Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

External validation of NTCP-models for radiation pneumonitis in lung cancer patients treated with chemoradiotherapy

PURPOSE: Normal tissue complication probability (NTCP) models can be used to estimate the risk of radiation pneumonitis (RP). The aim of this study was to externally validate the most frequently used prediction models for RP, i.e., the QUANTEC and APPELT models, in a large cohort of lung cancer patients treated with IMRT or VMAT. [1-2] METHODS AND MATERIALS: This prospective cohort study, included lung cancer patients treated between 2013 and 2018. A closed testing procedure was performed to test the need for model updating. To improve model performance, modification or removal of variables was considered. Performance measures included tests for goodness of fit, discrimination, and calibration.RESULTS: In this cohort of 612 patients, the incidence of RP ≥ grade 2 was 14.5%. For the QUANTEC-model, recalibration was recommended which resulted in a revised intercept and adjusted regression coefficient (from 0.126 to 0.224) of the mean lung dose (MLD),. The APPELT-model needed revision including model updating with modification and elimination of variables. After revision, the New RP-model included the following predictors (and regression coefficients): MLD (B = 0.250), age (B = 0.049, and smoking status (B = 0.902). The discrimination of the updated APPELT-model was higher compared to the recalibrated QUANTEC-model (AUC: 0.79 vs. 0.73).CONCLUSIONS: This study demonstrated that both the QUANTEC- and APPELT-model needed revision. Next to changes of the intercept and regression coefficients, the APPELT model improved further by model updating and performed better than the recalibrated QUANTEC model. This New RP-model is widely applicable containing non-tumour site specific variables, which can easily be collected.</p

Nationwide Outcome after Pancreatoduodenectomy in Patients at very High Risk (ISGPS-D) for Postoperative Pancreatic Fistula

OBJECTIVE: To assess nationwide surgical outcome after pancreatoduodenectomy (PD) in patients at very high risk for postoperative pancreatic fistula (POPF), categorized as ISGPS-D.SUMMARY BACKGROUND DATA: Morbidity and mortality after ISGPS-D PD is perceived so high that a recent randomized trial advocated prophylactic total pancreatectomy (TP) as alternative aiming to lower this risk. However, current outcomes of ISGPS-D PD remain unknown as large nationwide series are lacking.METHODS: Nationwide retrospective analysis including consecutive patients undergoing ISGPS-D PD (i.e., soft texture and pancreatic duct ≤3 mm), using the mandatory Dutch Pancreatic Cancer Audit (2014-2021). Primary outcome was in-hospital mortality and secondary outcomes included major morbidity (i.e., Clavien-Dindo grade ≥IIIa) and POPF (ISGPS grade B/C). The use of prophylactic TP to avoid POPF during the study period was assessed.RESULTS: Overall, 1402 patients were included. In-hospital mortality was 4.1% (n=57), which decreased to 3.7% (n=20/536) in the last 2 years. Major morbidity occurred in 642 patients (45.9%) and POPF in 410 (30.0%), which corresponded with failure to rescue in 8.9% (n=57/642). Patients with POPF had increased rates of major morbidity (88.0% vs. 28.3%; P&lt;0.001) and mortality (6.3% vs. 3.5%; P=0.016), compared to patients without POPF. Among 190 patients undergoing TP, prophylactic TP to prevent POPF was performed in 4 (2.1%).CONCLUSION: This nationwide series found a 4.1% in-hospital mortality after ISGPS-D PD with 45.9% major morbidity, leaving little room for improvement through prophylactic TP. Nevertheless, given the outcomes in 30% of patients who develop POPF, future randomized trials should aim to prevent and mitigate POPF in this high-risk category.</p

Familial Longevity Is Marked by Lower Diurnal Salivary Cortisol Levels: The Leiden Longevity Study

BACKGROUND: Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity. METHODS: Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors. RESULTS: Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28). CONCLUSION: Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed

Cognitive skills and literacy performance of Chinese adolescents with and without dyslexia

The present study sought to identify cognitive abilities that might distinguish Hong Kong Chinese adolescents with dyslexia and to assess how these abilities were associated with Chinese word reading, word dictation, and reading comprehension. The cognitive skills of interest were morphological awareness, visual-orthographic knowledge, rapid naming, and verbal working memory. A total of 90 junior secondary school students, 30 dyslexic, 30 chronological age controls, and 30 reading level controls was tested on a range of cognitive and literacy tasks. Dyslexic students were less competent than the control students in all cognitive and literacy measures. The regression analyses also showed that verbal working memory, rapid naming, morphological awareness, and visual-orthographic knowledge were significantly associated with literacy performance. Findings underscore the importance of these cognitive skills for Chinese literacy acquisition. Overall, this study highlights the persistent difficulties of Chinese dyslexic adolescents who seem to have multiple causes for reading and spelling difficulties

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions