No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen.Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.Peer reviewe

Mediation effect of beliefs about pleasure and emotional experience between social anhedonia and prediction of pleasant events

Few studies have examined whether there is a relationship between social anhedonia and prediction of future events and the role of beliefs about pleasure and emotional experience. In this study, 513 college students were recruited to complete a set of self-reported questionnaires, including the Revised Social Anhedonia Scale (CSAS), the Temporal Experience of Pleasure Scale (TEPS), the Belief about Pleasure Scale (BAPS) and the Beck Depression Inventory. Moreover, a checklist of 100 daily life events was also administrated to all participants. Mediation analysis found that social anhedonia had a direct impact on prediction of pleasant events. Emotional experience partly mediated the relationship between social anhedonia and subjective prediction of pleasant events. However, beliefs about pleasure had no significant mediation effect between social anhedonia and prediction of pleasant events, but were shown to influence the subjective prediction of pleasant events completely through emotional experience. These findings suggest that beliefs about pleasure and emotional experience may be considered promising factors for interventions in individuals with anhedonia.</p

Prefrontal cortex connectivity dysfunction in performing the Fist–Edge–Palm task in patients with first-episode schizophrenia and non-psychotic first-degree relatives

Neurological soft signs have been considered one of the promising neurological endophenotypes for schizophrenia. However, most previous studies have employed clinical rating data only. The present study aimed to examine the neurobiological basis of one of the typical motor coordination signs, the Fist–Edge–Palm (FEP) task, in patients with first-episode schizophrenia and their non-psychotic first degree relatives. Thirteen patients with first-episode schizophrenia, 14 non-psychotic first-degree relatives and 14 healthy controls were recruited. All of them were instructed to perform the FEP task in a 3 T GE Machine. Psychophysiological interaction (PPI) analysis was used to evaluate the functional connectivity between the sensorimotor cortex and frontal regions when participants performed the FEP task compared to simple motor tasks. In the contrast of palm-tapping (PT) vs. rest, activation of the left frontal–parietal region was lowest in the schizophrenia group, intermediate in the relative group and highest in the healthy control group. In the contrast of FEP vs. PT, patients with schizophrenia did not show areas of significant activation, while relatives and healthy controls showed significant activation of the left middle frontal gyrus. Moreover, with the increase in task complexity, significant functional connectivity was observed between the sensorimotor cortex and the right frontal gyrus in healthy controls but not in patients with first episode schizophrenia. These findings suggest that activity of the left frontal–parietal and frontal regions may be neurofunctional correlates of neurological soft signs, which in turn may be a potential endophenotype of schizophrenia. Moreover, the right frontal gyrus may play a specific role in the execution of the FEP task in schizophrenia spectrum disorders

Neural correlates of audiovisual sensory integration

Objective: The present study aimed to investigate the neural basis of information matching during sensory integration using a spatial-temporal matching task in healthy individuals. Method: A total of 37 healthy participants were recruited to match spatial dots with an auditory tone sequence in a 3T GE Discovery MR750 scanner. In addition, they were examined with the sensory integration subscale of the Cambridge Neurological Inventory. Results: We found that the bilateral occipital-parietal conjunction cortex and the precentral frontal gyrus were activated during the matching condition rather than in the nonmatching condition. Activation of the occipital-parietal conjunction cortex was associated with integration of information across visual and auditory modalities, whereas activation of the precentral frontal gyrus was associated with decision making of movements. In addition, activation of the left superior frontal gyrus was associated with scores on the sensory integration subscale of the Cambridge Neurological Inventory. Conclusions: These findings suggest that the bilateral occipital-parietal conjunction cortex is responsible for matching information input from multiple modalities during audiovisual sensory integration.</p

Searchlight classification based on Amplitude of Low Frequency Fluctuation and functional connectivity in individuals with obsessive-compulsive symptoms

Introduction Investigating obsessive-compulsive symptoms in subclinical populations provides a useful framework for understanding the early development of obsessive-compulsive spectrum disorders. The present study aimed to apply searchlight classification analysis on resting-state functional magnetic resonance imaging data to identify potential brain markers in subclinical individuals with obsessive-compulsive symptoms. Methods In this observational study, 40 college students with high obsessive-compulsive symptom scores and 40 with low obsessive-compulsive symptom scores were recruited from universities in China. We conducted searchlight classification and comparison analysis between the two groups based on Amplitude of Low Frequency Fluctuation (ALFF), fraction ALFF (fALFF) and resting-state functional connectivity using searchlight classification. Results We found that the highest accuracy rate in differentiating between the two groups was 85.00%. Significant discriminating features included the ALFF of the left medial superior frontal gyrus and the functional connectivity between the right thalamus and the bilateral medial superior frontal gyrus, and the right putamen, as well as the functional connectivity between the left caudate and the right insula. Conclusions These findings highlight the specific and distinguishing brain functional abnormalities associated with obsessive-compulsive symptoms

Cerebellar hypoactivation is associated with impaired sensory integration in schizophrenia.

To clarify the involvement of the cerebellum in impaired sensory integration in patients with schizophrenia, 52 first-episode patients with schizophrenia and 52 age- and sex-matched healthy controls underwent a verified sensory integration imaging task to examine the whole-brain dysfunction underlying impaired sensory integration. The familiality of cerebellar activation when integrating sensory stimuli was investigated in 25 siblings of the patients with schizophrenia, while the heritability of cerebellar activation was estimated in 56 monozygotic twins and 56 dizygotic twins. In addition, the functional connectivity between the cerebellum and the remaining regions of the whole brain was explored with psychophysiological interaction analysis. Relative to healthy controls, patients with schizophrenia showed reduced cerebellar activation when performing the sensory integration task in the whole-brain analysis. This reduced cerebellar activation was also found in the siblings of patients with schizophrenia. but to a lesser extent compared with schizophrenia patients. Cerebellar activation during sensory integration was also found to be significantly heritable. Furthermore, dysconnectivity within the cerebellum was found in patients with schizophrenia when integrating auditory and visual stimuli. These findings highlight the role of cerebellar dysfunction in the pathophysiology of schizophrenia symptoms and its potential role as an endophenotype of schizophrenia spectrum disorders

Validation of the Chinese version of the Multidimensional Schizotypy Scale (MSS): Convergent evidence from exploratory and confirmatory factor analyses

Background: Schizotypy has been shown to be a time-stable construct that exists across the schizophrenia spectrum. The Multidimensional Schizotypy Scale (MSS) was developed to capture the three factors underlying schizotypy: positive, disorganized and negative schizotypy. However, a recent validation study reported a four-factor construct with an additional negative social anhedonia factor. The factor structure of the Chinese version of the MSS remains unknown. This study aimed to identify and validate the factor structure of the Chinese version of the MSS. Methods: We recruited 641 Chinese speakers via on-line advertisement. We administered the Chinese version of the MSS, which was a self-report instrument. The scale consists of 77 items with true or false response options. We identified and removed 43 outliers. Finally, a total of 294 participants were randomly selected as the derivative sample for exploratory factor analysis (EFA). The remaining 304 participants were retained as the validation sample for confirmatory factor analysis (CFA). Results: EFA identified four factors: the positive factor, the disorganization factor, the negative affective and motivational anhedonia factor, and the negative social anhedonia factor. The EFA-identified four-factor model was compared with the unidimensional, three-factor bifactorial and theoretical three-factor models using CFAs. The three-factor bifactorial model fitted the data better than the EFA-identified four-factor model. Conclusion: Our finding suggests that the Chinese version of the MSS is a valid tool for assessing schizotypy in the Chinese setting