Posttraumatic stress disorder (PTSD) is a common and debilitating mental
disorder with a particularly high burden for women. Emerging evidence suggests
PTSD may be more heritable among women and evidence from animal models and human
correlational studies suggest connections between sex-linked biology and PTSD
vulnerability, which may extend to the disorder’s genetic architecture.
We conducted a genome-wide association study (GWAS) of PTSD in a primarily
African American sample of women from the Detroit Neighborhood Health Study
(DNHS) and tested for replication in an independent cohort of primarily European
American women from the Nurses Health Study II (NHSII).
We genotyped 413 DNHS women - 94 PTSD cases and 319 controls exposed to
at least one traumatic event - on the Illumina HumanOmniExpress BeadChip for
> 700,000 markers and tested 578 PTSD cases and 1963 controls from NHSII for
replication. We performed a network-based analysis integrating data from
GWAS-derived independent regions of association and the Reactome database of
We found genome-wide significant association for one marker mapping to a
novel RNA gene, lincRNA AC068718.1, for which we found
suggestive evidence of replication in NHSII. Our network-based analysis
indicates that our top GWAS results were enriched for pathways related to
telomere maintenance and immune function. Our findings implicate a novel RNA
gene, lincRNA AC068718.1, as risk factor for PTSD in women and
add to emerging evidence that non-coding RNA genes may play a crucial role in
shaping the landscape of gene regulation with putative pathological effects that
lead to phenotypic differences.
PTSD; GWAS; lincRNA; telomere maintenance; immune system
Posttraumatic stress disorder (PTSD) has been associated with adverse health consequences, including overweight, obesity, and cardiovascular disease. African Americans, particularly women, have among the highest rates of overweight and obesity in the U.S. compared to other racial groups. High rates of violence exposure in urban African Americans may lead to the development of PTSD and increase risk for overweight and obesity. The current study investigated the comorbidity of lifetime PTSD and overweight/obesity in a population-based African American, urban sample.
Data were from 463 African American male and female participants of the Detroit Neighborhood Health Study. Multivariable logistic regression models estimated the impact of lifetime PTSD on risk for overweight and obesity.
The prevalence of obesity was significantly higher among women (60.9%) than men (33.1%; p<0.001). In sex-stratified models, after controlling for demographic variables, PTSD was associated obesity (OR=4.4, 95% CI: 1.3, 14.3) only among women.
PTSD was associated with obesity, after controlling for confounding variables, among African American women. Results underscore the contribution of PTSD to obesity among African American women and the importance of addressing the physical health correlates of women with PTSD.
PTSD; obesity; urban; African American
Potentially traumatic events (PTEs) are common in the population, yet, the impact of total burden and specific types of PTEs on physical health has not been systematically investigated.
Data were drawn from the Detroit Neighborhood Health Study, a community sample of predominately African Americans living in Detroit, Michigan, interviewed in 2008–2009 (N = 1,547) and in 2009–2010 (N = 1,054). Kaplan–Meier and Cox proportional hazards models were used.
Respondents with the highest levels of PTE exposure (8+ events) had an average age of adverse physical health condition diagnosis that was 15 years earlier than respondents with no exposure. There was a monotonic relation between number of PTEs and arthritis risk. Compared to those who reported no lifetime events, respondents with 1–2, 3–4, 5–7, and 8+ traumatic events had 1.06, 1.12, 1.73, and 2.44 times the hazard of arthritis. Assaultive violence (HR = 1.7; 95% CI 1.2–2.3) and other threats to physical integrity (HR = 1.5, 95% CI 1.1–2.1) were particularly strong risk factors for arthritis.
These results provide novel evidence linking PTEs, particularly those involving violence and threat to life, to elevated risk for arthritic conditions. Efforts to prevent or mitigate traumatic event exposures may have a broad range of benefits for health.
trauma; traumatic events; chronic disease; arthritis; physical health; African Americans
A growing literature indicates that genetic variation, in combination with adverse early life experiences, shapes risk for later mental illness. Recent work also suggests that molecular variation at the ADCYAP1R1 locus is associated with posttraumatic stress disorder (PTSD) in women. We sought to test whether childhood maltreatment (CM) interacts with ADCYAP1R1 geno-type to predict PTSD in women.
