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Work 1-7 of 7

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Article

Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder.

by Z Kaminsky; H C Wilcox; W W Eaton; K Van Eck; V Kilaru; Tanja Jovanovic; Torsten Klengel; Bekh Bradley-Davino; Elisabeth Binder; Kerry Ressler; Alicia Smith

2015

Subjects
  • Health Sciences, Mental Health
  • Health Sciences, General
  • File Download
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Abstract:Close

Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P=0.003, and CI: 0.65-0.78, P<0.0001) and to mediate the suppression of cortisol following DST (β=0.5±0.19, F=1.51, degrees of freedom (df)=12/167, P=0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.

Article

Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial

by Vasiliki Michopoulos; Fulvia Mancini; Tammy L Loucks; Sarah L. Berga

2013

Subjects
  • Health Sciences, Obstetrics and Gynecology
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

Objective: To determine whether cognitive behavior therapy (CBT), which we had shown in a previous study to restore ovarian function in women with functional hypothalamic amenorrhea (FHA), could also ameliorate hypercortisolemia and improve other neuroendocrine and metabolic concomitants of in FHA. Design: Randomized controlled trial. Setting: Clinical research center at an academic medical university. Patient(s): Seventeen women with FHA were randomized either to CBT or observation. Intervention(s): CBT versus observation. Main Outcome Measure(s): Circulatory concentrations of cortisol, leptin, thyroid-stimulating hormone (TSH), total and free thyronine (T 3 ), and total and free thyroxine (T 4 ) before and immediately after completion of CBT or observation. (Each woman served as her own control.) Result(s): Cognitive behavior therapy but not observation reduced cortisol levels in women with FHA. There were no changes in cortisol, leptin, TSH, T 3 , or T 4 levels in women randomized to observation. Women treated with CBT showed increased levels of leptin and TSH, but their levels of T 3 and T 4 remained unchanged. Conclusion(s): In women with FHA, CBT ameliorated hypercortisolism and improved the neuroendocrine and metabolic concomitants of FHA while observation did not. We conclude that a cognitive, nonpharmacologic approach aimed at alleviating problematic attitudes not only can restore ovarian activity but also improve neuroendocrine and metabolic function in women with FHA.

Article

An epigenetic clock for gestational age at birth based on blood methylation data

by Anna K. Knight; Jeffrey M. Craig; Christiane Theda; Marie Bækvad-Hansen; Jonas Bybjerg-Grauholm; Christine S. Hansen; Mads V. Hollegaard; David M. Hougaard; Preben B. Mortensen; Shantel M. Weinsheimer; Thomas M. Werge; Patricia Brennan; Joseph Cubells; D. Jeffrey Newport; Zachary N. Stowe; Jeanie L.Y. Cheong; Philippa Dalach; Lex W. Doyle; Yuk J. Loke; Andrea A. Baccarelli; Allan C. Just; Robert O. Wright; Mara M. Tellez-Rojo; Katherine Svensson; Letizia Trevisi; Elizabeth M. Kennedy; Elisabeth B. Binder; Stella Iurato; Darina Czamara; Katri Räikkönen; Jari M.T. Lahti; Anu-Katriina Pesonen; Eero Kajantie; Pia M. Villa; Hannele Laivuori; Esa Hämäläinen; Hea Jin Park; Lynn B. Bailey; Sasha E. Parets; Varun Kilaru; Ramkumar Menon; Steve Horvath; Nicole R. Bush; Kaja Z. LeWinn; Frances A. Tylavsky; Karen Conneely; Alicia K Smith

2016

Subjects
  • Biology, Genetics
  • Health Sciences, General
  • Health Sciences, Obstetrics and Gynecology
  • File Download
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Abstract:Close

Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.

Article

Advances in the genetics of endometriosis

by Erica C Dun; Robert N Taylor; Fritz Wieser

2010

Subjects
  • Health Sciences, Obstetrics and Gynecology
  • Health Sciences, General
  • Biology, Genetics
  • View on PubMed Central
  • View Abstract

Abstract:Close

Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes.

