Common Variants Research Articles

Individual differences in sociocognitive traits in semi-free-ranging rhesus monkeys (Macaca mulatta).

Characterizing individual differences in cognition is crucial for understanding the evolution of cognition as well as to test the biological consequences of different cognitive traits. Here, we harnessed the strengths of a uniquely large, naturally-living primate population at the Cayo Santiago Biological Field Station to characterized individual differences in rhesus monkey performance across two social cognitive tasks. A total of n = 204 semi-free-ranging adult rhesus monkeys participated in a data collection procedure, where we aimed to test individuals on both tasks at two time-points that were one year apart. In the socioemotional responses task, we assessed monkeys' attention to conspecific photographs with neutral versus negative emotional expressions. We found that monkeys showed overall declines in interest in conspecific photographs with age, but relative increases in attention to threat stimuli specifically, and further that these responses exhibited long-term stability across repeated testing. In the gaze following task we assessed monkeys' propensity to co-orient with an experimenter. Here, we found no evidence for age-related change in responses, and responses showed only limited repeatability over time. Finally, we found some evidence for common individual variation for performance across the tasks: monkeys that showed greater interest in conspecific photographs were more likely to follow a human's gaze. These results show how studies of comparative cognitive development and aging can provide insights into the evolution of cognition, and identify core primate social cognitive traits that may be related across and within individuals.

Association of common genetic variants with chronic axonal polyneuropathy in the general population: a genome-wide association study.

IntroductionDisease susceptibility of chronic axonal polyneuropathy is not fully explained by clinical risk factors. Therefore, we determined the contribution of common genetic variants in chronic axonal polyneuropathy in the general population.MethodsThis study was performed in two population-based studies. Polyneuropathy diagnosis was based on screening in the Rotterdam Study and on ICD-10 codes in the UK Biobank. We determined the heritability of the sural nerve amplitude and performed genome-wide association studies of chronic axonal polyneuropathy and sural sensory nerve amplitude. Furthermore, we zoomed in on variants in and surrounding 100 autosomal genes known to cause polyneuropathy based on literature and expert knowledge (candidate genes), and we performed a gene-based analysis. Analyses were adjusted for age, sex and population stratification.ResultsChronic axonal polyneuropathy was present in 2,357 of the 458,567 participants and 54.3% of the total population was female. Heritability of sural nerve amplitude was 0.49 (p = 0.067) (N = 1,153). No variants (p < 5.0×10−8) or genes (p < 2.7×10−6) reached genome-wide significance for its association with polyneuropathy. Focusing on variants in and surrounding the candidate genes in the GWAS (p < 3.9×10−6) and on these genes in the gene-based analysis (p < 5.0×10−4) neither yielded significant results.DiscussionWe did not find common variants associated with chronic axonal polyneuropathy in the general population. Larger studies are needed to determine if genetic susceptibility based on both common and rare genetic variants affect the risk for chronic axonal polyneuropathy in the general population.

O-210 DNA methylation signature of monozygotic twinning: investigating the relationship with medically assisted reproduction, higher-order gestations, and common genetic variants