Data were obtained from 495 adult female participants from the Detroit Neighborhood Health Study. Genotyping of rs2267735, an ADCYAP1R1 variant, was conducted via TaqMan assay. PTSD, depression, and CM exposure were assessed via structured interviews. Main and interacting effects of ADCYAP1R1 and CM levels on past month PTSD and post-traumatic stress (PTS) severity were examined using logistic regression and a general linear model, respectively. As a secondary analysis, we also assessed main and interacting effects of ADCYAP1R1 and CM variation on risk of past-month depression diagnosis and symptom severity.
No significant main effects were observed for ADCYAP1R1 genotype on either PTSD/PTS severity. In contrast, a significant ADCYAP1R1 × CM interaction was observed for both past month PTSD and PTS severity, with carriers of the “C” allele showing enhanced risk for these outcomes among women exposed to CM. No significant main or interaction effects were observed for past month depression/depression severity.
Genetic variation at the ADCYAP1R1 locus interacts with CM to shape risk of later PTSD, but not depression, among women. The molecular mechanisms contributing to this interaction require further investigation.
PTSD; depression; childhood maltreatment; candidate gene; replication; gene-environment interaction
The recent sociodevelopmental cognitive model of schizophrenia/psychosis is a highly influential and compelling compendium of research findings. Here, we present logical extensions to this model incorporating ideas drawn from epigenetic mediation of psychiatric disease, and the plausible effects of epigenetics on the emergence of brain network function and dysfunction in adolescence. We discuss how gene–environment interactions, effected by epigenetic mechanisms, might in particular mediate the stress response (itself heavily implicated in the emergence of schizophrenia). Next, we discuss the plausible relevance of this framework for adolescent genetic risk populations, a risk group characterized by vexing and difficult-to-explain heterogeneity. We then discuss how exploring relationships between epigenetics and brain network dysfunction (a strongly validated finding in risk populations) can enhance understanding of the relationship between stress, epigenetics, and functional neurobiology, and the relevance of this relationship for the eventual emergence of schizophrenia/psychosis. We suggest that these considerations can expand the impact of models such as the sociodevelopmental cognitive model, increasing their explanatory reach. Ultimately, integration of these lines of research may enhance efforts of early identification, intervention, and treatment in adolescents at-risk for schizophrenia.
schizophrenia; adolescence; risk; epigenetics; brain networks
Urban residents experience a wide range of traumatic events and are at increased risk of assaultive violence. Although previous research has examined trajectories of posttraumatic stress (PTS) through latent class growth analysis (LCGA) among persons exposed to the same index events (e.g., a natural disaster), PTS trajectories have not been documented among urban residents. The aims of this study were to conduct LGCA with a sample of trauma survivors from Detroit, Michigan (N = 981), and to explore predictors of trajectory membership. Participants completed three annual telephone surveys, each of which included the posttraumatic stress disorder (PTSD) Check-list-Civilian Version. Four PTS trajectories were detected. Although the majority evidenced a trajectory of consistently few symptoms (Low: 72.5 %), 4.6 % were in a trajectory of chronic severe PTSD (High), and the remainder were in trajectories of consistently elevated, but generally subclinical, levels of PTS (Decreasing: 12.3 %; Increasing: 10.6 %). Socioeconomic disadvantage (e.g., lower income), more extensive trauma history (e.g., childhood abuse), and fewer social resources (e.g., lower social support) were associated with membership in higher PTS trajectories, relative to the Low trajectory. The results suggest that efforts to reduce PTS in urban areas need to attend to socioeconomic vulnerabilities in addition to trauma history and risk for ongoing trauma exposure.
