An update on the monogenic causes of Parkinson's disease: Impact on patient stratification and personalised medicine.

Recently, various anesthesiology societies have reported cases involving pediatric patients of Venezuelan origin who underwent surgery under general anesthesia and subsequently developed serious neurologic impairment or died. However, the cause of this condition was unknown. Clinical and genetic studies were conducted on seven patients who experienced severe acute neurologic deterioration after the administration of general anesthetics during predominantly minor surgical procedures. Genetic-molecular, biochemical, and cellular studies were also performed on fibroblasts and cybrids treated with general anesthetics. In our cohort, acute perioperative events were observed in temporal association with anesthetic exposure. No adverse events were observed in a subset of the same individuals when only intravenous anesthesia was used. All patients shared a mitochondrial DNA haplotype that includes the m.11232T>C genetic variant, which results in the substitution of proline for leucine at position 158 (L158P) of the ND4 subunit of respiratory complex I in the electron transport chain. In vitro studies showed that sevoflurane exposure in cells carrying this genetic variant induces a pronounced suppression of mitochondrial oxygen consumption, with prominent effects on complex I-dependent respiratory pathways. In contrast, propofol did not elicit a differential effect in cells harboring this genetic variant. These findings suggest that individuals carrying the m.11232T>C mitochondrial DNA variant may be at increased risk of severe neurologic deterioration after exposure to anesthetic agents. Further studies are needed to define the underlying mechanisms and to determine anesthetic-specific risks. These results have important implications for improving the safety of surgical interventions and open new avenues in the field of mitochondrial pharmacogenetics of general anesthesia.

Diabetes is a highly heritable risk factor for stroke, with many known genetic variants. The role of these genetic variants in cerebrovascular disease has not been studied in Kānaka Maoli (Native Hawaiian) populations. We aimed to determine if genetic predisposition to diabetes is associated with a higher risk of stroke in a Kānaka Maoli population. We conducted a genetic association case/control study using data from Kānaka Maoli participants in the Population Architecture using Genomics and Epidemiology (PAGE) study. Stroke cases were identified through health questionnaires and matched by age and sex at a 1:10 ratio. We modeled genetic predisposition to diabetes with a polygenic risk score that included independent genetic variants known to be associated with diabetes at a genome-wide significance level (p < 5 × 108). This polygenic risk score served as the independent variable in logistic regression models for both diabetes and stroke. A total of 440 Kānaka Maoli individuals were included (15% under 50 years old, 85% aged 50-69, 65% female). There were 40 stroke patients and 400 age- and sex-matched control subjects. Genetic predisposition to diabetes was linked to a 23% increased risk of developing diabetes (OR 1.23, CI 1.01-1.51; p = 0.04) and a 45% increased risk of stroke (OR 1.45, CI 1.03-2.05; p = 0.04). In a Kānaka Maoli population, genetic predisposition to diabetes is associated with an increased risk of stroke. Future research to identify effect modifiers of this relationship may uncover significant public health strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. Although genetic variants are linked to MASLD progression, whether their associations with fibrosis severity are consistent across clinical contexts remains unclear. A cross-sectional analysis of 6446 individuals with MASLD from a community-based (n = 4477) and a tertiary-care hepatology population (n = 1969) was conducted. Fibrosis severity was assessed using the fibrosis-4 (FIB-4) index. Associations between MASLD-related genetic variants (PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738) and fibrosis were evaluated using multivariable logistic regression within each population. Advanced fibrosis was more prevalent in the tertiary-care population than in the community-based population (FIB-4 > 1.30: 34.5% vs. 41.2%; FIB-4 ≥ 3.25: 8.4% vs. 0.4%). PNPLA3 rs738409 showed consistent associations with fibrosis severity in both populations, with markedly stronger effects in the tertiary-care setting. In the community-based population, the GG genotype was associated with significant fibrosis (FIB-4 > 1.30; adjusted OR 1.28; 95% CI, 1.03-1.60; P for trend = 0.015), but not with higher thresholds. In contrast, in the tertiary-care population, the GG genotype was strongly associated with FIB-4 > 1.30 (OR 3.11; 95% CI, 2.23-4.34), and FIB-4 ≥ 3.25 (OR 4.17; 95% CI, 2.60-6.67; all P for trend < 0.001). TM6SF2 rs58542926 showed modest associations only in the community-based population, while MBOAT7 rs641738 was not associated with fibrosis severity. Genetic associations with fibrosis in MASLD appear to be context dependent. PNPLA3 rs738409 shows consistent but markedly greater effect sizes in tertiary-care settings, suggesting that clinical and metabolic context may play an important role in modulating genetic risk beyond ancestry alone.