Abstract Study question To study a DNA methylation signature of monozygotic twins in relation to medically assisted reproduction (MAR), higher-order gestations, and genome-wide common genetic variants. Summary answer Monozygotic twinning and MAR show largely distinct DNA methylation signatures. Monozygotic triplets, like monozygotic twins, carry a comparable but stronger DNA methylation signature. What is known already Monozygotic twins arise when a zygote or embryo splits during pre-implantation stages of development. Higher-order monozygotic multiples including triplets have been hypothesized to arise from multiple consecutive splitting events. The underlying mechanisms are unknown. Some studies have reported a higher rate of monozygotic twins born after the use of medically-assisted reproductive technologies. We recently identified a DNA methylation signature in blood samples from adult monozygotic twins, which showed strong replication across cohorts and in buccal samples from children. This signature consists of 834 differentially methylated locations, enriched for loci with a role in embryonic processes, cell adhesion, and metastable epi-alleles. Study design, size, duration We compared buccal DNA methylation profiles of 934 naturally conceived monozygotic twins to 43 monozygotic twins conceived after IVF/ICSI (mean age=9). We generated monozygotic twinning DNA methylation scores in an independent buccal dataset (59 triplets, 198 twins, and 119 siblings of twins, mean age=15). A genome-wide association study (GWAS) on the DNA methylation score was performed in two datasets from the Netherlands Twin Register (NTR) (1: Blood, N = 2841, mean age=37, 2: Buccal, N = 1150, mean age=10). Participants/materials, setting, methods DNA methylation was assessed with Illumina arrays (450k/EPIC). To study the relationship between DNA methylation and MAR, we performed an epigenome-wide association study (EWAS) of MAR in monozygotic twins. We applied our previously developed DNA-methylation based predictor (trained on blood methylation data from twins using elastic net regression) to novel buccal methylation data from multiples including triplets. GWAS analysis was performed in gcta using --fastGWA-mlm correcting for 10 genetic ancestry PCs and genotype platform. Main results and the role of chance Through EWAS, we identified 29 differentially methylated CpGs in buccal cells from monozygotic twins conceived after MAR compared to naturally conceived monozygotic twins (after Bonferroni correction), of which 8 were previously identified in an EWAS meta-analysis of IVF on cord blood from singletons at birth. None of the 834 CpGs detected in our previous EWAS meta-analysis of monozygotic twinning were associated with MAR, suggesting that they are connected to natural monozygotic twinning. The monozygotic twinning epigenetic signature showed similar performance in buccal DNA methylation data from monozygotic twins as previously observed (81% of monozygotic twins correctly classified). Sensitivity was highest for monozygotic triplets (90% correctly classified), but specificity remains moderate (66% of DZ twins correctly predicted, 53% of non-twins correctly predicted). GWAS analysis of blood 450k array data identified three genome-wide significant loci. The top SNP (rs76157694, MAF=0.25) maps to TBX4; an embryonic transcription factor primarily known for its role in hindlimb development. This finding is consistent with our previous results of MZ-differentially methylated positions being enriched within TBX4 binding motifs. GWAS analysis of the buccal EPIC array data identified no genome-wide significant loci. We are planning a GWAS meta-analysis together with the Genetics of DNA methylation consortium. Limitations, reasons for caution Our research provides compelling hints towards an epigenomic event in monozygotic multiples, but whether the signature represents a cause, effect, or a byproduct of monozygotic twinning remains to be established. In ongoing research, we study the signature in pre- and perinatal tissues from twins (Dutch Fetal biobank and PANDA biobank). Wider implications of the findings The methylation signature may serve as a biomarker to retrospectively diagnose if a person was conceived as monozygotic twin, providing novel opportunities to examine links between vanishing monozygotic twin syndrome and certain congenital disorders. Examples include Beckwith-Wiedemann Syndrome and Amyoplasia (∼10-fold higher frequency of monozygotic twins among patients). Trial registration number not applicable

O-136 A comprehensive evaluation of spermatogenesis-related genes identifies novel common and rare risk loci for idiopathic severe spermatogenic failure

Abstract Study question Can genome-wide genotyping data be analysed in a hypothesis-driven fashion to better understand the genetic component of male infertility due to severe spermatogenic failure (SPGF)? Summary answer We revealed that both common and rare genetic variants in genomic regions involved in spermatogenesis contribute to the development of idiopathic SPGF. What is known already Spermatogenesis is a tightly regulated process involving the controlled expression of over 2,000 genes. Mutations in spermatogenesis-related genes have been associated with SPGF development. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of this condition. Additionally, genome-wide association studies (GWAS) have provided valuable insights into the role of common polymorphisms in complex forms of SPGF. Interestingly, novel methods have shown that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes, but this approach has never been applied to characterise the genetic component of a whole case-control cohort. Study design, size, duration We conducted a thorough examination of both common (minor allele frequency, MAF > 0.01) and rare (MAF < 0.01) genetic variation within a set of 1,797 spermatogenesis genes. This gene panel was meticulously curated through an exhaustive search in the literature and in different databases of male infertility genetics. The genotype data were obtained from a previously published GWAS in Europeans, encompassing over 6 million polymorphisms. Participants/materials, setting, methods We analysed a cohort that included 1,274 SPGF patients and 1,951 unaffected controls with European ancestry. Three independent approaches were follow: (1) variant-wise analysis using logistic regression models followed by a meta-analysis of the study cohorts; (2) gene-wise analysis using a Combined Multivariate and Collapsing (CMC) burden test; and (3) identification and characterisation of highly damaging rare coding variants in homozygosity. Multiple testing correction was applied to determine statistical significance Main results and the role of chance Our results suggested a potential association between SPGF and the rs12347237*T variant of the SHOC1 gene in the GWAS population (P = 3.17E-05, OR = 2.94). This association was subsequently validated in an independent Iberian cohort (Pcombined = 6.992E-06, OR = 2.61). Furthermore, our gene-wise analysis showed putative associations through the cumulative effect of some rare and low-frequency variants in SHOC1 (P = 4.9E-03), PCSK4 (P = 1E-04), AP3B1 (P = 5E-04), and DLK1 (P = 5E-04). Remarkably, the rare and common variants identified in SHOC1 are part of the same haplotype block, impacting both coding and non-coding regions. Additionally, we identified 35 individuals carrying 32 very rare and potentially pathogenic variants in homozygosity within the coding regions of the selected genes. Limitations, reasons for caution The analysis of low-frequency variants presents challenges in achieving sufficient statistical power to detect genetic associations. Consequently, independent studies involving large sample sets are essential to replicate our findings. In addition, the specific role of the identified variants in the pathogenic mechanisms of SPGF should be assessed using functional experiments. Wider implications of the findings The discovery of novel genetic risk factors for SPGF and the elucidation of the genetic causes underlying both monogenic and complex forms of SPGF provide new perspectives for personalized medicine and reproductive counselling. Trial registration number not applicable

