Microarray-Based Maps of Copy-Number Variant Regions in European and Sub-Saharan Populations

The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies. Here we provide a cross-population, microarray-based map of copy-number variant regions (CNVRs) to enable reliable interpretation of CNV association findings. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to scan the genomes of 1167 individuals from two ethnically distinct populations (Europe, N = 717; Rwanda, N = 450). Three different CNV-finding algorithms were tested and compared for sensitivity, specificity, and feasibility. Two algorithms were subsequently used to construct CNVR maps, which were also validated by processing subsamples with additional microarray platforms (Illumina 1M-Duo BeadChip, Nimblegen 385K aCGH array) and by comparing our data with publicly available information. Both algorithms detected a total of 42669 CNVs, 74% of which clustered in 385 CNVRs of a cross-population map. These CNVRs overlap with 862 annotated genes and account for approximately 3.3% of the haploid human genome

An improved synthesis for obtaining 2-deoxy-2-iodo-D-mannopyranose derivatives

The aim of this work was to synthesize 2-deoxy-2-iodo-manno sugars and 2-deoxy-2-iodo manno esters of a satisfactory purity in the highest possible yield. For this put-pose, the iodination reaction of D-glucal triacetate (1), 3,4-di-O-acetyl-6-O-to-syl-D-glucal (2) and 3,4-di-O-acetyl-6-S-acetyl-6-thio-D-glucal (3) were investigated using a mixture of NaIO4-NaI at pH 6 (acetate buffer) and pH 7 (phosphate buffer) in a tert-butanol-water solvent system. Depending on the buffer system used, a mixture of the 2-deoxy-2-iodo-manno esters 4, 6 or 8 together with corresponding 2-deoxy-2-iodo sugars 5, 7, or 9 were obtained, or separately

An improved synthesis for obtaining 2-deoxy-2-iodo-D-mannopyranose derivatives

The aim of this work was to synthesize 2-deoxy-2-iodo-manno sugars and 2-deoxy-2-iodo manno esters of a satisfactory purity in the highest possible yield. For this put-pose, the iodination reaction of D-glucal triacetate (1), 3,4-di-O-acetyl-6-O-to-syl-D-glucal (2) and 3,4-di-O-acetyl-6-S-acetyl-6-thio-D-glucal (3) were investigated using a mixture of NaIO4-NaI at pH 6 (acetate buffer) and pH 7 (phosphate buffer) in a tert-butanol-water solvent system. Depending on the buffer system used, a mixture of the 2-deoxy-2-iodo-manno esters 4, 6 or 8 together with corresponding 2-deoxy-2-iodo sugars 5, 7, or 9 were obtained, or separately

Tooth Loss and Survival Analysis after Traumatic Injuries in Primary Dentition

Background/Aim: The aim of the present study was to investigate the treatment options, survival rate of traumatized primary teeth and evaluate the factors influencing the outcome. Material and Methods: The sample consisted of all dental trauma cases treated over a 14 years period at the Department of Pediatric and Preventive Dentistry, Dental Clinic of Vojvodina, Novi Sad. Criteria for inclusion in this study were: dental trauma to primary teeth and age in the moment of injury up to seven years. Dental trauma records were analyzed in order to obtain the following: gender and age of the child at the time of trauma, type of trauma, as well as the type and timing of treatment received. After data analysis a survival rate of traumatized primary teeth was evaluated. Results: The study was designed as retrospective and it included 225 children, with 346 traumatized primary teeth. The occurrence of trauma was higher in male patients (60,4%) and in children up to 4 years of age. Luxations were more frequent (72.8%) compared to isolated teeth fractures (20.8%), while the two types of injury combined were rare (6,3%). One year following dental trauma 231 teeth (0.67%) developed complications. Falls were the main cause of trauma (68.9%) and the presence of more than one traumatized tooth was frequent. A percentage of 48.8 children received dental care during first 24 h after the injury. Conclusions: Survival of injured primary teeth is relatively low, regardless of trauma type, time interval between injury and treatment and the type of provided treatment

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma : Results from two independent African cohorts

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.publishe

Genetic variation is associated with PTSD risk and aversive memory : Evidence from two trauma-Exposed African samples and one healthy European sample

The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.publishe

DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers

Carleial S, Natt D, Unternaehrer E, et al. DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers. SCIENTIFIC REPORTS. 2021;11: 18493.The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma

Epigenetics of traumatic stress: The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy

Abstract Epigenetic processes allow plasticity in gene regulation in response to significant environmental events. Accumulating evidence suggests that effective psychotherapy is accompanied by epigenetic changes, rendering DNA methylation a potential biomarker of therapy success. Due to the central role of glucocorticoid dynamics in stress regulation and the alteration of aversive memories, glucocorticoid receptors are likely involved in the molecular processes that are required to successfully treat Posttraumatic Stress Disorder (PTSD). This study aimed to investigate the relationship between methylation at the glucocorticoid receptor gene (NR3C1) and PTSD treatment success of evidence-based psychotherapy. A sample of N = 153 conflict survivors from Northern Uganda (98 females and 55 males) with PTSD were treated with Narrative Exposure Therapy (NET). Diagnostic interviews and saliva sampling took place at pretreatment and 4 and 10 months after treatment completion. We investigated potential associations between PTSD symptom development and methylation changes at 38 CpG sites spanning NR3C1 over the three times of measurement using the repeated measures correlation. After accounting for multiple comparisons, DNA methylation at CpG site cg25535999 remained negatively associated with PTSD symptoms. These results were followed up by mixed models as well as structural equation modelling. These analyses revealed that treatment responders had a significant cg25535999 methylation increase after treatment with NET. Furthermore, lower methylation at cg25535999 pretreatment predicted a higher symptom improvement. Our results suggest different epigenetic profile dynamics at NR3C1 cg25535999 in therapy responders compared to non-responders and underscore the central role of glucocorticoid signaling in trauma-focused therapy

NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors

Vukojevic V, Coynel D, Ghaffari NR, et al. NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(35):21667-21672.Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N; 1; = 924) and Rwanda (N; 2; = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (p; uncorrected; = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (p; uncorrected; = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (p; corrected; = 0.003) and NOTCH receptor processing (p; corrected; = 0.01). The environmental factor trauma load was significant in all analyses (all p &lt; 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies