risks: a combined polygenic risk score approach.

BACKGROUND: Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD. METHODS: Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia. RESULTS: SCZ-, BD-, SCZ v. BD-PRSs were associated with case-control status (R2 = 0.020-0.061), and SCZ-PRS was associated with relative-control status (R2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients (p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs (p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > -0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group (d > -0.20). CONCLUSIONS: Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD.

Shared genetic basis between reproductive behaviors and anxiety-related disorders.

Reproductive behaviors are associated with risks for psychiatric disorders. Reproductive phenotypes are moderately heritable and have genetic overlaps with risks for psychiatric disorders. However, the genetic and causal relationships between anxiety-related disorders or specific anxiety disorders and reproductive phenotypes remain unknown. We utilized large-scale genome-wide association study (GWAS) results (n = 9537-542,901) for five reproductive phenotypes [age at menarche, age at first sexual intercourse (AFS), age at first birth (AFB), number of children ever born (NEB), and age at menopause] and five anxiety-related disorders [panic disorder, anxiety disorders from the ANGST and the UK biobank (UKBB), posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD)]. To assess genetic correlations and causal associations, linkage disequilibrium score regression and Mendelian randomization analyses, respectively, were performed. We found that AFS and AFB were negatively correlated with anxiety disorders ANGST (AFS: rg ± SE = -0.28 ± 0.08, p = 6.00 × 10-4; AFB: -0.45 ± 0.11, p = 3.26 × 10-5), anxiety disorders UKBB (AFS: -0.18 ± 0.03, p = 9.64 × 10-9; AFB; -0.25 ± 0.03, p = 2.90 × 10-13) and PTSD (AFS: -0.42 ± 0.12, p = 4.00 × 10-4; AFB: -0.44 ± 0.12, p = 2.00 × 10-4) and positively correlated with OCD (AFS: 0.25 ± 0.05, p = 2.46 × 10-6; AFB: 0.25 ± 0.05, p = 3.92 × 10-7). Conversely, NEB was negatively correlated with OCD (-0.28 ± 0.08, p = 6.00 × 10-4). We revealed bidirectional effects between earlier AFS and AFB and anxiety disorders (odds ratios: ORearlier AFS→Anxiety = 1.64, p = 2.27 × 10-8; ORearlier AFB→Anxiety = 1.15, p = 2.28 × 10-3; ORAnxiety→earlier AFS = 1.02, p = 6.62 × 10-8; ORAnxiety→earlier AFB = 1.08, p = 1.60 × 10-4). In contrast, we observed unidirectional effects of later AFS and AFB on OCD (ORlater AFS→OCD = 2.18, p = 2.16 × 10-6; ORlater AFB→OCD = 1.22, p = 0.016). We suggest that those who have earlier sexual debut and childbirth are prone to risk for anxiety disorders and vice versa, while those who have later sexual debut and childbirth are genetically prone to risk for OCD. Our findings further support revising the diagnostic criteria (DSM-5) such that OCD is independent from anxiety disorders.