High prevalence of m.1555A > G in patients with hearing loss in the Baikal Lake region of Russia as a result of founder effect

Mitochondrial forms account approximately 1–2% of all nonsyndromic cases of hearing loss (HL). One of the most common causative variants of mtDNA is the m.1555A > G variant of the MT-RNR1 gene (OMIM 561000). Currently the detection of the m.1555A > G variant of the MT-RNR1 gene is not included in all research protocols. In this study this variant was screened among 165 patients with HL from the Republic of Buryatia, located in the Baikal Lake region of Russia. In our study, the total contribution of the m.1555A > G variant to the etiology of HL was 12.7% (21/165), while the update global prevalence of this variant is 1.8% (863/47,328). The m.1555A > G variant was notably more prevalent in Buryat (20.2%) than in Russian patients (1.3%). Mitogenome analysis in 14 unrelated Buryat families carrying the m.1555A > G variant revealed a predominant lineage: in 13 families, a cluster affiliated with sub-haplogroup A5b (92.9%) was identified, while one family had the D5a2a1 lineage (7.1%). In a Russian family with the m.1555A > G variant the lineage affiliated with sub-haplogroup F1a1d was found. Considering that more than 90% of Buryat families with the m.1555A > G variant belong to the single maternal lineage cluster we conclude that high prevalence of this variant in patients with HL in the Baikal Lake region can be attributed to a founder effect.

Diffuse large B-cell lymphoma and follicular lymphoma: problem state in Russia

Background. Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of hematological malignancies, the vast majority of which are B-cell tumors. The most common variant of NHL is diffuse large B-cell lymphoma (DLBCL), characterized by an aggressive course, which accounts for 30–40% of all NHL. The second most common is follicular lymphoma (FL), traditionally classified as an indolent variant accounting for up to 25% of all NHL. Current therapies for these lymphoproliferative disorders which includes innovative drugs in the 1st line of therapy (LT) have demonstrated high efficacy. However, some patients develop a relapse or a refractory disease. Despite recent significant progress in the development and implementation of innovative targeted drugs, in most cases, it is not possible to achieve persistent long-term remissions after disease relapse, which leaves patients with an unmet need for effective and well-tolerated treatment options. Aim. To obtain objective data on the incidence, clinical course, and effectiveness of therapy for the most common variants of NHL in real-world practice in Russia. Materials and methods. From February to March 2023, 130 hematologists and oncologists from 30 regions of Russia were surveyed to update the data on DLBCL and FL. Results. Over the past 12 months, 5,689 patients with NHL were observed, of which 56% had DLBCL; 62% of them received the 1st LT, 22% received the 2nd LT, 10% received the 3rd LT, and only a few reached later lines. Analysis of the administered treatment options in the 2nd and 3rd LTs shows that there is no standard of care for this population, and the effectiveness of the regimens used in real-world Russian practice is extremely low. FL accounted for 23% of all 5,689 patients with NHL, of which 56% were newly diagnosed and 44% received treatment for relapse. The majority of patients with FL who received ≥3 LTs had an inferior prognosis and rapid disease progression: the median time from diagnosis to the beginning of the 3rd LT was only 26.4 months. The analysis of treatment options for patients with relapsed FL indicates a lack of standard and effective therapies. Conclusion. Relapsed and refractory DLBCL and FL represent a complex clinical situation where the main goal of treatment is disease control due to the impossibility of achieving stable remissions with existing treatment options. Clinicians with great hope are looking to the emergence of new classes of drugs that will be able to improve the prognosis for this complex population.

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants.

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.

The potential and translational application of infant genetic research.

In the current genomic revolution, the infancy life stage is the most neglected. Although clinical genetics recognizes the value of early identification in infancy of rare genetic causes of disorders and delay, common genetic variation is almost completely ignored in research on infant behavioral and neurodevelopmental traits. In this Perspective, we argue for a much-needed surge in research on common genetic variation influencing infant neurodevelopment and behavior, findings that would be relevant for all children. We now see convincing evidence from different research designs to suggest that developmental milestones, skills and behaviors of infants are heritable and thus are suitable candidates for gene-discovery research. We highlight the resources available to the field, including genotyped infant cohorts, and we outline, with recommendations, special considerations needed for infant data. Therefore, infant genetic research has the potential to impact basic science and to affect educational policy, public health and clinical practice.

The Diversity of CYP2C19 Polymorphisms in the Thai Population: Implications for Precision Medicine.

CYP2C19 plays a major role in the metabolism of various drugs. The most common genetic variants were the CYP2C19*2 and *3 alleles (rs4244285 and rs4986893, non-functional variants). In previous studies, we found that genetic polymorphisms in CYP2C19 variants influenced the active metabolites of clopidogrel and caused major adverse cardiovascular and cerebrovascular effects. However, the distribution of CYP2C19 varies among ethnic groups and according to adverse drug reactions. This study aimed to investigate the frequency of CYP2C19 genetic polymorphisms in the Thai population and analyze the differences in the frequency of CYP2C19 genetic polymorphisms between Thai and other populations. This study enrolled 211 unrelated healthy Thai individuals in total. We performed a real-time polymerase chain reaction to genotype CYP2C19*2 (681G > A) and CYP2C19*3 (636G > A). In the Thai population, the CYP2C19*1 allele was the most prevalent at 70.14%, while the CYP2C19*2 and *3 alleles were found at frequencies of 25.36% and 4.50%, respectively. Conversely, the CYP2C19*3 allele was not detected in Caucasian, Hispanic, African, Italian, Macedonian, Tanzanian, or North Indian populations. The phenotypic profile of this gene revealed that the frequency of intermediate metabolizers (IMs) is nearly equal to that of extensive metabolizers (EMs), at 42.65% and 48.82% respectively, with genotypes *1/*2 (36.02%) and *1/*3 (6.63%). Likewise, poor metabolizers (PMs) with genotypes *2/*2 (6.16%), *2/*3 (2.37%), and *3/*3 (<1%) are more prevalent in our population as well. The distribution of CYP2C19 genotype and phenotype influenced by non-functional alleles has potential as a pharmacogenomics biomarker for precision medicine and is dependent on an ethnic-specific genetic variation database.

Unveiling Blastocystis epidemiology in Morocco: subtype diversity among clinical patients with and without gastrointestinal manifestations in the Meknes region.

Blastocystis is an intestinal protist frequently identified in humans and other animals, though its clinical significance remains controversial. This study aimed to determine the prevalence and genetic diversity of Blastocystis in faecal samples from symptomatic (n = 55) and asymptomatic (n = 50) individuals seeking medical care in Meknes, Morocco. Detection of the protist was accomplished through coproparasitological examination and culture in Jones medium. Culture-positive samples were subjected to molecular analyses (PCR and Sanger sequencing) based on sequences of the small subunit ribosomal RNA gene. Epidemiological questionnaires on demographics and potential risk factors were collected from participating patients. The overall Blastocystis infection rate was 51.4% (54/105), with no differences between symptomatic (52.7%, 29/55) and asymptomatic (50.0%, 25/50) individuals. Sequence analyses identified three Blastocystis subtypes, with ST3 being the most prevalent (42.0%), followed by ST1 (34.0%), and ST2 (12.0%). Regarding intra-subtype diversity, allele 4 was found within ST1; alleles 11/12 and alleles 34/36 (alone or in combination) were identified within ST2 and ST3 respectively. Allele 34 in ST3 (40.8%) and allele 4 in ST1 (34.7%) were the most common genetic variants circulating in the surveyed clinical population. A statistically significant association between ST2 and the presence of flatulence was observed. This is the first study assessing the epidemiology and genetic diversity of Blastocystis sp. in the Meknes region, Morocco.

