A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis.

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.

Further evidence of DEPDC7 DNA hypomethylation in depression: A study in adult twins.

Late and early stressful factors have widely been recognized to play a role in the aetiology of depression. Recent research indicates that such adverse environmental stimuli may alter gene expression in humans via epigenetic modifications. While epigenetic changes such as DNA methylation are likely involved in these processes, it is still unknown what specific genomic loci may be hyper- or hypo-methylated in depression. The association between depressive symptoms during the last 30 days (Brief Symptom Inventory [BSI]) and peripheral-blood DNA methylation levels at genomic loci previously reported as epigenetically altered in saliva and brain of depressive patients was evaluated in a community sample of 34 adult Caucasian MZ twins (17 pairs). Intrapair DNA methylation differences in an intron of DEPDC7 (chr11:33040743) were associated with intrapair differences in current depressive symptoms. Accordingly, a site-specific 10% DNA hypomethylation in a co-twin would correlate with a current depressive symptom score around 3.1 BSI points above the score of his/her less-depressed co-twin. These findings indicate that DEPDC7 hypomethylation in peripheral blood DNA may be associated with recent depressive symptomatology, in line with previous results.

No progression of the alterations in the cortical thickness of individuals with schizophrenia-spectrum disorder: a three-year longitudinal magnetic resonance imaging study of first-episode patients.

BACKGROUND: Cortical thickness measurement offers an index of brain development processes. In healthy individuals, cortical thickness is reduced with increasing age and is related to cognitive decline. Cortical thinning has been reported in schizophrenia. Whether cortical thickness changes differently over time in patients and its impact on outcome remain unanswered. METHOD: Data were examined from 109 patients and 76 healthy controls drawn from the Santander Longitudinal Study of first-episode schizophrenia for whom adequate structural magnetic resonance imaging (MRI) data were available (n = 555 scans). Clinical and cognitive assessments and MRIs were acquired at three regular time points during a 3-year follow-up period. We investigated likely progressive cortical thickness changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The effects of cortical thickness changes on cognitive and clinical variables were also examined along with the impact of potential confounding factors. RESULTS: There were significant diagnoses × scan time interaction main effects for total cortical thickness (F 1,309.1 = 4.60, p = 0.033) and frontal cortical thickness (F 1,310.6 = 5.30, p = 0.022), reflecting a lesser thinning over time in patients. Clinical and cognitive outcome was not associated with progressive cortical changes during the early years of the illness. CONCLUSIONS: Cortical thickness abnormalities do not unswervingly progress, at least throughout the first years of the illness. Previous studies have suggested that modifiable factors may partly account for cortical thickness abnormalities. Therefore, the importance of implementing practical actions that may modify those factors and improve them over the course of the illness should be highlighted.

Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins.

Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.

Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: a twin study.

BACKGROUND: Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS: Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS: MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS: Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.

Cortical thickness correlates of psychotic experiences: examining the effect of season of birth using a genetically informative design.

Season of birth has been shown to influence risk for several neuropsychiatric diseases. Furthermore, it has been suggested that season of birth modifies a number of brain morphological traits. Since cortical thickness alterations have been reported across some levels of the psychosis-spectrum, this study was aimed at i) assessing the scarcely explored relationship between cortical thickness and severity of subclinical psychotic experiences (PEs) in healthy subjects, and ii) evaluating the potential impact of season of birth in the preceding thickness-PEs relationship. As both PEs and brain cortical features are heritable, the current work used monozygotic twins to separately evaluate familial and unique environmental factors. High-resolution structural MRI scans of 48 twins (24 monozygotic pairs) were analyzed to estimate cortical thickness using FreeSurfer. They were then examined in relation to PEs, accounting for the effects of birth season; putative differential relationships between PEs and cortical thickness depending on season of birth were also tested. Current results support previous findings indicative of cortical thickening in healthy individuals with high psychometrically assessed psychosis scores, probably in line with theories of compensatory aspects of brain features in non-clinical populations. Additionally, they suggest distinct patterns of cortical thickness-PEs relationships depending on birth seasonality. Familial factors underlying the presence of PEs may drive these effects.

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

PURPOSE: To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. METHOD: Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. RESULTS: In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. CONCLUSIONS: Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding.