LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Polygenic risk, childhood abuse and gene x environment interactions with depression development from middle to late adulthood: A U.S. national life-course study.

OBJECTIVE: Utilizing national longitudinal data, this study examines how polygenic depression risk and childhood abuse interactively influence the life-course development of depressive conditions from middle to late adulthood. METHOD: Data from 7512 participants (4323 females and 3189 males) of European ancestry aged 51-90, retrieved from the U.S. Health and Retirement Study (1992-2020), were analyzed. Childhood physical abuse and polygenic depression score were the primary predictors. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression (CESD) scale, and clinical depression risk was a binary indicator. Growth-curve linear mixed and logit mixed-effects models were conducted for analysis. RESULTS: Increasing polygenic depression scores were associated with elevated CES-D levels and potential risks of clinical depression. Males experienced more detrimental effects of childhood abuse on depression development from ages 51 to 90 years. In contract, non-maltreated females generally exhibited higher depressive symptoms and clinical depression risk than males. A significant interactive effect was found between polygenic depression risk and childhood abuse among males. Higher depression levels and clinical risk were observed with increasing polygenic depression score among maltreated males, surpassing those of females with standardized polygenic score ≥0 from age 51 to 90 years. CONCLUSIONS: The interaction between childhood abuse and genetic factors significantly shaped lifelong depression trajectories in males, while the negative impact of abusive parenting remained constant regardless of polygenic depression risk among females. Individualized prevention and intervention strategies could be crucial in mitigating lifelong depression development, especially for high-genetic-risk males with a history of childhood physical abuse.

Neurobiological and psychological factors to depression.

Major Depressive Disorder (MDD) is a common condition with complex psychological and biological background. While its aetiology is still unclear, chronic stress stands amongst major risk factors to MDD pathogenesis. When researching on MDD, it is necessary to be familiar with the neurobiological effects of several prominent contributors to the chronic stress factor experienced across hypothalamic-pituitary-adrenal (HPA) axis, neurotransmission, immune system reflexivity, and genetic alterations. Bi-directional flow of MDD pathogenesis suggests that psychological factors produce biological effects. Here, a summary of how the MDD expresses its mechanisms of action across an overactive HPA axis, the negative impacts of reduced neurotransmitter functions, the inflammatory responses and their gene x environment interactions. This paper builds on these conceptual factors and their input towards the MDD symptomatology with a purpose of synthesising the current findings and create an integrated view of the MDD pathogenesis. Finally, relevant treatment implications will be summarised, along with recommendations to a multimodal clinical practice.

Complementary Experimental Methods in Genetics Open Up New Avenues of Research to Elucidate the Pathogenesis of Periodontitis.

A complex disease such as periodontitis is the sum of environmental and genetic effects. The personal genetic constitution interacts with the effects of internal and external risk factors like smoking, oral hygiene, malnutrition, emotional stress, and age. Accordingly, individuals who live in the same environmental context and share comparable lifestyle habits have different disease risks. Genetic research offers the identification of DNA sequence variants that have a causal role in disease etiology and allows the identification of disease relevant immune and metabolic pathways that contribute to disease susceptibility and pathogenesis in specific situations. Real advances have been made in genetic medical research in the last years. Starting from candidate gene association studies, new approaches were employed that have expanded the study design of genomewide association studies to genomewide meta-analyses and gene x environment interaction studies. Cost efficient whole-exome and whole-genome sequencing of patients with rare severe forms of periodontitis has the potential to identify genes and pathways with a direct role in the pathogenesis of common forms. In parallel, animal models were developed that use genetically highly diverse mouse lines to identify risk genes of human diseases. This chapter presents the main studies and the identified susceptibility genes that have clear statistical evidence. In addition, it describes pioneering studies that used advanced methods in experimental dental research, opening up new avenues of research. Although the knowledge of the genetic architecture of periodontitis is still in its infancy, genetic research is building the basis for future works with the potential to advance dental medicine in ways that will determine the various causes of periodontal diseases. This knowledge may eventually allow making predictions about disease risk for individual patients and leading to diagnosis and treatments that do not treat the symptoms but heal the disease.

Hypertension genetics past, present and future applications.