Posttraumatic stress; Latent class growth analysis; Non-Hispanic Blacks; Urban environment
We describe the results of the first genome-wide association study of PTSD performed using trauma-exposed white non-Hispanic participants from a cohort of veterans and their intimate partners (295 cases and 196 controls). Several SNPs yielded evidence of association. One SNP (rs8042149), located in the retinoid-related orphan receptor alpha gene (RORA), reached genome-wide significance. Nominally significant associations were observed for other RORA SNPs in two African American replication samples—one from the veteran cohort (43 cases and 41 controls) and another independent cohort (100 cases and 421 controls). However, only the associated SNP from the veteran African American replication sample survived gene-level multiple testing correction. RORA has been implicated in prior GWAS studies of psychiatric disorders and is known to play an important role in neuroprotection and other behaviorally-relevant processes. This study represents an important step towards identifying the genetic underpinnings of PTSD.
Posttraumatic stress disorder; Genome-wide association; RORA
Low socioeconomic position (SEP) has previously been linked to a number of negative health indicators, including poor mental health. The biologic mechanisms linking SEP and mental health remain poorly understood. Recent work suggests that social exposures influence DNA methylation in a manner salient to mental health. We conducted a pilot investigation to assess whether SEP, measured as educational attainment, modifies the association between genomic methylation profiles and traumatic stress in a trauma-exposed sample. Results show that methylation × SEP interactions occur preferentially in genes pertaining to nervous system function, suggesting a plausible biologic pathway by which SEP may enhance sensitivity to stress, and, in turn, risk of post-traumatic stress disorder.
Epigenetic marks, including DNA methylation, are modifiable molecular factors that may underlie mental disorders, especially responses to trauma, including the development of and resilience to posttraumatic stress disorder (PTSD). Previous work has identified differential DNA methylation at CpG dinucleotide sites genomewide between trauma exposed individuals with and without PTSD, suggesting a role for epigenetic potential—the capacity to epigenetically regulate behavior and physiology in response to lived experiences. The human species is characterized by an increased period of adaptive plasticity during brain development. The evolutionary history of epigenetic potential in relation to adaptive plasticity is currently unknown. Using phylogenetic methods and functional annotation analyses, we trace the evolution of over 7000 CpG dinucleotides, including 203 associated with PTSD, during the descent of humans in during mammalian evolution and characterize the biological significance of this evolution. We demonstrate that few (7%) PTSD-associated CpG sites are unique to humans, while the vast majority of sites have deep evolutionary origins: 73 and 93% were unambiguously present in the last common ancestor of humans/orangutans and humans/chimpanzees, respectively. Genes proximal to evolved PTSD-associated CpG sites revealed significant enrichment for immune function during recent human evolution and regulation of gene expression during more ancient periods of human evolution. Additionally, 765 putative transcription factor binding motifs (TFBMs) were identified that overlap with PTSD-associated CpG sites. Elucidation of the evolutionary history of PTSD-associated CpG sites may provide insights into the function and origin of epigenetic potential in trauma responses, generally, and PTSD, specifically. The human capacity to respond to trauma with stable physiologic and behavioral changes may be due to epigenetic potentials that are shared among many mammalian species.
posttraumatic stress disorder; epigenetics; molecular evolution; DNA methylation; mental disorders
Exposure to child maltreatment is associated with elevated risk for behavioral disorders in adulthood. One explanation for this life-course association is that child maltreatment increases vulnerability to the effects of subsequent stressors; however, the extent to which maltreatment increases sensitivity to social context has never been examined. We evaluated whether the association between neighborhood physical disorder and binge drinking was modified by child maltreatment exposure.
Data were drawn from the Detroit Neighborhood Health Study, a prospective representative sample of predominately African Americans in the Detroit population. Neighborhood physical disorder was measured via systematic neighborhood assessment. Child maltreatment indicators included self-reported physical, sexual, and emotional abuse. Incident binge drinking was defined as at least one episode of ≥5 drinks (men) or ≥4 drinks (women) in the past 30-day period among those with no binge drinking at baseline (N=1,013).
Child maltreatment and neighborhood physical disorder interacted to predict incident binge drinking (B=0.16, p=0.02) and maximum number of past 30-day drinks (B=0.15, p=0.04), such that neighborhood physical disorder predicted problematic alcohol use only among individuals with high exposure to child maltreatment.
