Kazutaka Ohi

Structural alterations of the superior temporal gyrus in schizophrenia: Detailed subregional differences

BACKGROUND Reduced gray matter volumes in the superior temporal gyrus (STG) have been reported in patients with schizophrenia. Such volumetric abnormalities might denote alterations in cortical thickness, surface area, local gyrification or all of these factors. The STG can be anatomically divided into five subregions using automatic parcellation in FreeSurfer: lateral aspect of the STG, anterior transverse temporal gyrus of Heschl gyrus (HG), planum polare (PP) of the STG, planum temporale (PT) of the STG and transverse temporal sulcus. METHODS We acquired magnetic resonance imaging (MRI) 3T scans from 40 age- and sex-matched patients with schizophrenia and 40 healthy subjects, and the scans were automatically processed using FreeSurfer. General linear models were used to assess group differences in regional volumes and detailed thickness, surface area and local gyrification. RESULTS As expected, patients with schizophrenia had significantly smaller bilateral STG volumes than healthy subjects. Of the five subregions in the STG, patients with schizophrenia showed significantly and marginally reduced volumes in the lateral aspect of the STG and PT of the STG bilaterally compared with healthy subjects. The volumetric alteration in bilateral lateral STG was derived from both the cortical thickness and surface area but not local gyrification. There was no significant laterality of the alteration in the lateral STG between patients and controls and no correlation among the structures and clinical characteristics. CONCLUSIONS These findings suggest that of five anatomical subregions in the STG, the lateral STG is one of the most meaningful regions for brain pathophysiology in schizophrenia.

Specific gene expression patterns of 108 schizophrenia-associated loci in cortex

The latest genome-wide association study of schizophrenia identified 108 distinct genomic loci that contribute to schizophrenia. Brain development and function depend on the precise regulation of gene expression. The expression of many genes is differentially regulated across brain regions and developmental time points. We investigated the specific gene expression patterns arising from the 108 schizophrenia-associated loci using multiple publicly available databases and multiple regional brain datasets from developing and adult post-mortem human brains. The temporal-spatial expression analysis revealed that the genes in these loci were intensively enriched in the cortex during several developmental stages. These cortex-specific genes were particularly expressed in the fetal brain and adult neocortex.

A comprehensive meta-analysis of ZNF804A SNPs in the risk of schizophrenia among Asian populations.

Common variants in ZNF804A increased the risk of schizophrenia (and bipolar disorder), with low effect sizes in Europeans, which is in line with the polygenic nature of the illnesses, and implies that genetic analyses in small samples may not be sufficient to detect stable results. This notion is supported by the inconsistent replications of ZNF804A variations among individual small Asian samples, indicating the absence of definitive conclusions in this population. We collected psychiatric phenotypic and genetic data from Asian genome‐wide association (GWA) and individual replication studies, which include up to 13,452 cases, 17,826 healthy controls, and 680 families, that is, the largest‐scale study on ZNF804A in Asian populations to date. The European GWAS risk single nucleotide polymorphism (SNP) rs1344706 was nominally associated with schizophrenia in these Asian samples (one‐tailed P = 4.26 × 10−2, odds ratio [OR] = 1.048), and the association was further strengthened when bipolar disorder data was also included (one‐tailed P = 1.85 × 10−2, OR = 1.057). Besides, a non‐synonymous SNP rs1366842 in the exon 4 of ZNF804A was also associated with schizophrenia (P = 9.96 × 10−3, OR = 1.095). We additionally analyzed other 163 SNPs covering ZNF804A region, but none of them showed any evidence of association. Though the two SNPs did not remain significant if we applied multiple corrections, our analysis should be interpreted as a primary replication study with in prior hypothesis, and rs1344706 and rs1366842 might confer a small but detectable risk of schizophrenia (and bipolar disorder) in Asians. Moreover, the current data suggest the necessity of replication analyses in a large enough scale samples.

Impact of Familial Loading on Prefrontal Activation in Major Psychiatric Disorders: A Near-Infrared Spectroscopy (NIRS) Study

Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.

Differences in social functioning among patients with major psychiatric disorders: Interpersonal communication is impaired in patients with schizophrenia and correlates with an increase in schizotypal traits

Impaired social functioning is a hallmark of major psychiatric disorders. The purpose of this study was to detect a disorder-specific factor of social dysfunction among patients with major psychiatric disorders (PSY), including schizophrenia (SCZ), bipolar disorder (BIP) and major depressive disorder (MDD). Social functioning was assessed in patients with SCZ (n=80), BIP (n=27) or MDD (n=29) and healthy controls (HC, n=68) using the Social Functioning Scale (SFS). Compared to HC, the SCZ, BIP and MDD patient groups showed lower total SFS scores. No differences in the total scores for social functioning were observed between patient groups. We next investigated seven subscales of the SFS among PSY and observed significant diagnostic effects on all subscales of the SFS. Notably, patients with SCZ have poorer interpersonal communication than patients with MDD. Furthermore, the poorer interpersonal communication score was significantly correlated with an increase in schizotypal personality traits, as assessed by the Schizotypal Personality Questionnaire (SPQ) in HC. Although there were no differences in overall social functioning among PSY, disorder-specific factors, such as interpersonal communication, were evident in SCZ. The correlation between poor interpersonal communication and the increase in schizotypal traits suggests that poor interpersonal communication may be an intermediate phenotype of SCZ.

