Gene - maltreatment interplay in adult ADHD symptoms: main role of a gene-environment correlation effect in a Brazilian population longitudinal study.

Childhood maltreatment correlates with attention-deficit/hyperactivity disorder (ADHD) in previous research. The interaction between ADHD genetic predisposition and maltreatment's impact on ADHD symptom risk remains unclear. We aimed to elucidate this relationship by examining the interplay between a polygenic score for ADHD (ADHD-PGS) and childhood maltreatment in predicting ADHD symptoms during young adulthood. Using data from the 2004 Pelotas (Brazil) birth cohort comprising 4231 participants, we analyzed gene-environment interaction (GxE) and correlation (rGE). We further explored rGE mechanisms through mediation models. ADHD symptoms were assessed at age 18 via self-report (Adult Self Report Scale - ASRS) and mother-reports (Strength and Difficulties Questionnaire - SDQ). The ADHD-PGS was derived from published ADHD GWAS meta-analysis. Physical and psychological child maltreatment was gauged using the Parent-Child Conflict Tactics Scale (CTSPC) at ages 6 and 11, with a mean score utilized as a variable. The ADHD-PGS exhibited associations with ADHD symptoms on both ASRS (ß = 0.53; 95% CI: 0.03; 1.03, p = 0.036), and SDQ (ß = 0.20; 95% CI: 0.08; 0.32, p = 0.001) scales. The total mean maltreatment score was associated with ADHD symptoms using both scales [(ßASRS = 0.51; 95% CI: 0.26;0.77) and (ßSDQ = 0.24; 95% CI: 0.18;0.29)]. The ADHD-PGS was associated with total mean maltreatment scores (ß = 0.09; 95% CI: 0.01; 0.17; p = 0.030). Approximately 47% of the total effect of ADHD-PGS on maltreatment was mediated by ADHD symptoms at age 6. No evidence supported gene-environment interaction in predicting ADHD symptoms. Our findings underscore the significant roles of genetics and childhood maltreatment as predictors for ADHD symptoms in adulthood, while also indicating a potential evocative mechanism through gene-environment correlation.

Time Course of Mechanical Ventilation Driving Pressure Levels in Pediatric Acute Respiratory Distress Syndrome: Outcomes in a Prospective, Multicenter Cohort Study From Colombia, 2018-2022.

OBJECTIVES: High driving pressure (DP, ratio of tidal volume (V t ) over respiratory system compliance) is a risk for poor outcomes in patients with pediatric acute respiratory distress syndrome (PARDS). We therefore assessed the time course in level of DP (i.e., 24, 48, and 72 hr) after starting mechanical ventilation (MV), and its association with 28-day mortality. DESIGN: Multicenter, prospective study conducted between February 2018 and December 2022. SETTING: Twelve tertiary care PICUs in Colombia. PATIENTS: One hundred eighty-four intubated children with moderate to severe PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median (interquartile range [IQR]) age of the PARDS cohort was 11 (IQR 3-24) months. A total of 129 of 184 patients (70.2%) had a pulmonary etiology leading to PARDS, and 31 of 184 patients (16.8%) died. In the first 24 hours after admission, the plateau pressure in the nonsurvivor group, compared with the survivor group, differed (28.24 [IQR 24.14-32.11] vs. 23.18 [IQR 20.72-27.13] cm H 2 O, p < 0.01). Of note, children with a V t less than 8 mL/kg of ideal body weight had lower adjusted odds ratio (aOR [95% CI]) of 28-day mortality (aOR 0.69, [95% CI, 0.55-0.87]; p = 0.02). However, we failed to identify an association between DP level and the oxygenation index (aOR 0.58; 95% CI, 0.21-1.58) at each of time point. In a diagnostic exploratory analysis, we found that DP greater than 15 cm H 2 O at 72 hours was an explanatory variable for mortality, with area under the receiver operating characteristic curve of 0.83 (95% CI, 0.74-0.89); there was also increased hazard for death with hazard ratio 2.5 (95% CI, 1.07-5.92). DP greater than 15 cm H 2 O at 72 hours was also associated with longer duration of MV (10 [IQR 7-14] vs. 7 [IQR 5-10] d; p = 0.02). CONCLUSIONS: In children with moderate to severe PARDS, a DP greater than 15 cm H 2 O at 72 hours after the initiation of MV is associated with greater odds of 28-day mortality and a longer duration of MV. DP should be considered a variable worth monitoring during protective ventilation for PARDS.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.

Incidence of appendiceal neoplasms in appendectomy patients.

BACKGROUND: Non-operative management has been suggested as a therapy for uncomplicated appendicitis. Notwithstanding, the risk of missing an appendiceal tumor must be considered, being the surgical piece crucial to rule out neoplasms. Therefore, we aim to determine the incidence of appendiceal neoplasms in patients with acute appendicitis, tumor types and the importance of the anatomopathological study of the surgical piece. STUDY DESIGN: Retrospective study in which we described patients who underwent emergent appendectomy with histopathological findings of appendiceal neoplasms from January 2012 to September 2018. Descriptive analysis included demographic variables, diagnostic methods, and surgical techniques. RESULTS: 2993 patients diagnosed with acute appendicitis who underwent an emergency appendectomy. 64 neoplasms of the appendix were found with an incidence of 2,14%. 67.2% were women, the mean age was 46,4 years (± 19.5). The most frequent appendiceal neoplasms were neuroendocrine tumors (42,2%), followed by appendiceal mucinous neoplasms (35,9%), sessile serrated adenomas (18,8%), and adenocarcinomas (3,1%). In 89,1% of the cases, acute appendicitis was determined by imaging, and 14% of cases were suspected intraoperatively. Appendectomy was performed in 78,1% without additional procedures. CONCLUSIONS: Appendiceal tumors are rare and must be ruled out in patients with suspected acute appendicitis. The incidence of incidental neoplasms is higher in this study than in the previously reported series. This information must be included in decision-making when considering treatment options for acute appendicitis.

Allergy, asthma, and the risk of breast and prostate cancer: a Mendelian randomization study.

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).

A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study.

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93-1.06) per allele score. A 25 nmol·L-1 increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54-1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

Mendelian randomization does not support serum calcium in prostate cancer risk.

PURPOSE: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer. METHODS: A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls). RESULTS: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93). CONCLUSIONS: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

Influence of maternal and own genotype at tanning dependence-related SNPs on sun exposure in childhood.

BACKGROUND: Research suggests there may be a genetic influence on the likelihood of becoming tanning dependent (TD). The way in which mothers regulate their children's sun exposure may be affected by being TD. We investigated the associations between single nucleotide polymorphisms (SNPs) related to being TD and early sun exposure. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used. Associations between 17 TD related SNPs in children and their mothers and 10 sun exposure variables in children (assessed via questionnaire at age 8) were analyzed in logistic and ordinal logistic regressions. Analyses were adjusted for principal components of population structure and age (at time of questionnaire response). Models with additional adjustment for maternal or offspring genotypes were also tested. Secondary analyses included adjustment for sex and skin pigmentation. RESULTS: Among ALSPAC children, the rs29132 SNP in the Vesicle-associated membrane protein-associated protein A (VAPA) gene was associated with five sun exposure variables whilst the rs650662 SNP in the Opioid Receptor Mu 1 (OPRM1) gene was associated with three. The remaining SNPs did not show associations beyond what was expected by chance. After Bonferroni correction one SNP in the children was associated with an increased likelihood of using sun cream whilst in the sun at 8 years old (rs60050811 in the Spermatogenesis and Centriole Associated 1 (SPATC1) gene, OR per C allele = 1.34, 95% CI 1.11-1.62, p = .003). In the mothers, rs650662 in OPRM1 was associated with the use of a lower factor of sun cream in their children, (OR per A allele = 0.89, 95% CI 0.82-0.96, p = .002). Whilst rs2073478 in the Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) gene was associated with a reduced odds of their child using a sun block or cream with a 4 star rating (OR per T allele = 0.68, 95% CI 0.53-0.88, p = .003). Similar but weaker associations were observed for the main findings in the secondary analyses. CONCLUSIONS: We found weak evidence to suggest that genes previously associated with TD are associated with sun exposure in children of European ancestry from southwest England.

Association of timing of menarche with depressive symptoms and depression in adolescence: Mendelian randomisation study.

BACKGROUND: Observational studies report associations between early menarche and higher levels of depressive symptoms and depression. However, no studies have investigated whether this association is causal. AIMS: To determine whether earlier menarche is a causal risk factor for depressive symptoms and depression in adolescence. METHOD: The associations between a genetic score for age at menarche and depressive symptoms at 14, 17 and 19 years, and depression at 18 years, were examined using Mendelian randomisation analysis techniques. RESULTS: Using a genetic risk score to indicate earlier timing of menarche, we found that early menarche is associated with higher levels of depressive symptoms at 14 years (odds ratio per risk allele 1.02, 95% CI 1.005-1.04, n = 2404). We did not find an association between the early menarche risk score and depressive symptoms or depression after age 14. CONCLUSIONS: Our results provide evidence for a causal effect of age at menarche on depressive symptoms at age 14.