Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans.

BACKGROUND: The variation in the rate at which humans age may be rooted in early events acting through the genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging. RESULTS: We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (Ndiscovery = 5087, Nreplication = 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks. CONCLUSIONS: These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the "early development of origin" hypothesis for aging in humans.

Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging.

Variation in the rate at which humans age may be rooted in early life events acting through genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions either enriched for genetically controlled imprinting effects (the typical type of POE) or atypical POE introduced by environmental effects associated with parents. This part of the methylome is heavily influenced by early life events, making it a potential route connecting early environmental exposures, the epigenome and the rate of aging. Here, we aim to test the association of POE-influenced methylation of CpG dinucleotides (POE-CpG sites) with early and later environmental exposures and subsequently with health-related phenotypes and adult aging phenotypes. We do this by performing phenome-wide association analyses of the POE-influenced methylome using a large family-based population cohort (GS:SFHS, Ndiscovery=5,087, Nreplication=4,450). At the single CpG level, 92 associations of POE-CpGs with phenotypic variation were identified and replicated. Most of the associations were contributed by POE-CpGs belonging to the atypical class and the most strongly enriched associations were with aging (DNAmTL acceleration), intelligence and parental (maternal) smoking exposure phenotypes. We further found that a proportion of the atypical-POE-CpGs formed co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased internal module connectivity (strength of methylation correlation across constituent CpGs) with age. Atypical POE-CpGs also displayed high levels of methylation heterogeneity and epigenetic drift (i.e. information loss with age) and a strong correlation with CpGs contained within epigenetic clocks. These results identified associations between the atypical-POE-influenced methylome and aging and provided new evidence for the "early development of origin" hypothesis for aging in humans.

Neural Correlates of Auditory Verbal Hallucinations in Schizophrenia and the Therapeutic Response to Theta-Burst Transcranial Magnetic Stimulation.

Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia, and resistant to antipsychotic medication in a substantial proportion of patients. This study aimed to investigate the neural correlates of AVHs in schizophrenia patients and its response to a modified continuous theta-burst stimulation (cTBS) by transcranial magnetic stimulation. In a cross-sectional experiment, resting-state functional magnetic resonance images were collected from 31 AVH schizophrenia patients, 26 non-AVH schizophrenia patients, and 33 sex-/age-matched healthy controls (HCs). Functional connectivity strength (FCS) maps were compared among groups by 1-way analysis of variance (ANOVA). In a longitudinal experiment, 16 and 11 AVH patients received real and sham cTBS treatment for 15 days, respectively. Notably, this was not a randomized control trail. Changes in AVH and FCS were analyzed by 2-way ANOVA and 2-sample t-test, respectively. In the cross-sectional experiment, comparison of FCS maps identified 8 clusters among groups, but only one cluster (in left cerebellum) differed significantly in AVH patients compared to both HCs and non-AVH patients. In the longitudinal experiment, the real cTBS group showed a greater improvement in symptoms and a larger FCS decrease in left cerebellum than the sham group. Pearson's correlation analysis indicated that baseline FCS of the overlapping cerebellum cluster (between the cross-sectional and longitudinal findings) was negatively correlated with symptom improvement in the real treatment group. These findings emphasize the role of the left cerebellum in both the pathophysiology and clinical treatment of AVHs in schizophrenia patients.

Slow Binocular Rivalry as a Potential Endophenotype of Schizophrenia.

Objectives: Binocular rivalry is a typical example of bistable perception that arises when two monocular images are simultaneously presented to each eye. Binocular rivalry is a heritable perceptual cognitive function that is impaired in patients with schizophrenia (SZ). Despite its potential suitability as a visual endophenotype, binocular rivalry has hardly been studied in the unaffected siblings of schizophrenia (SIB). There is also little research about whether binocular rivalry is a potential visual endophenotype between SZ and SIB. Methods: In our cross-sectional study, we included 40 SZ and their unaffected SIBs, as well as 40 age- and sex-matched healthy controls (HC). All subjects underwent the binocular rivalry test, the Positive and Negative Syndrome Scale (PANSS) and a battery of cognitive neuropsychological assessments evaluating attention, memory and executive function domains. Results: Our results demonstrate that the switching rate in SZ was significantly slower than in HC (p < 0.001), and compared to the SIB, the mean alternation rates were significantly different (p < 0.01). Moreover, there was a significant difference in mean switching rate between the SIB and the HC (p < 0.001). There was no significant correlation between the alternation rate of binocular rivalry and these cognitive tasks and the PANSS scores. Conclusion: The present study shows that SZ and SIB both exhibit changes in binocular rivalry, with SIB exhibiting intermediate performance compared with that of SZ and the HC. This supports the claim that the switching rate for SZ differs from that of SIB and suggests that binocular rivalry may qualify as a visual endophenotype for SZ.

Increased delayed reward during intertemporal decision-making in schizophrenic patients and their unaffected siblings.

Intertemporal choices are decisions with consequences in multiple time periods and constitute a significant part of social cognition. The shared neuropathological characteristics of patients with schizophrenia and their siblings might express intermediate phenotypes in behavior that could be used to further characterize the illness. Schizophrenic patients, unaffected siblings, and healthy controls underwent a computerized version of the "Intertemporal Choice Task". All participants could choose between sooner-smaller (SS) and later-larger (LL) options in now-trials and in not-now-trials. Subjects also underwent a battery of cognitive neuropsychological assessment. Our results indicated that schizophrenic patients and unaffected siblings both had a tendency to choose LL options in now-trials or not-now-trials compared to healthy controls. Schizophrenic patients had significantly lower scores in several cognitive tasks, including MoCA, attention, executive functions, and information processing when compared with the other two groups. Moreover, within the schizophrenic patient group, significant correlations were found between intertemporal decision-making performance and executive function. The present study showed that both schizophrenic patients and unaffected siblings preferred to choose larger-delayed rewards during intertemporal decision-making, which may result from frontal-striatal and frontal-parietal network dysfunction. Their intertemporal decision-making performance was associated with executive function performance.