Article

Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type

by Alicia K Smith; Varun Kilaru; Mehmet Kocak; Lynn M Almli; Kristina B Mercer; Kerry Ressler; Frances A Tylavsky; Karen N Conneely

2014

Subjects
  • Health Sciences, General
  • Psychology, General
  • File Download
  • View Abstract

Abstract:Close

Background Individual genotypes at specific loci can result in different patterns of DNA methylation. These methylation quantitative trait loci (meQTLs) influence methylation across extended genomic regions and may underlie direct SNP associations or gene-environment interactions. We hypothesized that the detection of meQTLs varies with ancestral population, developmental stage, and tissue type. We explored this by analyzing seven datasets that varied by ancestry (African American vs. Caucasian), developmental stage (neonate vs. adult), and tissue type (blood vs. four regions of postmortem brain) with genome-wide DNA methylation and SNP data. We tested for meQTLs by constructing linear regression models of methylation levels at each CpG site on SNP genotypes within 50 kb under an additive model controlling for multiple tests. Results Most meQTLs mapped to intronic regions, although a limited number appeared to occur in synonymous or nonsynonymous coding SNPs. We saw significant overlap of meQTLs between ancestral groups, developmental stages, and tissue types, with the highest rates of overlap within the four brain regions. Compared with a random group of SNPs with comparable frequencies, meQTLs were more likely to be 1) represented among the most associated SNPs in the WTCCC bipolar disorder results and 2) located in microRNA binding sites. Conclusions These data give us insight into how SNPs impact gene regulation and support the notion that peripheral blood may be a reliable correlate of physiological processes in other tissues.

Article

Relationship between Epigenetic Maturity and Respiratory Morbidity in Preterm Infants

by Anna Knight; Alicia Smith; Karen Conneely; Philippa Dalach; Yuk J. Loke; Jeanie L. Cheong; Peter G. Davis; Jeffrey M. Craig; Lex W. Doyle; Christiane Theda

2018

Subjects
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

Objective: To assess associations between epigenetic maturity of extremely preterm babies (born at less than 28 weeks of gestation), neonatal interventions, and respiratory outcomes, including the administration of surfactant and postnatal corticosteroids, duration of assisted ventilation, and development of bronchopulmonary dysplasia (BPD). Study design: DNA was extracted from neonatal blood spots collected after birth from 143 extremely preterm infants born 1991-1992 in Victoria, Australia and used to determined DNA methylation (DNAm). A DNAm based gestational age was determined using our previously published method. The residual of DNAm gestational age and clinically estimated gestational age (referred to as “gestational age acceleration”) was used as a measure to assess developmental maturity. Associations between gestational age acceleration and respiratory interventions and morbidities were determined. Results: Infants with higher gestational age acceleration were less likely to receive surfactant (P =.009) or postnatal corticosteroids (P =.008), had fewer days of assisted ventilation (P =.01), and had less BPD (P =.02). Respiratory measures are known to correlate with gestational age; however, models comparing each with clinically estimated gestational age were improved by the addition of the gestational age acceleration measure in the model. Conclusions: Gestational age acceleration correlates with respiratory interventions and outcomes of extremely preterm babies. Surfactant and postnatal corticosteroid use, assisted ventilation days, and BPD rates were all lower in babies who were epigenetically more mature than their obstetrically estimated gestational age. This suggests that gestational age acceleration is a clinically relevant metric of developmental maturity.

Article

Perinatal outcomes in HIV positive pregnant women with concomitant sexually transmitted infections

by Erin Burnett; Tammy Loucks; Michael Lindsay

2015

Subjects
  • Health Sciences, General
  • File Download
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Abstract:Close

Objective. To evaluate whether HIV infected pregnant women with concomitant sexually transmitted infection (STIs) are at increased risk of adverse perinatal and neonatal outcomes. Methods. We conducted a cohort study of HIV positive women who delivered at an inner-city hospital in Atlanta, Georgia, from 2003 to 2013. Demographics, presence of concomitant STIs, prenatal care information, and maternal and neonatal outcomes were collected. The outcomes examined were the association of the presence of concomitant STIs on the risk of preterm birth (PTB), postpartum hemorrhage, chorioamnionitis, preeclampsia, intrauterine growth restriction, small for gestational age, low Apgar scores, and neonatal intensive care admission. Multiple logistic regression was performed to adjust for potential confounders. Results. HIV positive pregnant women with concomitant STIs had an increased risk of spontaneous PTB (odds ratio (OR) 2.11, 95% confidence interval [CI] 1.12-3.97). After adjusting for a history of preterm birth, maternal age, and low CD4+ count at prenatal care entry the association between concomitant STIs and spontaneous PTB persisted (adjusted OR 1.96, 95% CI 1.01-3.78). Conclusions. HIV infected pregnant women with concomitant STIs relative to HIV positive pregnant women without a concomitant STI are at increased risk of spontaneous PTB.
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