Diabetes-associated Genetic Variation in MTNR1B and Its Effect on Islet Function.

Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes. To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes. The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model. The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN. Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of TCF7L2 genotype at rs7903146 from the Mayo Biobank. Two-hour, 7-sample OGTT. Fasting, nadir, and integrated glucagon concentrations. One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype. The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.

Effect of lumbosacral transitional vertebra on developmental alterations of the hip: a quantitative investigation of the lumbo-pelvic-hip complex via whole-body computed tomography.

Lumbosacral transitional vertebra (LSTV) is a common spinal variant, with the reported prevalence varying from 8.1% to 36%. LSTV has been shown to alter the lumbo-pelvic parameters and reduce the benefits of total hip arthroplasty, but the specific effects of LSTV on hip development remain unclear. The aim of this study was thus to investigate the impact of LSTV on developmental alterations of the hip. A total of 310 individuals were categorized into three groups according to whole-body computed tomography (CT) imaging: a group with sacralization of 23 presacral vertebrae (PSV) (n=102), a group with lumbarization of 25 PSV (n=108), and a normal control group with 24 PSV (n=100). Quantitative parameters of the lumbo-pelvic-hip complex (LPHC) including lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), axial and sagittal acetabular anteversion angle (AAA), center-edge (CE) angle, Sharp angle, and femoral neck-shaft angle (FNSA) were measured and analyzed. Statistical analyses were used to compare the differences of these quantitative parameters among the three groups and to assess the relationship between hip and lumbar-pelvic parameters. Significant differences between each pair of three groups and the LSTV subgroups were only found in the sagittal AAA (left side: P=0.008; right side: P<0.001), with no differences found for the other parameters. Compared to the normal group (24 PSV), both the 23 PSV and 25 PSV groups exhibited increased values in the sagittal AAA, especially in the right side of the 23 PSV group. Only the sagittal AAA showed low-to-moderate positive correlations with pelvic parameters of PI (r=0.195-0.429; P=0.001-0.08) and PT (r=0.239-0.605; P=0.001-0.03). Variations of LSTV are correlated with the hip anatomical development via LPHC transmission and may potentially reduce the sagittal acetabular coverage, particularly in the 23 PSV subtype on the right side.

Unraveling genetic threads: Identifying novel therapeutic targets for allergic rhinitis through Mendelian randomization

BackgroundAllergic rhinitis (AR) is a pervasive global health issue, and currently, there is a scarcity of targeted drug therapies available. This study aims to identify potential druggable target genes for AR using Mendelian randomization (MR) analysis. MethodsMR analysis was conducted to assess the causal effect of expression quantitative trait loci (eQTL) in the blood on AR. Data on AR were collected from 2 datasets: FinnGen(R9) (11,009 cases and 359,149 controls) and UK Biobank (25,486 cases and 87,097 controls). Colocalization analysis was utilized to assess the common causal genetic variations between the identified drug target genes and AR. We also employed available genome-wide association studies (GWAS) data to gauge the impact of druggable genes on AR biomarkers and other allergic diseases. ResultsThis study employs MR to analyze the relationship between 3410 druggable genes and AR. After Bonferroni correction, 10 genes were found to be significantly associated with AR risk (P < 0.05/3410). Colocalization analysis revealed a significant causal relationship between the expression variation of CFL1 and EFEMP2 genes and AR, sharing direct causal variants (colocalization probability PP.H3 + PP.H4 > 0.8), highlighting their importance as potential therapeutic targets for AR. The CFL1 gene showed a causal link with levels of thymic stromal lymphopoietin (TSLP), eosinophil count, and interleukin-13 (IL-13) (P = 0.016, 7.45E-16, 0.00091, respectively). EFEMP2 was also causally related to eosinophil count, IL-13, and interleukin-17 (IL-17) (P = 0.00012, 0.00091, 0.032, respectively). PheWAS analysis revealed significant associations of CFL1 with asthma, whereas EFEMP2 showed associations with both asthma and eczema. Protein-Protein Interaction (PPI) network analysis further unveiled the direct interactions of EFEMP2 and CFL1 with proteins related to immune regulation and inflammatory responses, with 77.64% of the network consisting of direct bindings, indicating their key roles in modulating AR-related immune and inflammatory responses. Notably, there was an 8.01% significant correlation between immune-related pathways and genes involved in inflammatory responses. ConclusionThese genes present notable associations with AR biomarkers and other autoimmune diseases, offering valuable targets for developing new AR therapies.