Polygenetic components for schizophrenia, bipolar disorder and rheumatoid arthritis predict risk of schizophrenia

Genome-wide association studies (GWASs) have revealed a polygenic component to the risk of Schizophrenia (SCZ) that comprises the additive effects of a large number of common independent singlenucleotide polymorphisms (SNPs) with weak effects (Purcell et al., 2009; Ripke et al., 2014). Polygenic risk profile scores (PRS) for SCZ in discovery GWAS samples explain approximately 20% of the variance in the liability for SCZ in independent target subjects (Ripke et al., 2014). An important factor in determining whether the polygenic component can predict a target trait in independent subjects is the sample size of the discovery sample (Dudbridge, 2013). The Cross-Disorder Group of the Psychiatric Genomics Consortium (PGC) examined shared polygenetic features among major psychiatric disorders [SCZ, Bipolar Disorder (BIP), Major Depression Disorder (MDD), Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD)] in individuals of European descent (Smoller et al., 2013) and found shared cross-disorder effects among the adultonset disorders SCZ, BIP and MDD. These findings could be due to common genetic factors for the risk of SCZ and other psychiatric disorders. To our knowledge, it is unknown whether the polygenic component can predict a target trait in an independent ethnic sample of individuals of non-European ancestry. In addition, SCZmay share a genetic component with autoimmune and/or metabolic non-psychiatric disorders. Here, we tested the hypothesis that genetic variants related to the risk of SCZ overlap with genetic variants related to psychiatric and non-psychiatric disorders by conducting a polygenic component analysis. As shown in Supplementary Table S1, we used publicly available GWASdatasets as discovery samples to calculate PRS for five psychiatric disorders [SCZ, BIP (Smoller et al., 2013), MDD (Smoller et al., 2013), ASD (Smoller et al., 2013) and ADHD (Smoller et al., 2013)] and five non-psychiatric diseases [Rheumatoid Arthritis (RA) (Stahl et al., 2010), Ulcerative Colitis (UC) (Liu et al., 2015), Crohns Disease (CD) (Liu et al., 2015), Coronary Artery Disease (CAD) (Schunkert et al., 2011) and Type 2 Diabetes (T2D) (Mahajan et al., 2014)]. Three types of GWASs for SCZ [the most recent available GWAS by the Schizophrenia Working Group of the PGC (PGC2 SCZ) (Ripke et al., 2014), PGC1 plus Swedish SCZ (PGC1 + Swe) (Ripke et al., 2013) and crossdisorder SCZ (Smoller et al., 2013)] were used as discovery samples. Furthermore, meta-analyzed data among cross-disorders or between SCZ and BIP in cross-disorder GWAS were also used. PRSs derived from these GWASswere calculated for Japanese target subjects (341 patients with SCZ and 588 controls). Details of the samples included in the discovery and target GWASs are summarized in Supplementary Methods, Results, Figs. S1–S2, and Tables S1–S4. Briefly, genotyping data from multiple sites were

Schizophrenia risk variants in ITIH4 and CALN1 regulate gene expression in the dorsolateral prefrontal cortex.

On the basis of the findings from European GenomeWide Association Studies (GWAS) in the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC1) [9394 cases and 12 462 controls for GWAS and 8442 cases and 21 397 for replication (Ripke et al., 2011)] and the subsequent study (CLOZUK) [2640 cases and 2878 controls (Hamshere et al., 2013)], Li et al. (2015) have tried to replicate the associations of genetic variants including genome-wide significant variants and variants located in the predicted MIR137 target genes in the Han Chinese population (Li et al., 2015). They have found that two single-nucleotide polymorphisms (SNPs) in the interalpha-trypsin inhibitor heavy chain family, member 4 (ITIH4) (rs2239547) and the calneuron 1 (CALN1) (rs2944829) genes, were associated with risk for schizophrenia at genome-wide significant threshold in Chinese GWAS (3750 cases and 6468 controls) and/or the replication (3585 cases and 5496 controls) cohorts. They compared these SNP findings between PGC1/ PGC1+CLOZUK and their studies; however, they used rs12699131 (35.4 kb upstream from rs2944829, r= 0.79 in CEU 1000 Genomes Pilot 1) but not rs2944829 in only PGC1 GWAS sample for the comparison. Recently, the latest and largest GWAS, which combined all available schizophrenia samples in the PGC2 (34 241 cases, 45 604 controls and 1235 trios for GWAS and 1513 cases and 66 236 controls for replication), has been published (Ripke et al., 2014), and these two SNPs (rs2239547 and rs2944829) in the GWAS were available directly in the public database (https://www.med.unc.edu/pgc/downloads). Therefore, we combined the Chinese GWAS and the replication data with those of PGC2 using their odds ratios (OR) and SE derived from 95% confidence interval of OR. The meta-analysis still supported their findings at genome-wide significant level [rs2239547 (minor C-allele) OR= 0.93, P= 1.98× 10, rs2944829 (minor A-allele) OR= 0.94, P= 1.97× 10]. These findings suggest that these SNPs could contribute to risk for schizophrenia in both European and Asian populations.

