DNA methylation associated with postpartum depressive symptoms overlaps findings from a genome-wide association meta-analysis of depression

Background Perinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology. Results Genome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within 7 months of delivery. Linear models were constructed to identify differentially methylated sites and regions, and permutation testing was utilized to assess significance. Differentially methylated regions (DMRs) were defined as genomic regions of consistent DNAm change with at least two probes within 1 kb of each other. Maternal age, current smoking status, estimated cell-type proportions, ancestry-relevant principal components, days since delivery, and chip position served as covariates to adjust for technical and biological factors. Current postpartum depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Ninety-eight DMRs were significant (false discovery rate \u3c 5%) and overlapped 92 genes. Three of the regions overlap loci from the latest Psychiatric Genomics Consortium meta-analysis of depression. Conclusions Many of the genes identified in this analysis corroborate previous allelic, transcriptomic, and DNAm association results related to depressive phenotypes. Future work should integrate data from multi-omic platforms to understand the functional relevance of these DMRs and refine DNAm association results by limiting phenotypic heterogeneity and clarifying if DNAm differences relate to the timing of onset, severity, duration of perinatal mental health outcomes of the current pregnancy or to previous history of depressive psychopathology

Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest—fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans

Racial Differences in Genetic and Environmental Risk to Preterm Birth

Preterm birth is more prevalent in African Americans than European Americans and contributes to 3.4 times more African American infant deaths. Models of social inequity do not appreciably account for this marked disparity and molecular genetic studies have yet to characterize whether allelic differences that exist between races contribute to this gap. In this study, biometrical genetic models are applied to a large mixed-race sample consisting of 733,339 births to measure the extent that heritable factors and environmental exposures predict the timing of birth and explain differences between racial groups. Although we expected significant differences in mean gestational age between racial groups, we did not anticipate the variance of gestational age in African Americans (σ2 = 7.097) to be nearly twice that of European Americans (σ2 = 3.764). Our results show that this difference in the variance of gestational age can largely be attributed to environmental sources; which were 3.1 times greater in African Americans. Specifically, environmental factors that change between pregnancies, versus exposures that influence all pregnancies within a family, are largely responsible for the increased reproductive heterogeneity observed in African American mothers. Although the contribution of both fetal and maternal genetic factors differed between race categories, genetic studies may best be directed to understanding the differences in the socio-cultural sources of this heterogeneity, and their possible interaction with genetic differences within and between races. This study provides a comprehensive description of the relative genetic and environmental contributions to racial differences in gestational age

Modeling Longitudinal Change in Cervical Length Across Pregnancy

Introduction: A short cervix (cervical length \u3c 25 mm) in the mid-trimester (18 to 24 weeks) of pregnancy is a powerful predictor of spontaneous preterm delivery (gestational age at delivery \u3c 37 weeks). Although the biological mechanisms of cervical remodeling have been the subject of extensive investigation, very little is known about the rate of change in cervical length over the course of a pregnancy, or the extent to which rapid cervical shortening increases maternal risk for spontaneous preterm delivery. Methods: A cohort of 5,160 unique women carrying 5,971 singleton pregnancies provided two or more measurements of cervical length during pregnancy. Cervical length was measured in millimeters using a transvaginal 12-3 MHz ultrasound endocavity probe (SuperSonic Imagine). Maternal characteristics, including relevant medical history and birth outcome data, were collected for each participant. Gestational age at delivery was measured from the first day of each woman’s last menstrual period and confirmed by ultrasound. Repeated measurements of cervical length during pregnancy were modeled as a longitudinal, multilevel growth curve in MPlus. A three-level variance structure was used to account for non-independence of repeated measurements clustered within pregnancies, which are clustered within participants. Results: The average number of cervical length measurements per pregnancy is 6. Shorter mid-trimester cervical lengths and accelerated rates of cervical shortening are associated with shorter gestational duration. A smaller initial cervical length (p \u3c 1*10-4) and a faster rate of change in cervical change length during pregnancy (p \u3c 1*10-4) are significantly associated with an earlier gestational age at delivery. A higher pre-pregnancy body mass index (BMI) is associated with shorter initial cervical length in early pregnancy (p \u3c 1*10-4), while maternal age is associated with a more rapid rate of change in cervical length (p \u3c 1*10-4). Parameters describing cervical length and its rate change during pregnancy (i.e., intercept, linear slope, and quadratic slope parameters) explained 59% more variance in gestational age at delivery than a single mid-rimester cervical length measurement, which is the current gold standard in clinical practice. However, a significant amount of residual variance in individual estimates of cervical length growth parameters remains (p \u3c 1*10-4), which could be accounted for, in part, by common variation in the population. Conclusion: We have developed longitudinal models of cervical length that describe individual and group level trajectories of cervical change across pregnancy. Extensions of this model incorporating genomic data, can be used to estimate the heritability of cervical length and its role in mediating the timing of birth.https://scholarscompass.vcu.edu/gradposters/1141/thumbnail.jp