Prognostic relevance of selected nucleotide variants in canine cutaneous mast cell tumors.

Genetic predisposition plays a key role in autoimmune and complex diseases such as multiple sclerosis (MS). However, identifying the specific variants or genomic regions responsible for disease susceptibility remains a significant challenge. In this study a family-based fine mapping approach was applied to analyze 142 trios, aiming to identify associated genetic variants linked to MS. The targeted genomic region resides within the 17:30,820,506-32,483,270bp (Ch37/hg19), which includes the protein-coding gene ASIC2, previously implicated in MS and other neurological conditions, with surrounding genes comprising strongly correlated genetic variants to capture the broader signal from the region. Given the high prevalence of MS in Sardinia and the unique genetic characteristics of the Sardinian population, including reduced heterogeneity and extended linkage disequilibrium, we designed our study specifically within this population and focused on family-based data to enhance the power for detecting genetic signals, avoiding false discoveries. Genotype imputation found 2537 variants, which were then analyzed using the knockoff Trio method to identify loci associated with MS susceptibility. We found rs756787 (3'UTR of MYO1D) increased disease risk (OR 1.57, 95% CI [1.07-2.29], p = 0.02), while rs56175840 (intronic ASIC2) showed a protective effect (OR 0.17, 95% CI [0.04-0.74], p = 0.02), demonstrating the power of knockoff-based fine mapping in family datasets. Integrating LD-based expression and trait analyses helped reveal how rs756787 correlates with variants affecting genes involved in neurodegeneration and the immune response to Epstein-Barr virus, a known environmental factor implicated in MS pathogenesis. Our study highlights the effectiveness of knockoff-based fine mapping combined with expression-trait integration to identify genetic variants influencing MS risk in the Sardinian population.

PM2.5 exposure and breast cancer risk: Independent and combined effects of ESR1 rs2046210 and FGFR2 rs2981582 in a Taiwanese cohort.

To assess the impact of cardiorespiratory fitness (CRF) and muscle strength on depression and individual depression symptoms. Mendelian randomisation (MR) analysis was conducted in up to 341,326 participants of European ancestry from UK Biobank (aged 37-73years). Genetic variants from previous genome-wide association studies (GWAS) of CRF and grip strength (to proxy overall muscle strength) were utilised to instrument exposures. A broad depression phenotype based on self-report and hospital records, as well as individual measures of depression symptoms from the Patient Health Questionnaire-9 (PHQ-9) were used as outcomes. Analysis was repeated stratifying by sex and using summary statistics from a major depressive disorder (MDD) GWAS. There was no clear evidence for association between CRF and any depression outcome. There was robust evidence suggesting greater grip was associated with lower odds of broad depression (OR per 0.1kg increase in weight adjusted grip: 0.86, 95% CI:0.80,0.93), as well as the PHQ-9 items appetite changes (OR:0.56, 95% CI:0.49,0.65), and anhedonia (OR:0.79, 95% CI:0.69,0.90), a core symptom of depression. There was also some evidence for associations between greater grip and lower odds of depressed mood (OR:0.85, 95% CI:0.74,0.97), psychomotor changes (OR:0.79, 95% CI:0.64,0.97), fatigue (OR:0.83, 95% CI:0.74,0.93) and concentration problems (OR:0.85, 95% CI:0.74,0.98) in the MR-inverse variance weighted analysis. Effects were mostly driven by stronger associations in females and results replicated in the two-sample MR for MDD. Muscle strength may represent an important modifiable factor for preventing and treating depression and several specific symptoms, including core symptoms such as anhedonia.

The role and mechanisms of methylation modifications in the development and progression of hypertension.

Associations between AhR Gene Polymorphisms and Expression in Agent Orange/Dioxin Exposed Individuals.

Prevalence and sociodemographic, clinical, and genetic characteristics of Fabry disease in north-central Chile, 2013-2023.

Machine learning-based prediction of Familial Hemiplegic Migraine risk from genetic variants.

Sudden unexpected death in young adults poses significant challenges for both forensic and clinical medicine. The integration of genetic testing in postmortem investigations has provided valuable insights into the potential role of genetic variants in cardiac-related mortality, particularly in cases involving cardiomyopathies. Here, we report 3 cases of sudden death in active-duty military personnel where anatomic findings alone were sufficient for a cause of death determination. However, postmortem genetic testing identified 3 distinct genetic variants, thus providing complementary diagnostic information and enabling targeted genetic counseling and risk assessment for surviving family members. These cases demonstrate the importance of gross, histologic, and genetic findings in identifying underlying causes of death, guiding family counseling, and improving our understanding of genotype-phenotype relationships in inherited cardiac conditions.

