Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care(1) or hospitalization(2-4) after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.Peer reviewe

Understanding discrepancies in parent-child reporting of emotional and behavioural problems: Effects of relational and socio-demographic factors

<p>Abstract</p> <p>Background</p> <p>Discrepancies between parents and children in their assessment of children's mental health affect the evaluation of need for services and must be taken seriously. This article presents the differences between parents' and children's reports of the children's symptoms and social impairment, based on the results of the Strengths and Difficulties Questionnaire (SDQ). The interrelationship between relational aspects and socio-demographic factors with patterns of disagreement are explored.</p> <p>Methods</p> <p>Differences in the prevalence and means of SDQ symptom and impact scores were obtained from 8,154 primary school children, aged between 10 and 13 years, and their parents. Agreement between matched pairs was measured using Pearson's and Spearman's rho correlations. Socio-demographic variables, communication patterns and parental engagement were analysed as possible correlates of informant discrepancies using bivariate and multivariate logistic regression models.</p> <p>Results</p> <p>In general, although children reported more symptoms, they reported less impact of perceived difficulties than parents. The parents were more consistent in their evaluation of symptoms and impact than were the children. Exploration of highly discrepant subgroups showed that, when children reported the most symptoms and impact, qualitative aspects of the parent-child relationship and family structure seemed to be more powerful predictors of disagreement than were gender of the child and socio-demographic variables. When parents reported the most symptoms and impact, low parental educational level, low income and male gender of the child played an additional role.</p> <p>Conclusions</p> <p>Our findings underline the importance of paying attention to child reports of emotional-behavioural difficulties, particularly when parents do not identify these problems. Considerations on what meaning parent-child discrepancy might have in the context of the parent-child relationship or the family's psychosocial status should be integrated in the overall understanding of the child's situation and subsequent recommendations.</p

Comparing three short questionnaires to detect psychosocial dysfunction among primary school children: a randomized method

BACKGROUND: Good questionnaires are essential to support the early identification of children with psychosocial dysfunction in community based settings. Our aim was to assess which of three short questionnaires was most suitable for this identification among school-aged children METHODS: A community-based sample of 2,066 parents of children aged 7-12 years (85% of those eligible) filled out the Child Behavior Checklist (CBCL) and - randomly determined - one of three questionnaires to be compared: the Strengths and Difficulties Questionnaire with Impact Supplement (SDQ), the Pediatric Symptom Checklist (PSC) and the PSYBOBA, a Dutch-origin questionnaire. Preventive Child Healthcare professionals assessed children's psychosocial functioning during routine health examinations. We assessed the scale structure (by means of Structural Equation Modelling), validity (correlation coefficients, sensitivity and specificity) and usability (ratings by parents and professionals) of each questionnaire and the degree to which they could improve the identification based only on clinical assessment (logistic regression). RESULTS: For the three questionnaires, Cronbach's alphas varied between 0.80 and 0.89. Sensitivities for a clinical CBCL at a cut off point with specificity = 0.90 varied between 0.78 and 0.86 for the three questionnaires. Areas under the Receiver Operating Curve, using the CBCL as criterion, varied between 0.93 and 0.96. No differences were statistically significant. All three questionnaires added information to the clinical assessment. Odds ratios (95% confidence intervals) for added information were PSC: 29.3 (14.4-59.8), SDQ: 55.0 (23.1-131.2) and PSYBOBA: 68.5 (28.3-165.6). Parents preferred the SDQ and PSYBOBA. Preventive Child Health Care professionals preferred the SDQ. CONCLUSIONS: This randomized comparison of three questionnaires shows that each of the three questionnaires can improve the detection of psychosocial dysfunction among children substantially

Common origin of the gelsolin gene variant in 62 Finnish AGel amyloidosis families

Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326–124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.Peer reviewe

Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration

Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1 alpha in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1 alpha dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1 alpha dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD.Peer reviewe

New evidence of factor structure and measurement invariance of the SDQ across five European nations

The main purpose of the present study was to test the internal structure and to study the measurement invariance of the Strength and Difficulties Questionnaire (SDQ), self-reported version, in five European countries. The sample consisted of 3012 adolescents aged between 12 and 17 years (M = 14.20; SD = 0.83). The five-factor model (with correlated errors added), and the five-factor model (with correlated errors added) with the reverse-worded items allowed to cross-load on the Prosocial subscale, displayed adequate goodness of-fit indices. Multi-group confirmatory factor analysis showed that the five-factor model had partial strong measurement invariance by countries. A total of 11 of the 25 items were non-invariant across samples. The level of internal consistency of the Total difficulties scores was .84, ranging between .69 and .78 for the SDQ subscales. The findings indicate that the SDQ's scales need to be modified in various ways for screening emotional and behavioural problems in the five European countries that were analyzed

Validity and Reliability of the Strengths and Difficulties Questionnaire in 5–6 Year Olds: Differences by Gender or by Parental Education?

Introduction: The Strengths and Difficulties Questionnaire (SDQ) is a relatively short instrument developed to detect psychosocial problems in children aged 3-16 years. It addresses four dimensions: emotional problems, conduct problems, hyperactivity/inattention problems, peer problems that count up to the total difficulties score, and a fifth dimension; prosocial behaviour. The validity and reliability of the SDQ has not been fully investigated in younger age groups. Therefore, this study assesses the validity and reliability of the parent and teacher versions of the SDQ in children aged 5-6 years in the total sample, and in subgroups according to child gender and parental education level. Methods: The SDQ was administered as part of the Dutch regularly provided preventive health check for children aged 5-6 years. Parents provided information on 4750 children and teachers on 4516 children. Results: Factor analyses of the parent and teacher SDQ confirmed that the original five scales were present (parent RMSEA = 0.05; teacher RMSEA = 0.07). Interrater correlations between parents and teachers were small (ICCs of 0.21-0.44) but comparable to what is generally found for psychosocial problem assessments in children. These correlations were larger for males than for females. Cronbach's alphas for the total difficulties score were 0.77 for the parent SDQ and 0.81 for the teacher SDQ. Four of the subscales on the parent SDQ and two of the subscales on the teacher SDQ had an alpha <0.70. Alphas were generally higher for male children and for low parental education level. Discussion: The validity and reliability of the total difficulties score of the parent and teacher SDQ are satisfactory in all groups by informant, child gender, and parental education level. Our results support the use of the SDQ in younger age groups. However, some subscales are less reliable and we recommend only to use the total difficulties score for screening purposes

Psychometric Properties of the Parent and Teacher Versions of the Strengths and Difficulties Questionnaire for 4- to 12-Year-Olds: A Review

Since its development, the Strengths and Difficulties Questionnaire (SDQ) has been widely used in both research and practice. The SDQ screens for positive and negative psychological attributes. This review aims to provide an overview of the psychometric properties of the SDQ for 4- to 12-year-olds. Results from 48 studies (N = 131,223) on reliability and validity of the parent and teacher SDQ are summarized quantitatively and descriptively. Internal consistency, test–retest reliability, and inter-rater agreement are satisfactory for the parent and teacher versions. At subscale level, the reliability of the teacher version seemed stronger compared to that of the parent version. Concerning validity, 15 out of 18 studies confirmed the five-factor structure. Correlations with other measures of psychopathology as well as the screening ability of the SDQ are sufficient. This review shows that the psychometric properties of the SDQ are strong, particularly for the teacher version. For practice, this implies that the use of the SDQ as a screening instrument should be continued. Longitudinal research studies should investigate predictive validity. For both practice and research, we emphasize the use of a multi-informant approach

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types