Coronary artery disease (CAD) is the leading global cause of mortality and has substantial heritability with a polygenic architecture. Recent approaches of risk prediction were based on polygenic ...risk scores (PRS) not taking possible nonlinear effects into account and restricted in that they focused on genetic loci associated with CAD, only. We benchmarked PRS, (penalized) logistic regression, naïve Bayes (NB), random forests (RF), support vector machines (SVM), and gradient boosting (GB) on a data set of 7,736 CAD cases and 6,774 controls from Germany to identify the algorithms for most accurate classification of CAD status. The final models were tested on an independent data set from Germany (527 CAD cases and 473 controls). We found PRS to be the best algorithm, yielding an area under the receiver operating curve (AUC) of 0.92 (95% CI 0.90, 0.95, 50,633 loci) in the German test data. NB and SVM (AUC ~ 0.81) performed better than RF and GB (AUC ~ 0.75). We conclude that using PRS to predict CAD is superior to machine learning methods.
Autophagy is an essential cellular process affecting virus infections and other diseases and Beclin1 (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 ...(SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions.
Background
The enduring impact of childhood maltreatment on biological systems and ensuing psychopathology remains incompletely understood. Long‐term effects of stress may be reflected in cumulative ...cortisol secretion over several months, which is now quantifiable via hair cortisol concentrations (HCC). We conducted a first comprehensive investigation utilizing the potential of hair cortisol analysis in a large sample of maltreated and nonmaltreated children and adolescents.
Method
Participants included 537 children and adolescents (3–16 years; 272 females) with maltreatment (n = 245) or without maltreatment histories (n = 292). Maltreated subjects were recruited from child protection services (CPS; n = 95), youth psychiatric services (n = 56), and the community (n = 94). Maltreatment was coded using the Maltreatment Classification System drawing on caregiver interviews and complemented with CPS records. Caregivers and teachers reported on child mental health. HCC were assessed in the first 3 cm hair segment.
Results
Analyses uniformly supported that maltreatment coincides with a gradual and dose‐dependent reduction in HCC from 9 to 10 years onwards relative to nonmaltreated controls. This pattern emerged consistently from both group comparisons between maltreated and nonmaltreated subjects (27.6% HCC reduction in maltreated 9–16‐year‐olds) and dimensional analyses within maltreated subjects, with lower HCC related to greater maltreatment chronicity and number of subtypes. Moreover, both group comparisons and dimensional analyses within maltreated youth revealed that relative HCC reduction mediates the effect of maltreatment on externalizing symptoms.
Conclusions
From middle childhood onwards, maltreatment coincides with a relative reduction in cortisol secretion, which, in turn, may predispose to externalizing symptoms.
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Background
There has been extensive research into adverse childhood experiences (ACEs), however, less consideration has been given to the prevalence and impact of ACEs for staff working with people ...with intellectual disabilities.
Method
Participants were staff employed by agencies that care for people with intellectual disabilities. An online survey collected demographic information and measures of ACEs, resilience, trauma‐informed organisational climate, burnout and secondary traumatic stress. Correlation, regression, mediation and moderation analyses were used.
Results
81.7% of 109 participants had experienced at least one ACE. Burnout, secondary traumatic stress and resilience were greater in the present study than in comparable samples. Trauma‐informed organisational climate significantly predicted burnout and secondary traumatic stress. Resilience significantly predicted burnout.
Conclusions
Staff working with people with intellectual disabilities are likely to have experienced ACEs. Working in a trauma‐informed organisational climate and resilience may be effective avenues for reducing burnout and secondary traumatic stress.
Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for ...homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this ...migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are ...warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10
) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p
= 0.05 in the training GWAS: OR = 1.231.16; 1.30 per standard deviation increase; p = 8 × 10
), bipolar disorder (1.531.44; 1.63; p = 1 × 10
), schizophrenia (1.361.28; 1.45; p = 4 × 10
), psychiatric cross-disorder susceptibility (1.231.16; 1.30; p = 3 × 10
), cortical thickness of the transverse temporal gyrus (0.900.86; 0.96; p = 5 × 10
), educational attainment (0.860.82; 0.91; p = 2 × 10
), and intelligence (0.720.68; 0.76; p = 9 × 10
). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
Social behavior is naturally occurring in vertebrate species, which holds a strong evolutionary component and is crucial for the normal development and survival of individuals throughout life. ...Behavioral neuroscience has seen different influential methods for social behavioral phenotyping. The ethological research approach has extensively investigated social behavior in natural habitats, while the comparative psychology approach was developed utilizing standardized and univariate social behavioral tests. The development of advanced and precise tracking tools, together with post-tracking analysis packages, has recently enabled a novel behavioral phenotyping method, that includes the strengths of both approaches. The implementation of such methods will be beneficial for fundamental social behavioral research but will also enable an increased understanding of the influences of many different factors that can influence social behavior, such as stress exposure. Furthermore, future research will increase the number of data modalities, such as sensory, physiological, and neuronal activity data, and will thereby significantly enhance our understanding of the biological basis of social behavior and guide intervention strategies for behavioral abnormalities in psychiatric disorders.
Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the ...impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.
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