Essential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome-wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining ∼6% of the single nucleotide polymorphism-based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic-BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re-purposing opportunities, including SLC5A1 and canagliflozin (a type-2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene-environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients.

Interaction of FKBP5 variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex.

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.

Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene-set analysis.

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.

Fasting and time of day independently modulate circadian rhythm relevant gene expression in adipose and skin tissue.

BACKGROUND: Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season. RESULTS: We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR < 5%) with hours of fasting conditionally independent of time of day and season, with 19 genes common to both tissues. Among these genes, we replicated 38 in human, 157 in non-human studies, and 178 are novel associations. Fasting-responsive genes were enriched for regulation of and response to circadian rhythm. We identified 99 genes in adipose and 54 genes in skin whose expression was associated to time of day; these genes were also enriched for circadian rhythm processes. In genes associated to both exposures the effect of time of day was stronger and in an opposite direction to that of hours fasted. We also investigated the relationship between fasting and genetic regulation of gene expression, including GxE eQTL analysis to identify personal responses to fasting. CONCLUSION: This study robustly implicates circadian rhythm genes in the response to hours fasting independently of time of day, seasonality, age and BMI. We identified tissue-shared and tissue-specific differences in the transcriptional response to fasting in a large sample of healthy volunteers.

Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging.

Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging.

Social support and the serotonin transporter genotype (5-HTTLPR) moderate levels of resilience, sense of coherence, and depression.

Gene x environment interactions have mainly been investigated in models of psychopathology. However, the putative interplay between genes and beneficial environmental conditions on positive outcomes has rarely been addressed. We therefore examined the interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and social support on the sense of coherence (SOC), resilience, and depressive symptoms. Furthermore, we scrutinized our examinations by differentiating between individuals with and without childhood abuse. The sample included 1,811 participants from the general population (Study of Health in Pomerania, Germany). The triallelic genotype of 5-HTTLPR was determined and longitudinal data of social support were used. Among individuals with high social support no significant differences between 5-HTTLPR genotypes regarding all outcome variables were found. However, among those with low social support, carriers of at least one short allele reported significantly increased levels of SOC and resilience, as well as less depressive symptoms than carriers of the l/l genotype. This result was not modified by differentiating between those with childhood abuse and those without. In less supportive social environments the impact of distinct genotypes on behavioral outcomes might be more relevant than in supportive environments where social compensation might take place. Our findings indicate that both alleles of 5-HTTLPR contribute to the adaptability to different environmental conditions.

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

BACKGROUND: We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs METHODS: Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs RESULTS: Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation. CONCLUSION: These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.

[Epigenetics of schizophrenia: a review]. / Hypothèse épigénétique de la schizophrénie : revue de la littérature.

BACKGROUND: Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. OBJECT: The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. METHODS: We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post-translational histone modifications. RESULTS: First, in terms of epidemiology and transmission, the theoretical model of epigenetics applies to schizophrenia. Then, most environmental factors that have proved a link with this disease, may generate epigenetic mechanisms. Next, mutations have been found in regions implied in epigenetic mechanism among populations with schizophrenia. Some epigenetic alterations in DNA regions have been previously linked with neurodevelopmental abnormalities. In psychosis, some authors have found methylation differences in COMT gene, in reelin gene and in some genes implicated in dopaminergic, serotoninergic, GABAergic and glutamatergic pathways. Histone modifications have been described, in particular the H3L4 histone methylation. Finally, we tried to underline the difficulties in epigenetic research, notably in psychiatry, and the limits in this matter. CONCLUSION: The epigenetic field may explain a lot of questions around the physiopathology of the complex psychiatric disease that is schizophrenia. It may be a substratum to the prevailing hypothesis of gene x environment interaction. The research in the matter is definitely expanding. It justifies easily the need to improve the effort in the domain to overpass some limits inherent to the matter.

Disentangling Multiple Sclerosis heterogeneity in the French territory among genetic and environmental factors via Bayesian heritability analysis.

