| 1. |
- Ip, H. F., et al.
(författare)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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| 2. |
- Kirişli, Hortense, et al.
(författare)
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Standardized evaluation framework for evaluating coronary artery stenosis detection, stenosis quantification and lumen segmentation algorithms in computed tomography angiography
- 2013
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Ingår i: Medical Image Analysis. - : Elsevier. - 1361-8415 .- 1361-8423. ; 17:8, s. 859-876
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Tidskriftsartikel (refereegranskat)abstract
- Though conventional coronary angiography (CCA) has been the standard of reference for diagnosing coronary artery disease in the past decades, computed tomography angiography (CIA) has rapidly emerged, and is nowadays widely used in clinical practice. Here, we introduce a standardized evaluation framework to reliably evaluate and compare the performance of the algorithms devised to detect and quantify the coronary artery stenoses, and to segment the coronary artery lumen in CIA data. The objective of this evaluation framework is to demonstrate the feasibility of dedicated algorithms to: (I) (semi-)automatically detect and quantify stenosis on CIA, in comparison with quantitative coronary angiography (QCA) and CIA consensus reading, and (2) (semi-)automatically segment the coronary lumen on CIA, in comparison with expert's manual annotation. A database consisting of 48 multicenter multivendor cardiac CIA datasets with corresponding reference standards are described and made available. The algorithms from 11 research groups were quantitatively evaluated and compared. The results show that (1) some of the current stenosis detection/quantification algorithms may be used for triage or as a second-reader in clinical practice, and that (2) automatic lumen segmentation is possible with a precision similar to that obtained by experts. The framework is open for new submissions through the website, at http://coronary.bigr.nl/stenoses/.
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| 3. |
- Jami, E. S., et al.
(författare)
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Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms
- 2022
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Ingår i: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier BV. - 0890-8567 .- 1527-5418. ; 61:7, s. 934-945
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.
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| 4. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 5. |
- Alfayez, E, et al.
(författare)
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DAR 16-II Primes Endothelial Cells for Angiogenesis Improving Bone Ingrowth in 3D-Printed BCP Scaffolds and Regeneration of Critically Sized Bone Defects
- 2022
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- Bone is a highly vascularized tissue and relies on the angiogenesis and response of cells in the immediate environmental niche at the defect site for regeneration. Hence, the ability to control angiogenesis and cellular responses during osteogenesis has important implications in tissue-engineered strategies. Self-assembling ionic-complementary peptides have received much interest as they mimic the natural extracellular matrix. Three-dimensional (3D)-printed biphasic calcium phosphate (BCP) scaffolds coated with self-assembling DAR 16-II peptide provide a support template with the ability to recruit and enhance the adhesion of cells. In vitro studies demonstrated prompt the adhesion of both human umbilical vein endothelial cells (HUVEC) and human mesenchymal stem cells (hMSC), favoring endothelial cell activation toward an angiogenic phenotype. The SEM-EDS and protein micro bicinchoninic acid (BCA) assays demonstrated the efficacy of the coating. Whole proteomic analysis of DAR 16-II-treated HUVECs demonstrated the upregulation of proteins involved in cell adhesion (HABP2), migration (AMOTL1), cytoskeletal re-arrangement (SHC1, TMOD2), immuno-modulation (AMBP, MIF), and morphogenesis (COL4A1). In vivo studies using DAR-16-II-coated scaffolds provided an architectural template, promoting cell colonization, osteogenesis, and angiogenesis. In conclusion, DAR 16-II acts as a proactive angiogenic factor when adsorbed onto BCP scaffolds and provides a simple and effective functionalization step to facilitate the translation of tailored 3D-printed BCP scaffolds for clinical applications.
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| 6. |
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| 7. |
- Neumann, A, et al.
(författare)
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A genome-wide association study of total child psychiatric problems scores
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:8, s. e0273116-
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Tidskriftsartikel (refereegranskat)abstract
- Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
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