Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G+CA) and interactive (GxCA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G+CA or GxCA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with GxCA interactions explaining most variance. The consistent GxCA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.Peer reviewe

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G+CA) and interactive (GxCA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G+CA or GxCA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with GxCA interactions explaining most variance. The consistent GxCA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks

The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease

Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases

Shared genetic architecture between mental health and the brain functional connectome in the UK Biobank

Abstract Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45–82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population

Associated Genetics and Connectomic Circuitry in Schizophrenia and Bipolar Disorder

Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share symptomatology and genetic etiology and are regularly hypothesized to share underlying neuropathology. Here, we examined how genetic liability to SCZ and BD shapes normative variations in brain connectivity. Methods: We examined the effect of the combined genetic liability for SCZ and BD on brain connectivity from two perspectives. First, we examined the association between polygenic scores for SCZ and BD for 19,778 healthy subjects from the UK Biobank and individual variation in brain structural connectivity reconstructed by means of diffusion weighted imaging data. Second, we conducted genome-wide association studies using genotypic and imaging data from the UK Biobank, taking SCZ-/BD-involved brain circuits as phenotypes of interest. Results: Our findings showed brain circuits of superior parietal and posterior cingulate regions to be associated with polygenic liability for SCZ and BD, circuitry that overlaps with brain networks involved in disease conditions (r = 0.239, p <.001). Genome-wide association study analysis showed 9 significant genomic loci associated with SCZ-involved circuits and 14 loci associated with BD-involved circuits. Genes related to SCZ-/BD-involved circuits were significantly enriched in gene sets previously reported in genome-wide association studies for SCZ and BD. Conclusions: Our findings suggest that polygenic liability of SCZ and BD is associated with normative individual variation in brain circuitry

The genetic architectures of functional and structural connectivity properties within cerebral resting-state networks

Functional connectivity within resting-state networks (RSN-FC) is vital for cognitive functioning. RSN-FC is heritable and partially translates to the anatomical architecture of white matter, but the genetic component of structural connections of RSNs (RSN-SC) and their potential genetic overlap with RSN-FC remain unknown. Here we perform genome-wide association studies (Ndiscovery=24,336; Nreplication=3,412) and annotation on RSN-SC and RSN-FC. We identify genes for visual network-SC that are involved in axon guidance and synaptic functioning. Genetic variation in RSN-FC impacts biological processes relevant to brain disorders that previously were only phenotypically associated with RSN-FC alterations. Correlations of the genetic components of RSNs are mostly observed within the functional domain, whereas less overlap is observed within the structural domain and between the functional and structural domains. This study advances the understanding of the complex functional organization of the brain and its structural underpinnings from a genetics viewpoint.Significance StatementBrain regions with synchronized activity can be clustered into distinct networks. We investigate which genetic effects contribute to structural and functional connectivity within seven networks and assess their degree of shared genetic signal. Multiple genetic effects are identified and highlight relevant biological processes for brain connectivity and brain disorders related to the networks. Overlap between the genetics of network connectivity is mostly observed within the functional domain. These results advance our biological understanding of the complex functional organisation of the brain and its structural underpinnings, and their relevance for the genetics of neuropsychiatry

Associated Genetics and Connectomic Circuitry in Schizophrenia and Bipolar Disorder

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share symptomatology and genetic etiology and are regularly hypothesized to share underlying neuropathology. Here, we examined how genetic liability to SCZ and BD shapes normative variations in brain connectivity. METHODS: We examined the effect of the combined genetic liability for SCZ and BD on brain connectivity from two perspectives. First, we examined the association between polygenic scores for SCZ and BD for 19,778 healthy subjects from the UK Biobank and individual variation in brain structural connectivity reconstructed by means of diffusion weighted imaging data. Second, we conducted genome-wide association studies using genotypic and imaging data from the UK Biobank, taking SCZ-/BD-involved brain circuits as phenotypes of interest. RESULTS: Our findings showed brain circuits of superior parietal and posterior cingulate regions to be associated with polygenic liability for SCZ and BD, circuitry that overlaps with brain networks involved in disease conditions (r = 0.239, p < .001). Genome-wide association study analysis showed 9 significant genomic loci associated with SCZ-involved circuits and 14 loci associated with BD-involved circuits. Genes related to SCZ-/BD-involved circuits were significantly enriched in gene sets previously reported in genome-wide association studies for SCZ and BD. CONCLUSIONS: Our findings suggest that polygenic liability of SCZ and BD is associated with normative individual variation in brain circuitry

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

A genome-wide association study on MRI cerebellar volume in the UK Biobank cohort identifies 30 loci with genome-wide significance that might be relevant to brain structure and cognitive function