BACKGROUND: This study aimed to investigate the factors contributing to the variability of Multiple Sclerosis (MS) among individuals born and residing in France. Geographical variation in MS prevalence was observed in France, but the role of genetic and environmental factors in explaining this heterogeneity has not been yet elucidated. METHODS: We employed a heritability analysis on a cohort of 403 trios with an MS-affected proband in the French population. This sample was retrieved from REFGENSEP register of MS cases collected in 23 French hospital centers from 1992 to 2017. Our objective was to quantify the proportion of MS liability variability explained by genetic variability, sex, shared environment effects, region of birth and year of birth. We further considered gene x environment (GxE) interaction effects between genetic variability and region of birth. We have implemented a Bayesian liability threshold model to obtain posterior distributions for the parameters of interest adjusting for ascertainment bias. RESULTS: Our analysis revealed that GxE interaction effects between genetic variability and region of birth represent the primary significant explanatory factor for MS liability variability in French individuals (29 % [95 %CI: 5 %; 53 %]), suggesting that additive genetic effects are modified by environmental factors associated to the region of birth. The individual contributions of genetic variability and region of birth explained, respectively, ≈15 % and ≈16 % of MS variability, highlighting a significantly higher MS liability in individuals born in the Northern regions compared to the Southern region. Overall, the joint contribution of genetic variability, region of birth, and their interaction was then estimated to explain 65 % [95 %CI: 35 %; 92 %] of MS liability variability. The remaining proportion of MS variability is attributed to environmental exposures associated with the year of birth, shared within the same household, and specific to individuals. CONCLUSION: Overall, our analysis highlighted the interaction between genetic variability and environmental exposures linked to the region of birth as the main factor explaining MS variability within individuals born and residing in France. Among the environmental exposures prevalent in the Northern regions, and potentially interacting with genetic variability, lower vitamin D levels due to reduced sun exposure, higher obesity prevalence and higher pollution levels represent the main risk factors in influencing MS risk. These findings emphasize the importance of accounting for environmental factors linked to geographical location in the investigation of MS risk factors, as well as to further explore the influence of GxE interactions in modifying genetic risk.

NR3C1 and NR3C2 Genes Increase the Risk of Suicide Attempt in Psychiatric Disorder Patients with History of Childhood Trauma.

Background: Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. Participants and Methods: A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). Results: The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9-3.9], p<0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4-3.1], p<0.0001), emotional abuse (OR=2.1, 95% CI [1.5-3], p<0.0001), and sexual abuse (OR=2.4, 95% CI [1.4-2.9], p<0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p<0.0001; p<0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p<0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p<0.0001). Conclusion: Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.

Epigenetic regulation of nervous system development and function.

Building a brain is complicated but maintaining one may be an even greater challenge. Epigenetic mechanisms, including DNA methylation, histone and chromatin modifications, and the actions of non-coding RNAs, play an indispensable role in both. They orchestrate long-term changes in gene expression that underpin establishment of cellular identity as well as the distinct functionality of each cell type, while providing the needed plasticity for the brain to respond to a changing environment. The rapid expansion of studies on these epigenetic mechanisms over the last few decades has brought an evolving definition of the term epigenetics, including in the specialized context of the nervous system. The goal of this special issue is thus not only to bring a greater understanding of the myriad ways in which epigenetic mechanisms regulate nervous system development and function, but also to provide a platform for discussion of what is and what is not epigenetics. To this end, the editors have compiled a collection of review articles highlighting some of the remarkable breadth of epigenetic mechanisms that act at all stages of neuronal development and function, spanning from neurodevelopment, through learning and memory, and neurodegeneration.

Parenting and the Serotonin Transporter Gene (5HTTLPR), Is There an Association? A Systematic Review of the Literature.

The current systematic review examines whether there is an association between the genetic 5-HTTPLR polymorphism and parenting, and the mechanisms by which this association operates. The literature was searched in various databases such as PubMed, Scopus, and ScienceDirect. In line with our inclusion criteria, nine articles were eligible out of 22. Most of the studies analysed in this review found an association between 5HTTLPR and parenting. Four studies found a direct association between 5-HTTLPR and parenting with conflicting findings: two studies found that mothers carrying the short variant were more sensitive to their infants, while two studies found that parents carrying the S allele were less sensitive. In addition, several studies found strong interaction between genetic and environmental factors, such as childhood stress and disruptive child behaviour, quality of early care experiences, poor parenting environment, and quality of the environment. Only one study found an association between children's 5HTTLPR and parenting. Parenting can be described as a highly complex construct influenced by multiple factors, including the environment, as well as parent and child characteristics. According to the studies, maternal 5-HTTLPR polymorphism is most likely to be associated with sensitive parenting.

