The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely ...related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors.
Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD). Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle.
Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT). Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p.
(1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.
Tumor cells of classic Hodgkin lymphoma (cHL) are derived from antigen presenting B cells that are infected by Epstein Barr virus (EBV) in ~30% of patients. Polymorphic Killer cell ...immunoglobulin-like receptors (KIRs) expressed on NK cells interact with human leukocyte antigen (HLA) class I and play a key role in immune surveillance against virally infected cells and tumor cells. We investigated the effect of KIR types on cHL susceptibility overall (n=211) and in EBV-stratified subgroups using the Dutch GoNL cohort as controls (n=498). The frequency of the KIR haplotype B subgroup was significantly different between EBV+ and EBV- cHL patients (62% vs. 77%, p=0.04) and this difference was more pronounced in nodular sclerosis (NS) cHL (49% vs. 79%, p=0.0003). The frequency of KIR haplotype B subgroup was significantly lower in EBV+ NS cHL compared to controls (49% vs. 67%, p=0.01). Analyses of known KIR - HLA interaction pairs revealed lower carrier frequencies of
- HLA-C1 (29% vs. 46%, p=0.03) and
- HLA-C1 (29% vs. 45%, p=0.04) in EBV+ NS cHL patients compared to controls. Carriers of the KIR haplotype B subgroup are less likely to develop EBV+ NS cHL, probably because of a more efficient control over EBV-infected B cells.
Tumor cells in classic Hodgkin lymphoma produce high quantities of the thymus- and activation-related chemokine (TARC). We measured TARC levels in prediagnostic serum samples and found strikingly ...increased values in the vast majority of patients, up to >6 years before diagnosis.
Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected ...sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of “CHIP” and “CCUS.”
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•Spliceosome (SF3B1/SRSF2/U2AF1) and JAK2 mutated clones show highest growth rates•DNMT3A and TP53 mutated clones increase only marginally over time•Clonal expansion is independent of general cancer risk factors or cytopenia/cytosis•Spliceosome, TP53, JAK2, and K/NRAS mutations confer highest risk for myeloid cancer
Zeventer et al. report on longitudinal analyses of clonal hematopoiesis in 3,359 community-based individuals. Patterns of clonal evolution reveal large heterogeneity, irrespective of blood count abnormalities. Clonal expansion, patterns of sequential mutation acquisition, and the risk to develop myeloid malignancy are dependent on the specific mutated gene. The results warrant a gene-specific approach in the management of “CHIP” and “CCUS.”
Abstract
Background
It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to ...quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study.
Methods
We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λ
R
) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h
2
), shared environment, and genetic correlation (r
g
) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age
2
, and sex.
Results
Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λ
FDR
of 1.23 (95% CI 1.20–1.25) for hypertension to λ
FDR
of 2.48 (95% CI 2.15–2.86) for T2D. Most of these were higher than in spouses (λ
Spouses
< λ
FDR
), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h
2
CRP
: 0.26 to h
2
HDL
: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λ
FDR obesity-MetS
: 1.28 (95% CI 1.24–1.32) to λ
FDR MetS-T2D
: 1.61 (95% CI 1.52–1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from r
g HDL-Triglycerides
: − 0.53 to r
g LDL-Apolipoprotein B
: 0.94).
Conclusions
There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.
Despite the recent explosive rise in number of genetic markers for complex disease traits identified in genome-wide association studies, there is still a large gap between the known heritability of ...these traits and the part explained by these markers. To gauge whether this 'heritability gap' is closing, we first identified genome-wide significant SNPs from the literature and performed replication analyses for 32 highly relevant traits from five broad disease areas in 13 436 subjects of the Lifelines Cohort. Next, we calculated the variance explained by multi-SNP genetic risk scores (GRSs) for each trait, and compared it to their broad- and narrow-sense heritabilities captured by all common SNPs. The majority of all previously-associated SNPs (median=75%) were significantly associated with their respective traits. All GRSs were significant, with unweighted GRSs generally explaining less phenotypic variance than weighted GRSs, for which the explained variance was highest for height (15.5%) and varied between 0.02 and 6.7% for the other traits. Broad-sense common-SNP heritability estimates were significant for all traits, with the additive effect of common SNPs explaining 48.9% of the variance for height and between 5.6 and 39.2% for the other traits. Dominance effects were uniformly small (0-1.5%) and not significant. On average, the variance explained by the weighted GRSs accounted for only 10.7% of the common-SNP heritability of the 32 traits. These results indicate that GRSs may not yet be ready for accurate personalized prediction of complex disease traits limiting widespread adoption in clinical practice.
Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has ...been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.
Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.
Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 odds ratio (OR) = 0.64;
= 0.006 within the
gene, and for the T allele of rs35788393 (OR = 0.75;
= 0.041) located in the
gene. In the mitochondrial haplogroup analysis, the most significant
-value was reached by haplogroup K (
= 1.2 × 10
), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7-13.1).
We identified an association between POAG and polymorphisms in the mitochondrial genes
(rs2853496) and
(rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.
Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug ...metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses.
Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses.
No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects.
We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.
The aim of this retrospective clinical study was to determine the survival of extensive direct resin composite restorations after amalgam replacement on vital molars and premolars after a mean ...observation period of 15 years.
Between January 2007 and September 2013, a total of 117 extensive cusp replacing direct resin composite restorations were placed in 88 patients in a general dental practice. These were indicated for replacement of existing amalgam restorations. Tooth vitality, the absence of at least one cusp in premolars, and at least two cusps in molars were considered for inclusion. The long-term follow-up of the restorations, re-evaluated after up to 17 years using the original evaluation criteria is reported.
81 of 88 patients (92.1%) and 106 of 117 restorations (90.6%) were available for follow-up. The cumulative success rate was 62.0% (95% CI: 47.3–76.2, AFR 2.79%) after a mean observation time of 163.4 months, the cumulative survival rate was 74.7% (95% CI: 59.8–89.6%, AFR: 1.70%) after a mean observation time of 179.1 months. The number of cusps replaced in premolars had a statistically significant influence on the success and survival rate of the restorations (HR of respectively, 2.974 and 3.175, p = <0.0005). Premolars with two cusps replaced had 297% more chance of failure than premolars with one cusp replaced.
Extensive direct resin composite restorations placed after amalgam replacement showed good survival after a mean observation period of 15 years. The number of cusps involved had a statistically significant influence on the longevity of the restorations in premolars.
With good survival and low annual failure rates, direct resin composite restorations are a suitable treatment for repairing extensive defects in posterior teeth involving multiple cusps and surfaces, provided that they are placed by a dentist who has long experience and is skilled in the placement of direct composite materials.
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