Prospective Longitudinal Study of the Pregnancy DNA Methylome: The US Pregnancy, Race, Environment, Genes (PREG) Study

Purpose The goal of the Pregnancy, Race, Environment, Genes study was to understand how social and environmental determinants of health (SEDH), pregnancy-specific environments (PSE) and biological processes influence the timing of birth and account for the racial disparity in preterm birth. The study followed a racially diverse longitudinal cohort throughout pregnancy and included repeated measures of PSE and DNA methylation (DNAm) over the course of gestation and up to 1 year into the postpartum period. Participants All women were between 18 and 40 years of age with singleton pregnancies and no diagnosis of diabetes or indication of assisted reproductive technology. Both mother and father had to self-identify as either African-American (AA) or European-American (EA). Maternal peripheral blood samples along with self-report questionnaires measuring SEDH and PSE factors were collected at four pregnancy visits, and umbilical cord blood was obtained at birth. A subset of participants returned for two additional postpartum visits, during which additional questionnaires and maternal blood samples were collected. The pregnancy and postpartum extension included n=240 (AA=126; EA=114) and n=104 (AA=50; EA=54), respectively. Findings to date One hundred seventy-seven women (AA=89, EA=88) met full inclusion criteria out of a total of 240 who were initially enrolled. Of the 63 participants who met exclusion criteria after enrolment, 44 (69.8%) were associated with a medical reason. Mean gestational age at birth was significantly shorter for the AA participants by 5.1 days (M=272.5 (SD=10.5) days vs M=277.6 (SD=8.3)). Future plans Future studies will focus on identifying key environmental factors that influence DNAm change across pregnancy and account for racial differences in preterm birth

Continuum and Emission-Line Properties of Broad Absorption Line Quasars

We investigate the continuum and emission-line properties of 224 broad absorption line quasars (BALQSOs) with 0.9<z<4.4 drawn from the Sloan Digital Sky Survey (SDSS) Early Data Release (EDR), which contains 3814 bona fide quasars. We find that low-ionization BALQSOs (LoBALs) are significantly reddened as compared to normal quasars, in agreement with previous work. High-ionization BALQSOs (HiBALs) are also more reddened than the average nonBALQSO. Assuming SMC-like dust reddening at the quasar redshift, the amount of reddening needed to explain HiBALs is E(B-V)~0.023 and LoBALs is E(B-V)~0.077 (compared to the ensemble average of the entire quasar sample). We find that there are differences in the emission-line properties between the average HiBAL, LoBAL, and nonBAL quasar. These differences, along with differences in the absorption line troughs, may be related to intrinsic quasar properties such as the slope of the intrinsic (unreddened) continuum; more extreme absorption properties are correlated with bluer intrinsic continua. Despite the differences among BALQSO sub-types and nonBALQSOs, BALQSOs appear to be drawn from the same parent population as nonBALQSOs when both are selected by their UV/optical properties. We find that the overall fraction of traditionally defined BALQSOs, after correcting for color-dependent selection effects due to different SEDs of BALQSO and nonBALQSOs, is 13.4+/-1.2% and shows no significant redshift dependence for 1.7<z<3.45. After a rough completeness correction for the effects of dust extinction, we find that approximately one in every six quasars is a BALQSO.Comment: 35 pages, 11 figures (1 color), 1 table; accepted by A

Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study

<p>Abstract</p> <p>Background</p> <p>Preeclampsia affects 3-8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This complex disorder is characterized by alterations in the immune and vascular systems and involves multiple organs. There is strong evidence for a genetic contribution to preeclampsia. Two different single nucleotide polymorphisms (SNPs) in the <it>endoplasmic reticulum aminopeptidase 2 (ERAP2) </it>gene were recently reported to be associated with increased risk for preeclampsia in two different populations. <it>ERAP2 </it>is expressed in placental tissue and it is involved in immune responses, inflammation, and blood pressure regulation; making it is an attractive preeclampsia candidate gene. Furthermore, <it>ERAP2 </it>expression is altered in first trimester placentas of women destined to develop preeclampsia.</p> <p>Methods</p> <p>A case-control design was used to test for associations between two SNPs in <it>ERAP2</it>, rs2549782 and rs17408150, and preeclampsia status in 1103 Chilean maternal-fetal dyads and 1637 unpaired African American samples (836 maternal, 837 fetal).</p> <p>Results</p> <p>We found that the fetal minor allele (G) of rs2549782 was associated with an increased risk for preeclampsia in the African American population (<it>P </it>= 0.009), but not in the Chilean population. We found no association between rs17408150 and risk for preeclampsia in the Chilean population. Association between rs17408150 and risk for preeclampsia was not tested in the African American population due to the absence of the minor allele in this population.</p> <p>Conclusions</p> <p>We report an association between fetal <it>ERAP2 </it>and preeclampsia in an African American population. In conjunction with previous studies, which have found maternal associations with this gene in an Australian/New Zealand population and a Norwegian population, <it>ERAP2 </it>has now been associated with preeclampsia in three populations. This provides strong evidence that <it>ERAP2 </it>plays a role in the development of preeclampsia.</p

Epigenetic Alterations and an Increased Frequency of Micronuclei in Women with Fibromyalgia

Fibromyalgia (FM), characterized by chronic widespread pain, fatigue, and cognitive/mood disturbances, leads to reduced workplace productivity and increased healthcare expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM () to those seen in comparably aged healthy controls ( (MN); (methylation)). The mean (sd) MN frequency of women with FM (51.4 (21.9)) was significantly higher than that of controls (15.8 (8.5)) (; df = 1; ). Significant differences ( sites) in methylation patterns were observed between cases and controls considering a 5% false discovery rate. The majority of differentially methylated (DM) sites (91%) were attributable to increased values in the women with FM. The DM sites included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. Results support the need for future research to further examine the potential role of epigenetic and acquired chromosomal alterations as a possible biological mechanism underlying FM

4D In-Situ Microscopy of Aerosol Filtration in a Wall Flow Filter

The transient nature of the internal pore structure of particulate wall flow filters, caused by the continuous deposition of particulate matter, makes studying their flow and filtration characteristics challenging. In this article we present a new methodology and first experimental demonstration of time resolved in-situ synchrotron micro X-ray computed tomography (micro-CT) to study aerosol filtration. We directly imaged in 4D (3D plus time) pore scale deposits of TiO2 nanoparticles (nominal mean primary diameter of 25 nm) with a pixel resolution of 1.6 μm. We obtained 3D tomograms at a rate of ∼1 per minute. The combined spatial and temporal resolution allows us to observe pore blocking and filling phenomena as they occur in the filter’s pore space. We quantified the reduction in filter porosity over time, from an initial porosity of 0.60 to a final porosity of 0.56 after 20 min. Furthermore, the penetration depth of particulate deposits and filtration rate was quantified. This novel image-based method offers valuable and statistically relevant insights into how the pore structure and function evolves during particulate filtration. Our data set will allow validation of simulations of automotive wall flow filters. Evolutions of this experimental design have potential for the study of a wide range of dry aerosol filters and could be directly applied to catalysed automotive wall flow filters

The Cluster Mass Function from Early SDSS Data: Cosmological Implications

The mass function of clusters of galaxies is determined from 400 deg^2 of early commissioning imaging data of the Sloan Digital Sky Survey; ~300 clusters in the redshift range z = 0.1 - 0.2 are used. Clusters are selected using two independent selection methods: a Matched Filter and a red-sequence color magnitude technique. The two methods yield consistent results. The cluster mass function is compared with large-scale cosmological simulations. We find a best-fit cluster normalization relation of sigma_8*omega_m^0.6 = 0.33 +- 0.03 (for 0.1 ~< omega_m ~< 0.4), or equivalently sigma_8 = (0.16/omega_m)^0.6. The amplitude of this relation is significantly lower than the previous canonical value, implying that either omega_m is lower than previously expected (omega_m = 0.16 if sigma_8 = 1) or sigma_8 is lower than expected (sigma_8 = 0.7 if omega_m = 0.3). The best-fit mass function parameters are omega_m = 0.19 (+0.08,-0.07) and sigma_8 = 0.9 (+0.3,-0.2). High values of omega_m (>= 0.4) and low sigma_8 (=~ 2 sigma.Comment: AASTeX, 25 pages, including 7 figures, accepted for publication in ApJ, vol.585, March 200