Genetic and epigenetic architecture of Obsessive-Compulsive Disorder: In search of possible diagnostic and prognostic biomarkers.

Obsessive-Compulsive Disorder (OCD) is a prevalent and severe clinical condition whose hallmarks are excessive, unwanted thoughts (obsessions) and repetitive behaviors (compulsions). The onset of symptoms generally occurs during pre-adult life and typically affects subjects in different aspects of their life's, compromising social and professional relationships. Although robust evidence suggests a genetic component in the etiopathogenesis of OCD, the causes of the disorder are still not completely understood. It is thus of relevance to take into account how genes interact with environmental risk factors, thought to be mediated by epigenetic mechanisms. We here provide an overview of genetic and epigenetic mechanisms of OCD, focusing on the modulation of key central nervous system genes, in the attempt to suggest possible disease biomarkers.

microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression.

Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.

Change of pace: How developmental tempo varies to accommodate failed provision of early needs.

The interplay of genes and environments (GxE) is a fundamental source of variation in behavioral and developmental outcomes. Although the role of developmental time (T) in the unfolding of such interactions has yet to be fully considered, GxE operates within a temporal frame of reference across multiple timescales and degrees of biological complexity. Here, we consider GxExT interactions to understand adversity-induced developmental acceleration or deceleration whereby environmental conditions hasten or hinder children's development. To date, developmental pace changes have been largely explained through a focus on the individual: for example, how adversity "wears down" aging biological systems or how adversity accelerates or decelerates maturation to optimize reproductive fitness. We broaden such theories by positing shifts in developmental pace in response to the parent-child dyad's capacity or incapacity for meeting children's early, physiological and safety needs. We describe empirical evidence and potential neurobiological mechanisms supporting this new conceptualization of developmental acceleration and deceleration. We conclude with suggestions for future research on the developmental consequences of early adverse exposures.

Gene Environment Interactions in the Etiology of Neural Tube Defects.

Human structural congenital malformations are the leading cause of infant mortality in the United States. Estimates from the United States Center for Disease Control and Prevention (CDC) determine that close to 3% of all United States newborns present with birth defects; the worldwide estimate approaches 6% of infants presenting with congenital anomalies. The scientific community has recognized for decades that the majority of birth defects have undetermined etiologies, although we propose that environmental agents interacting with inherited susceptibility genes are the major contributing factors. Neural tube defects (NTDs) are among the most prevalent human birth defects and as such, these malformations will be the primary focus of this review. NTDs result from failures in embryonic central nervous system development and are classified by their anatomical locations. Defects in the posterior portion of the neural tube are referred to as meningomyeloceles (spina bifida), while the more anterior defects are differentiated as anencephaly, encephalocele, or iniencephaly. Craniorachischisis involves a failure of the neural folds to elevate and thus disrupt the entire length of the neural tube. Worldwide NTDs have a prevalence of approximately 18.6 per 10,000 live births. It is widely believed that genetic factors are responsible for some 70% of NTDs, while the intrauterine environment tips the balance toward neurulation failure in at risk individuals. Despite aggressive educational campaigns to inform the public about folic acid supplementation and the benefits of providing mandatory folic acid food fortification in the United States, NTDs still affect up to 2,300 United States births annually and some 166,000 spina bifida patients currently live in the United States, more than half of whom are now adults. Within the context of this review, we will consider the role of maternal nutritional status (deficiency states involving B vitamins and one carbon analytes) and the potential modifiers of NTD risk beyond folic acid. There are several well-established human teratogens that contribute to the population burden of NTDs, including: industrial waste and pollutants [e.g., arsenic, pesticides, and polycyclic aromatic hydrocarbons (PAHs)], pharmaceuticals (e.g., anti-epileptic medications), and maternal hyperthermia during the first trimester. Animal models for these teratogens are described with attention focused on valproic acid (VPA; Depakote). Genetic interrogation of model systems involving VPA will be used as a model approach to discerning susceptibility factors that define the gene-environment interactions contributing to the etiology of NTDs.