Scabies and Nodules in Children: An Intriguing Entity

Nodular scabies (NS) is a relatively common variant of classical scabies whose pathogenesis is unclear. It is clinically characterized by pruritic, firm nodules most commonly involving the genitalia followed by axilla and groin region. A clinical diagnosis of NS is often straightforward. NS may persist despite the administration of antiscabicidal drugs such as permethrin and ivermectin. Topical and intralesional corticosteroids form the mainstay of treatment. Postscabietic nodule is a complication that primarily occurs in patients with previous history of scabies that had been successfully treated.

Epigenetics of schizophrenia

Schizophrenia is a severe mental illness characterized by a disconnection from reality, significantly impacting a person's ability to function and leading to substantial disability. While the exact causes of schizophrenia remain unclear, it is understood to result from a combination of genetic, neurochemical, and environmental factors. The heritability of schizophrenia is high, although it does not follow Mendelian patterns. The symptomatology includes both positive symptoms such as hallucinations, delusions, and psychotic episodes, and negative symptoms like apathy and speech difficulties, which fluctuate in severity over time. Environmental influences, including prenatal and perinatal factors, trauma, and lifestyle, also play a crucial role in its development. The prevalence of schizophrenia is approximately 12.1% globally, with incidence rates higher in males than females. Genetic studies have identified several associations that contribute to the disease's pathophysiology, including common variants and copy number variants. Epigenetic mechanisms, such as DNA methylation and histone modifications, further influence gene expression and disease manifestation. The interplay between genetic predisposition and environmental factors underscores the complexity of schizophrenia and the importance of a multifaceted approach to its study and treatment.

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.

Spinal muscular atrophy (SMA) is a genetic disorder that causes progressive degeneration of lower motor neurons and the subsequent loss of muscle function throughout the body. It is the second most common recessive disorder in individuals of European descent and is present in all populations. Accurate tools exist for diagnosing SMA from genome sequencing data. However, there are no publicly available tools for GRCh38-aligned data from panel or exome sequencing assays which continue to be used as first line tests for neuromuscular disorders. This deficiency creates a critical gap in our ability to diagnose SMA in large existing rare disease cohorts, as well as newly sequenced exome and panel datasets. We therefore developed and extensively validated a new tool - SMA Finder - that can diagnose SMA not only in genome, but also exome and panel sequencing samples aligned to GRCh37, GRCh38, or T2T-CHM13. It works by evaluating aligned reads that overlap the c.840 position of SMN1 and SMN2 in order to detect the most common molecular causes of SMA. We applied SMA Finder to 16,626 exomes and 3,911 genomes from heterogeneous rare disease cohorts sequenced at the Broad Institute Center for Mendelian Genomics as well as 1,157 exomes and 8,762 panel sequencing samples from Tartu University Hospital. SMA Finder correctly identified all 16 known SMA cases and reported nine novel diagnoses which have since been confirmed by clinical testing, with another four novel diagnoses undergoing validation. Notably, out of the 29 total SMA positive cases, 23 had an initial clinical diagnosis of muscular dystrophy, congenital myasthenic syndrome, or myopathy. This underscored the frequency with which SMA can be misdiagnosed as other neuromuscular disorders and confirmed the utility of using SMA Finder to reanalyze phenotypically diverse neuromuscular disease cohorts. Finally, we evaluated SMA Finder on 198,868 individuals that had both exome and genome sequencing data within the UK Biobank (UKBB) and found that SMA Finder's overall false positive rate was less than 1 / 200,000 exome samples, and its positive predictive value (PPV) was 97%. We also observed 100% concordance between UKBB exome and genome calls. This analysis showed that, even though it is located within a segmental duplication, the most common causal variant for SMA can be detected with comparable accuracy to monogenic disease variants in non-repetitive regions. Additionally, the high PPV demonstrated by SMA Finder, the existence of treatment options for SMA in which early diagnosis is imperative for therapeutic benefit, as well as widespread availability of clinical confirmatory testing for SMA, warrants the addition of SMN1 to the ACMG list of genes with reportable secondary findings after genome and exome sequencing.

Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals.

Big data generated from exome sequencing (ES) and genome sequencing (GS) analyses can be used to detect actionable and high-penetrance variants that are not directly associated with the primary diagnosis of patients but can guide their clinical follow-up and treatment. Variants that are classified as pathogenic/likely pathogenic and are clinically significant but not directly associated with the primary diagnosis of patients are defined as secondary findings (SF). The aim of this study was to examine the frequency and variant spectrum of cancer-related SF in 2020 Turkish ES data and to discuss the importance of the presence of cancer-related SF in at-risk family members in terms of genetic counseling and follow-up. A total of 2020 patients from 2020 different families were evaluated by ES. SF were detected in 28 unrelated cases (1.38%), and variants in BRCA2 (11 patients) and MLH1 (4 patients) genes were observed most frequently. A total of 21 different variants were identified, with 4 of them (c.9919_9932del and c.3653del in the BRCA2 gene, c.2002A>G in the MSH2 gene, c.26_29del in the TMEM127 gene) being novel variations. In three different families, c.1189C>T (p.Gln397*) variation in BRCA2 gene was detected, suggesting that this may be a common variant in the Turkish population. This study represents the largest cohort conducted in the Turkish population, examining the frequency and variant spectrum of cancer-related SF. With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real-life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

Removal of per- and polyfluoroalkyl substances (PFAS) from wastewater using the hydrodynamic cavitation on a chip concept

The elimination of micropollutants such as highly fluorinated substances, including per- and polyfluoroalkyl substances (PFAS), in wastewater treatment plants has been receiving growing attention due to the urgent need to minimize their adverse effects on natural water and associated ecosystems. Conventional treatment methods often fall short in effectively removing PFAS. In this study, the Hydrodynamic Cavitation on a Chip concept (HCOC) was utilized to degrade 11 common PFAS variants (PFAS11) for the first time in three different hydrodynamic cavitation reactor set-ups, each enhanced with surface modifications involving roughness elements. Stockholm municipal wastewater treated by a Membrane BioReactor (MBR) process was subjected to fully developed cavitating flow treatment using the three distinct microscale hydrodynamic cavitation (HC) reactors. The obtained results indicate that the chemical-free HCOC technique employed in this study has a significant potential in the degradation of nearly all investigated PFAS11 compounds at a notable rate of 36.1 % while the combination with MBR process can prevent blockage within the fluidic channels, enabling continuous operation with high throughput processing rates. Our proposed methodology demonstrated promising results in eliminating PFAS and could contribute to advancements in the use of microscale HC to treat micropollutants in wastewater. These findings could be a major leap in water treatment technologies addressing the global burden of resource-efficient micropollutant water treatment.

The microbiota of ensiled forages and of bulk tank milk on dairy cattle farms in northern Sweden

Factors contributing to variations in the quality and microbiota of ensiled forages and in bulk tank microbiota in milk from cows fed different forages were investigated. Nutritional quality, fermentation parameters and hygiene quality of forage samples and corresponding bulk tank milk samples collected in 3 periods from 18 commercial farms located in northern Sweden were compared. Principal coordinates analysis revealed that the microbiota in forage and bulk milk, analyzed using 16S rRNA gene-based amplicon sequencing, were significantly different. The genera Lactobacillus, Weissella, and Leuconostoc dominated in forage samples, whereas Pseudomonas, Staphylococcus, and Streptococcus dominated in bulk milk samples. Forage quality and forage-associated microbiota were affected by ensiling method and by use of silage additive. Forages stored in bunker and tower silos (confounded with use of additive) were associated with higher levels of acetic and lactic acid and Lactobacillus. Forage ensiled as bales (confounded with no use of additive) was associated with higher DM content, water-soluble carbohydrate content, pH, yeast count, and the genera Weissella, Leuconostoc, and Enterococcus. For bulk tank milk samples, milking system was identified as the major factor affecting the microbiota and type of forage preservation had little effect. Analysis of common amplicon sequence variants (ASV) suggested that forage was not the major source of Lactobacillus found in bulk tank milk.

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid β -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.