The results add to the growing literature that African Americans in the U.S. are exposed to an array of stressors that have pernicious consequences for problematic alcohol use. Our results document the need for increased attention to the potential for at-risk alcohol use among populations with a high degree of stress exposure.
binge drinking; child maltreatment; neighborhood effects; neighborhood physical disorder; African Americans
The social environment plays a considerable role in determining major psychiatric disorders. Emerging evidence suggests that features of the social environment modify gene expression independently of the primary DNA sequence through epigenetic processes. Accordingly, dysfunction of epigenetic mechanisms offers a plausible mechanism by which an adverse social environment gets “into the mind” and results in poor mental health. The purpose of this review is to provide an overview of the studies suggesting that epigenetic changes introduced by the social environment then manifest as psychological consequences. Our goal is to build a platform to discuss the ways in which future epidemiologic studies may benefit from including epigenetic measures. We focus on schizophrenia, major depressive disorder, post-traumatic stress disorder, anorexia nervosa, and substance dependence as examples that highlight the ways in which social environmental exposures, mediated through epigenetic processes, affect mental health.
Epigenetics; Social environment; Psychiatric disorders; Methylation
Depression is a major public health problem among youth, currently estimated to affect as many as 9% of US children and adolescents. The recognition that both genes (“nature”) and environments (“nurture”) are important for understanding the etiology of depression has led to rapid growth in research exploring gene–environment interactions (GxE). However, there has been no systematic review of GxE in youth depression to date.
The goal of this article was to systematically review evidence on the contribution of GxE to the risk of child and adolescent depression. Though a search of PubMed and PsycINFO databases to 1 April 2010, we identified 20 candidate gene–environment interaction studies focused on depression in youth (up to age 26) and compared each study in terms of the following characteristics: research design and sample studied; measure of depression and environment used; genes explored; and GxE findings in relation to these factors.
In total 80% of studies (n=16) found at least one significant GxE association. However, there was wide variation in methods and analyses adopted across studies, especially with respect to environmental measures used and tests conducted to estimate GxE. This heterogeneity made it difficult to compare findings and evaluate the strength of the evidence for GxE.
The existing body of GxE research on depression in youth contains studies that are conceptually and methodologically quite different, which contributes to mixed findings and makes it difficult to assess the current state of the evidence. To decrease this heterogeneity, we offer 20 recommendations that are focused on: (1) reporting GxE research; (2) testing and reporting GxE effects; (3) conceptualizing, measuring, and analyzing depression; (4) conceptualizing measuring, and analyzing environment; (5) increasing power to test for GxE; and (6) improving the quality of genetic data used. Although targeted to GxE research on depression, these recommendations can be adopted by GxE researchers focusing on other mental health outcomes.
depression; children; adolescents; youth; gene; environment; interaction
Emerging work suggests that both environmental and genetic factors contribute to risk of depression in adolescents, and that these factors may differ between genders. We assessed whether features of the social environment (SE), measured at varying levels, and genetic factors jointly shape the risk of depression in adolescent males and females.
Using data from a national survey of U.S. adolescents, we applied cross-sectional, multilevel mixed models to assess the contribution of: (i) 5-HTTLPR genotype and respondent-level building conditions to depressive sympton score (DSS); and (ii) 5-HTTLPR genotype and neighborhood-level building conditions to DSS. Models testing potential gene-SE (G × SE) interactions were also conducted. All models were stratified by gender and adjusted for age, race/ethnicity, family structure, parental education and social support.
Among females, adjusted analyses indicated that sl genotype carriers enjoyed a marginally significant (p=0.07) protective effect against higher DSS in models assessing respondent-level building conditions. In contrast, among males, adjusted analyses predicted significantly higher DSS for residents of neighborhoods with relatively poor building conditions (p<0.01). No significant G X SE interactions were detected for either gender.
These results suggest that adverse, macro-level SE effects increase risk of depression to a greater extent in adolescent males than females. Intervention strategies designed to improve mental health in adolescent populations should consider a growing body of work suggesting that the contextual effects conferring increased risk of depression differ among males and females.
social epidemiology; genetics; mental health; gender
Posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder that occurs following exposure to a traumatic event. However, most individuals do not develop PTSD following even a severe trauma, leading to a search for new variables—such as genetic and other molecular variation— associated with vulnerability and resilience in the face of trauma exposure.