GxE in psychiatry - challenges and opportunities.

Understanding the genome-wide diversity of jute mallow (Corchorus olitorius L.) is crucial for unlocking the potential of global genebank collections, enabling the discovery and use of traits that support climate resilience, improve nutrition, and increase productivity. Using 23,471 high-quality diversity array technology sequencing single-nucleotide polymorphisms (SNPs), this study assessed the genetic diversity, population structure, and linkage disequilibrium (LD) of 607 accessions. Moderate genetic diversity was detected with a total gene diversity of 0.28, an expected heterozygosity of 0.26, and a Shannon index of 0.42. Four distinct genetic clusters were identified, reflecting geographic patterns, where Cluster 1 (n=62) and Cluster 4 (n=354) were predominantly composed of West African accessions. An analysis of molecular variance revealed significant genetic structuring (p<0.001), with most genetic variation occurring within countries (45.2%), followed by within individuals (32.5%), while differentiation among clusters accounted for 18.2% and variation among regions was minimal (2.9%). LD revealed low genome-wide r2 values (mean=0.028; r2 90=0.067) and a very rapid decay (LD50 ≈ 1bp), with only 4.2% of SNP pairs showing significant LD (r2>0.1, p<0.05), indicating extensive historical recombination. The findings suggest that a significant portion of the existing genetic variation remains untapped in breeding. Strategic conservation of the unique genetic variants through core and mini-core collections, coupled with targeted crosses among diverse regional accessions, can broaden the genetic base and support the development of resilient, high-yielding, and nutrient-rich dual-purpose varieties (i.e., leafy vegetables and industrial fibers) across diverse environments.

Emerging LncRNA HOTAIR and NME1 polymorphisms in ovarian cancer risk: A pilot case-control study in South Indian women.

The development of recombinant casein with precision fermentation creates an opportunity to use specific genetic variants of casein for the development of foams. Small differences in the amino acid sequence between variants will affect their interfacial, thin film, and foaming properties, allowing for a more targeted design of products. This study explores these effects in αs1-casein variant A and B (RCA and RCB), where RCA lacks amino-acid residues 14-26 compared to RCB, which results in a tail-train interfacial configuration after adsorption, whereas RCB assumes a train-loop-train configuration. Air-water interfaces stabilized with both variants were studied with large amplitude oscillatory dilatation and shear, and imaged with AFM. Films stabilized with RCA or RCB were also studied with a thin film balance combined with micro interferometry. Foam properties of both variants were determined using a FoamScan. In thin film balance experiments, low concentrations of RCB (0.05%) formed mobile interfaces that allowed for Gibbs-Marangoni flows and led to superior foam stability (t1/2: 1h). At increased concentrations of RCB the Gibbs-Marangoni flows were inhibited, and foam stability decreased. RCA formed a stiffer, less mobile interface (dilatation and shear) and therefore inhibited the Gibbs-Marangoni flows altogether, which led to low foam stability which improved with increasing concentration (t1/2: 8-20min). Clearly, the deletion of amino acids in caseins can greatly impact their interfacial and foaming behavior. These results highlight the potential for using different genetic variants of recombinant caseins for tuning its functionality.

Highly sensitive persons' responses to acute and post-earthquake stress: Exploratory insights into genetic moderation.

A potential genetic link between inflammatory bowel disease (IBD) and educational attainment has been suggested. Understanding the underlying mechanisms of this genetic relationship is crucial for advancing the knowledge of their co-occurrence patterns. Using genome-wide association study data for both IBD and educational attainment, a multiphase analytical approach was applied to examine their genetic correlation. The study involved three phases: first, linkage disequilibrium score regression and high-definition likelihood models were used to assess genome-wide genetic correlation; second, SUPERGNOVA was employed to analyze the genetic structure across specific chromosomal regions; and third, conditional/conjunctional false discovery rate (cond/conjFDR) methods were applied to measure genetic overlap and identify shared genetic loci between the two traits. The genome-wide analysis revealed significant genetic correlations between IBD, especially Crohn's disease, and educational attainment, while the association with ulcerative colitis was weaker. Regional analyses identified localized genetic correlation signals across several chromosomal regions between these traits. The application of the conjFDR framework confirmed the presence of overlapping genetic components, leading to the identification of key genetic variants contributing to disease susceptibility and progression. This genetic study provides new theoretical insights into the association between IBD and educational attainment, contributing to a deeper understanding of the mechanisms underlying their co-occurrence.

Competitive interactions between invasive Phragmites australis and Spartina alterniflora: Mechanisms and management implications for marsh migration