Cognitive clustering in schizophrenia patients, their first-degree relatives and healthy subjects is associated with anterior cingulate cortex volume

Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ.

Spatial and temporal expression patterns of genes around nine neuroticism-associated loci

ABSTRACT Neuroticism is a high‐order personality trait. Individuals with higher neuroticism have increased risks of various psychiatric disorders and physical health outcomes. Neuroticism is related to physiological differences in the brain. A recent genome‐wide association study identified nine distinct genomic loci that contribute to neuroticism. Brain development and function depend on the precise regulation of gene expression, which is differentially regulated across brain regions and developmental stages. Using multiple publicly available human post‐mortem databases, we investigated, in brain and non‐brain tissues and across several developmental life stages, the spatial and temporal expression patterns of genes arising from nine neuroticism‐associated loci. Functional gene‐network analysis for neuroticism‐associated genes was performed. The spatial expression analysis revealed that the nearest genes (GRIK3, SRP9, KLHL2, PTPRD, ELAVL2, CRHR1 and CELF4) from index single‐nucleotide polymorphisms (SNPs) at the nine loci were intensively enriched in the brain compared with their representation in non‐brain tissues (p < 1.56 × 10− 3). The nearest genes associated with the glutamate receptor activity network consisted mainly of GRIK3 (FDR q = 4.25 × 10− 2). The temporal expression analysis revealed that the neuroticism‐associated genes were divided into three expression patterns: KLHL2, CELF4 and CRHR1 were preferentially expressed during postnatal stages; PTPRD, ELAVL2 and MFHAS1 were expressed during prenatal stages; and the other three genes were not expressed during specific life stages. These findings suggest that the glutamate network might be a target for investigating the neurobiological mechanisms underlying susceptibilities to higher neuroticism and several psychiatric disorders and that neuroticism is mediated by genes specifically expressed in the brain during several developmental stages. HIGHLIGHTSThe spatial and temporal expression patterns of genes around nine neuroticism‐associated loci were investigated.The nearest genes at the nine loci preferentially expressed in brain tissues rather than non‐brain tissues.The nearest genes were associated with the glutamate receptor activity network.Neuroticism is mediated by genes specifically expressed in the brain during several developmental stages.

A Brief Assessment of Intelligence Decline in Schizophrenia As Represented by the Difference between Current and Premorbid Intellectual Quotient

Patients with schizophrenia elicit several clinical features, such as psychotic symptoms, cognitive impairment, and subtle decline of intelligence. The latter two features become evident around the onset of the illness, although they may exist even before the disease onset in a substantial proportion of cases. Here, we review the literature concerning intelligence decline (ID) during the progression of schizophrenia. ID can be estimated by comparing premorbid and current intellectual quotient (IQ) by means of the Adult Reading Test and Wechsler Adult Intelligence Scale (WAIS), respectively. For the purpose of brief assessment, we have recently developed the WAIS-Short Form, which consists of Similarities and Symbol Search and well reflects functional outcomes. According to the degree of ID, patients were classified into three distinct subgroups; deteriorated, preserved, and compromised groups. Patients who show deteriorated IQ (deteriorated group) elicit ID from a premorbid level (≥10-point difference between current and premorbid IQ), while patients who show preserved or compromised IQ do not show such decline (<10-point difference). Furthermore, the latter patients were divided into patients with preserved and compromised IQ based on an estimated premorbid IQ score >90 or below 90, respectively. We have recently shown the distribution of ID in a large cohort of schizophrenia patients. Consistent with previous studies, approximately 30% of schizophrenia patients had a decline of less than 10 points, i.e., normal intellectual performance. In contrast, approximately 70% of patients showed deterioration of IQ. These results indicate that there is a subgroup of schizophrenia patients who have mild or minimal intellectual deficits, following the onset of the disorder. Therefore, a careful assessment of ID is important in identifying appropriate interventions, including medications, cognitive remediation, and social/community services.