Novel GxE effects and resilience: A case:control longitudinal study of psychosocial stress with war-affected youth.

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT, and catechol-O-methyltransferase, COMT) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents.

Shape analysis of the basioccipital bone in Pax7-deficient mice.

We compared the cranial base of newborn Pax7-deficient and wildtype mice using a computational shape modeling technology called particle-based modeling (PBM). We found systematic differences in the morphology of the basiooccipital bone, including a broadening of the basioccipital bone and an antero-inferior inflection of its posterior edge in the Pax7-deficient mice. We show that the Pax7 cell lineage contributes to the basioccipital bone and that the location of the Pax7 lineage correlates with the morphology most effected by Pax7 deficiency. Our results suggest that the Pax7-deficient mouse may be a suitable model for investigating the genetic control of the location and orientation of the foramen magnum, and changes in the breadth of the basioccipital.

Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study.

BACKGROUND: The role of endoplasmic reticulum (ER) stress response in mental illness is not well understood. Human studies and animal models of depression show elevated brain ER stress response. In addition, some ER stress associated disorders (e.g. cardiovascular disease) show higher rates of depression compared to the general population, raising the possibility that ER stress response contributes to depression risk. It remains unknown, however, if ER stress response is present among individuals suffering from other stress-related mental illness, and whether such a response would be evident in a non-clinical sample. This study tests for systemic changes in ER stress response associated with Major Depressive Disorder (MDD) or post-traumatic stress disorder (PTSD) among community-dwelling individuals. METHODS: We analyzed expression of BiP, EDEM1, CHOP, and XBP1, the major indicators of ER stress response, with real-time PCR in leukocyte-derived RNA samples from 86 participants of the Detroit Neighborhood Health Study. Participants were selected based on the presence of either past year MDD or past year PTSD; controls were age and sex matched. RESULTS: Relative to controls, MDD is associated with a 1.34-fold increase in BiP (P=0.004), 1.35-fold increase in EDEM1 (P=0.001), 1.68-fold increase in CHOP (P=0.002), and 1.60-fold increase in XBP1 (P=0.004). These results remained significant after correction for multiple testing. In contrast, PTSD is associated with a 1.27-fold increase in EDEM1 expression only (P=0.027), a result that is attenuated to non-significance following adjustment for multiple testing; however, a subsample of participants with past month PTSD showed elevated expression of BiP and EDEM1 (uncorrected P value 0.049 and 0.017, respectively). CONCLUSIONS: These data indicate systemic and persistent activation of the ER stress response pathway in MDD among community-dwelling individuals. Systemic activation of the ER stress response may also occur in PTSD among persons with more recent symptoms.

Microscopic computed tomography-based skeletal phenotyping for genetic model organisms.

Forward and reverse genetics now enable researchers to understand embryonic and postnatal gene functioning in a wide range of species. Some genetic mutations cause obvious morphological change, whereas other mutations can lead to more subtle phenotypes and might be overlooked without adequate observations and quantifications. Due to the increase in number of genetic model organisms examined by the growing field of phenomics, standardized but sensitive methods for quantitative analysis are increasingly necessary in the everyday practice of analyzing ever-increasing quantities of phenotypic data. In this chapter, we have presented platform-independent parameters for the use of microscopic X-ray computed tomography (microCT) for phenotyping species-specific skeletal morphology of a variety of different genetic model organisms.

The Homo floresiensis cranium (LB1): size, scaling, and early Homo affinities.

The skeletal remains of a diminutive small-brained hominin found in Late Pleistocene cave deposits on the island of Flores, Indonesia were assigned to a new species, Homo floresiensis [Brown P, et al. (2004) A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature 431: 1055-1061]. A dramatically different interpretation is that this material belongs not to a novel hominin taxon but to a population of small-bodied modern humans affected, or unaffected, by microcephaly. The debate has primarily focused on the size and shape of the endocranial cavity of the type specimen, LB1, with less attention being paid to the morphological evidence provided by the rest of the LB1 cranium and postcranium, and no study thus far has addressed the problem of how scaling would affect shape comparisons between a diminutive cranium like LB1 and the much larger crania of modern humans. We show that whether or not the effects of its small cranial size are accounted for, the external cranial morphology of the LB1 cranium cannot be accommodated within a large global sample of normal modern human crania. Instead, the shape of LB1, which is shown by multivariate analysis to differ significantly from that of modern humans, is similar to that of Homo erectus sensu lato, and, to a lesser extent, Homo habilis. Our results are consistent with hypotheses that suggest the Liang Bua specimens represent a diminutive population closely related to either early H. erectus s. l. from East Africa and/or Dmanisi or to H. habilis.

Optimization of volumetric computed tomography for skeletal analysis of model genetic organisms.

Forward and reverse genetics now allow researchers to understand embryonic and postnatal gene function in a broad range of species. Although some genetic mutations cause obvious morphological change, other mutations can be more subtle and, without adequate observation and quantification, might be overlooked. For the increasing number of genetic model organisms examined by the growing field of phenomics, standardized but sensitive methods for quantitative analysis need to be incorporated into routine practice to effectively acquire and analyze ever-increasing quantities of phenotypic data. In this study, we present platform-independent parameters for the use of microscopic x-ray computed tomography (microCT) for phenotyping species-specific skeletal morphology of a variety of different genetic model organisms. We show that microCT is suitable for phenotypic characterization for prenatal and postnatal specimens across multiple species.