Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins

Recent discoveries highlight the importance of stochastic epigenetic changes, as indexed by epigenetic outlier DNA methylation signatures, as a valuable tool to understand aberrant cell function and subsequent human pathology. There is evidence of such changes in different complex disorders as diverse as cancer, obesity and, to a lesser extent, depression. The current study was aimed at identifying outlying DNA methylation signatures of depressive psychopathology. Here, genome-wide DNA methylation levels were measured (by means of Illumina Infinium HumanMethylation450 Beadchip) in peripheral blood of thirty-four monozygotic twins informative for depressive psychopathology (lifetime DSM-IV diagnoses). This dataset was explored to identify outlying epigenetic signatures of depression, operationalized as extreme hyper- or hypo-methylation in affected co-twins from discordant pairs that is not observed across the rest of the study sample. After adjusting for blood cell count, there were thirteen CpG sites across which depressed co-twins from the discordant pairs exhibited outlying DNA methylation signatures. None of them exhibited a methylation outlier profile in the concordant and healthy pairs, and some of these loci spanned genes previously associated with neuropsychiatric phenotypes, such as GHSR and KCNQ1. This exploratory study provides preliminary proof-of-concept validation that epigenetic outlier profiles derived from genome-wide DNA methylation data may be related to depression risk

Birth Weight and Adult IQ, but Not Anxious-Depressive Psychopathology, Are Associated with Cortical Surface Area: A Study in Twins

BACKGROUND: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. AIMS: We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. RESULTS: Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. CONCLUSION: The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.This work was supported by the Spanish SAF2008-05674, European Twins Study Network on Schizophrenia Research Training Network (grant number EUTwinsS; MRTN-CT-2006-035987), the Catalan 2014SGR1636 and the PIM2010-ERN- 00642 in frame of ERA-NET NEURON. A. Córdova- Palomera was funded by The National Council for Science and Technology (CONACyT, Mexico). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

MRI Indices of Cortical Development in Young People With Psychotic Experiences: Influence of Genetic Risk and Persistence of Symptoms

Background Psychotic experiences (PEs) are considered part of an extended psychosis phenotype and are associated with an elevated risk of developing a psychotic disorder. Risk of transition increases with persistence of PEs, and this is thought to be modulated by genetic and environmental factors. However, it is unclear if persistence is associated with progressive schizophrenia-like changes in neuroanatomy. Methods We examined cortical morphometry using MRI in 247 young adults, from a population-based cohort, assessed for the presence of PEs at ages 18 and 20. We then incorporated a polygenic risk score for schizophrenia (PRS) to elucidate the effects of high genetic risk. Finally, we used atlas-based tractography data to examine the underlying white matter. Results Individuals with persisting PEs showed reductions in gyrification (local gyrification index: lGI) in the left temporal gyrus as well as atypical associations with brain volume (TBV) in the left occipital and right prefrontal gyri. No main effect was found for the PRS, but interaction effects with PEs were identified in the orbitofrontal, parietal, and temporal regions. Examination of underlying white matter did not provide strong evidence of further disturbances. Conclusions Disturbances in lGI were similar to schizophrenia but findings were mostly limited to those with persistent PEs. These could reflect subtle changes that worsen with impending psychosis or reflect an early vulnerability associated with the persistence of PEs. The lack of clear differences in underlying white matter suggests our findings reflect early disturbances in cortical expansion rather than progressive changes in brain structure

Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

Altres ajuts: Max Planck Society (Germany).The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes

Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5

Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain

Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium.

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders

Early Neurodevelopment, adult human cognition and depressive psychopathology: analysis of neuroimaging brain correlates and epigenetic mediators

[eng] In the behavioral sciences, the concept of phenotypic plasticity can be roughly categorized into two classes: developmental and activational plasticity. Developmental plasticity denotes the capacity of an individual carrying a specific genetic background to adopt different developmental trajectories under distinct settings. Complementarily, activational plasticity refers to the differential activation of adaptation mechanisms: an individual with high activational plasticity would be able to detect a wide range of environments, and to respond to it using a psychobiological phenotype from a relatively large catalogue. In this context, it is feasible postulating that several etiopathogenic mechanisms of depression-related phenotypes can be clarified by expanding on processes of biobehavioral plasticity in response to the experience. This expansion can be elaborated on the basis of both neurodevelopmental phenomena (developmental plasticity) and novel biological mechanisms detectable through neuroimaging and epigenetics approaches (activational plasticity). The present work expands on two specific hypotheses. First, depression-related psychopathological phenotypes are induced by factors altering the early neurodevelopment, and these long-lasting changes can be assessed in adulthood (depression and developmental plasticity). Secondly, the clinical manifestation of depression-related psychopathological phenotypes can be understood as activational plasticity deficits; these deficits can be assessed as neurobiological disease traits using novel epigenetic and neuroimaging techniques (depression and activational plasticity). The results of this work provide support to the neuroplasticity hypothesis of depression, from both developmental and activational perspectives. Developmentally, they suggest putative etiopathogenic pathways leading from an altered early neurodevelopment to an increased risk for depression-related phenotypes. By exploring and combining genetic, environmental and psychopathologic concepts, the feasibility of these results has been explained by combining the popular genetic pleiotropy hypothesis in psychiatry with a notion of disease-specificity liability driven by the environment. With regards to activational plasticity, this work has proposed novel genetic and epigenetic signatures potentially underlying the clinical manifestation of neuropsychiatric and neurocognitive features of depression (i.e., the genetics of DNMT3B and the epigenetics of DEPDC7); additionally, it has proposed new putative neurobiological mechanisms to explain depressive traits (i.e., a combination of differential and variable methylation, a genetically-mediated hippocampal communication deficit, and a new amygdalar synchrony failure driven by the genes)

Twin study designs as a tool to identify new candidate genes for depression: A systematic review of DNA methylation studies

Monozygotic (MZ) twin studies constitute a key resource for the dissection of environmental and biological risk factors for human complex disorders. Given that epigenetic differences accumulate throughout the lifespan, the assessment of MZ twin pairs discordant for depression offers a genetically informative design to explore DNA methylation while accounting for the typical confounders of the field, shared by co-twins of a pair. In this review, we systematically evaluate all twin studies published to date assessing DNA methylation in association with depressive phenotypes. However, difficulty to recruit large numbers of MZ twin pairs fails to provide enough sample size to develop genome-wide approaches. Alternatively, region and pathway analysis revealed an enrichment for nervous system related functions; likewise, evidence supports an accumulation of methylation variability in affected subjects when compared to their co-twins. Nevertheless, longitudinal studies incorporating known risk factors for depression such as childhood trauma are required for understanding the role that DNA methylation plays in the etiology of depression

Letter to editor: Low Birth Weight And Adult Depression: Eliciting Their Association

Theories supporting fetal origins of adult health and disease are nowadays widely accepted regarding some psychiatric conditions. However, whether genetic or environmental factors disrupting fetal growth might constitute a rick factor for depressive and/or anxious psychopathology remains still controversial