We examined whether serotonin transporter (SLC6A4) promoter genotype and methylation status modified the association between number of traumatic events experienced and PTSD in a subset of 100 individuals from the Detroit Neighborhood Health Study.
Number of traumatic events was strongly associated with risk of PTSD. Neither SLC6A4 genotype or nor methylation status were associated with PTSD in main effects models. However, SLC6A4 methylation levels modified the effect of number of traumatic events on PTSD after controlling for SLC6A4 genotype. Persons with more traumatic events were at increased risk for PTSD but only at lower methylation levels. At higher methylation levels, individuals with more traumatic events were protected from this disorder. This interaction was observed whether the outcome was PTSD diagnosis, symptom severity, or number of symptoms.
Gene-specific methylation patterns may offer potential molecular signatures of increased risk for and resilience to PTSD.
posttraumatic stress disorder; epigenetic; methylation; SLC6A4; trauma
Recent work suggests that the 9-repeat (9R) allele located in the 3′UTR VNTR of the SLC6A3 gene increases risk of posttraumatic stress disorder (PTSD). However, no study reporting this association to date has been based on population-based samples. Furthermore, no study of which we are aware has assessed the joint action of genetic and DNA methylation variation at SLC6A3 on risk of PTSD. In this study, we assessed whether molecular variation at SLC6A3 locus influences risk of PTSD. Participants (n = 320; 62 cases/258 controls) were drawn from an urban, community-based sample of predominantly African American Detroit adult residents, and included those who had completed a baseline telephone survey, had provided blood specimens, and had a homozygous genotype for either the 9R or 10R allele or a heterozygous 9R/10R genotype. The influence of DNA methylation variation in the SLC6A3 promoter locus was also assessed in a subset of participants with available methylation data (n = 83; 16 cases/67 controls). In the full analytic sample, 9R allele carriers had almost double the risk of lifetime PTSD compared to 10R/10R genotype carriers (OR = 1.98, 95% CI = 1.02–3.86), controlling for age, sex, race, socioeconomic status, number of traumas, smoking, and lifetime depression. In the subsample of participants with available methylation data, a significant (p = 0.008) interaction was observed whereby 9R allele carriers showed an increased risk of lifetime PTSD only in conjunction with high methylation in the SLC6A3 promoter locus, controlling for the same covariates. Our results confirm previous reports supporting a role for the 9R allele in increasing susceptibility to PTSD. They further extend these findings by providing preliminary evidence that a “double hit” model, including both a putatively reduced-function allele and high methylation in the promoter region, may more accurately capture molecular risk of PTSD at the SLC6A3 locus.
In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR≅0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development.
For the first time in human history, more than half of the world's population lives in urban areas and this is projected to increase to two-thirds by 2030. This increased urbanity of the world's population has substantial public health implications. Nearly a century of research has shown higher risk of mental disorder among persons living in urban versus rural areas. Epidemiologic research has documented that associations between particular features of the urban environment, such as concentrated disadvantage, residential segregation and social norms, contribute to the risk of mental illness. We propose that changes in DNA methylation may be one potential mechanism through which features of the urban environment contribute to psychopathology. Recent advances in animal models and human correlation studies suggest DNA methylation as a promising mechanism that can explain how the environment “gets under the skin.” Aberrant DNA methylation signatures characterize mental disorders in community settings. Emerging evidence of associations between exposure to features of the environment and methylation patterns may lead toward the identification of mechanisms that explain the link between urban environments and mental disorders. Importantly, evidence that epigenetic changes are reversible offers new opportunities for ameliorating the impact of adverse urban environments on human health.
urban environment; mental disorders; DNA methylation; epigenetics; posttraumatic stress disorder; depression
Limited vaccine availability and the potential for resistance to antiviral medications have led to calls for establishing the efficacy of non-pharmaceutical measures for mitigating pandemic influenza. Our objective was to examine if the use of face masks and hand hygiene reduced rates of influenza-like illness (ILI) and laboratory-confirmed influenza in the natural setting. A cluster-randomized intervention trial was designed involving 1,178 young adults living in 37 residence houses in 5 university residence halls during the 2007–2008 influenza season. Participants were assigned to face mask and hand hygiene, face mask only, or control group during the study. Discrete-time survival models using generalized estimating equations to estimate intervention effects on ILI and confirmed influenza A/B infection over a 6-week study period were examined. A significant reduction in the rate of ILI was observed in weeks 3 through 6 of the study, with a maximum reduction of 75% during the final study week (rate ratio [RR] = 0.25, [95% CI, 0.07 to 0.87]). Both intervention groups compared to the control showed cumulative reductions in rates of influenza over the study period, although results did not reach statistical significance. Generalizability limited to similar settings and age groups. Face masks and hand hygiene combined may reduce the rate of ILI and confirmed influenza in community settings. These non-pharmaceutical measures should be recommended in crowded settings at the start of an influenza pandemic.
As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD). Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes' methylation values and number of potentially traumatic events (PTEs), adjusting for age and other covariates. Results revealed that only one candidate gene—MAN2C1—showed a significant methylation × PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p=0.04). These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder.
epigenetics; psychiatric epidemiology; trauma; interaction; genomics
Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades.
Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species.
We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days).
The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20–30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species.
The well-documented gender differences in the risk for depression may be explained by genetic factors, by different responses to social context, or by a combination of both. We sought to assess whether there were gender differences in the longitudinal associations between serotonin transporter promoter (5-HTTLPR) genotype and depressive symptoms in adolescents, and whether macrosocial context plays a role in explaining any observed differences.
Using data from a nationally representative survey of adolescents, we applied multilevel mixed models to assess, separately for adolescent males and females (a) the relation between 5-HTTLPR genotype and depressive symptoms; and (b) the interaction of county-level deprivation and 5-HTTLPR genotype in models predicting depressive symptoms. All models adjusted for age and other covariates.
Among females (n=560), main effects models showed an association between the sl genotype and lowered risk of depressive symptoms (b=−0.18, p=0.03). Among males (n=524), interaction models showed an association between sl genotype and lowered risk of depressive symptoms in deprived counties only (b=−0.32, p=0.04).
In adolescent females, the 5-HTTLPR sl genotype confers protection against depressive symptoms independent of county-level social context whereas in adolescent males, protection by the same genotype is conferred only within the context of county-level deprivation. Future work should aim to understand how genetic and macrosocial factors jointly shape risk for mental illness, and how these factors shape gender differences in mental illness.
social epidemiology; serotonin transporter promoter; gene-environment interaction; macrosocial environment
As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD). Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes’ methylation values and number of potentially traumatic events (PTEs), adjusting for age and other covariates. Results revealed that only one candidate gene–MAN2C1–showed a significant methylation x PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p = 0.04). These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder.
Epigenetics; psychiatric epidemiology; trauma; interaction; genomics
Inhibitory interneurons participate in local processing circuits, playing a central role in executive cognitive functions of the prefrontal cortex. Although humans differ from other primates in a number of cognitive domains, it is not currently known whether the interneuron system has changed in the course of primate evolution leading to our species. In this study, we examined the distribution of different interneuron subtypes in the prefrontal cortex of anthropoid primates as revealed by immunohistochemistry against the calcium-binding proteins calbindin, calretinin and parvalbumin. In addition, we tested whether genes involved in the specification, differentiation and migration of interneurons show evidence of positive selection in the evolution of humans. Our findings demonstrate that cellular distributions of interneuron subtypes in human prefrontal cortex are similar to other anthropoid primates and can be explained by general scaling rules. Furthermore, genes underlying interneuron development are highly conserved at the amino acid level in primate evolution. Taken together, these results suggest that the prefrontal cortex in humans retains a similar inhibitory circuitry to that in closely related primates, even though it performs functional operations that are unique to our species. Thus, it is likely that other significant modifications to the connectivity and molecular biology of the prefrontal cortex were overlaid on this conserved interneuron architecture in the course of human evolution.
language; theory of mind; prefrontal cortex; chimpanzee; great ape