Genotypes and phenotypes of capillary malformation-arteriovenous malformation: characterization and correlation analysis.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) is a rare genetic disorder characterized by multiple small capillary malformations (CMs) and arteriovenous malformations (AVMs), which has been linked with pathogenic variants in RASA1 and EPHB4. However, more data are needed to explore the phenotypic characteristics and the association between genotypes and clinical phenotypes. OBJECTIVES: Our aim was to investigate the phenotypic and genetic characteristics of CM-AVM in East Asians, identify potential unique phenotypes, and conduct genotype-phenotype association analyses. METHODS: This is a single-center study prospectively collecting CM-AVM patients' clinical data, with genetic data from blood or tissue samples. RESULTS: A total of 59 patients were enrolled. Thirty-two individuals had a leading CM greater than Schobinger stage II. The trigeminal nerve branches and greater auricular, transverse cervical, and lesser occipital nerves' somatosensory innervation zones divided head and neck CMs into six zones: V1, V2, V3, GA, TC, and LO zones. GA, TC, and LO zones had a positive correlation with one another but a negative correlation with V2 zone involvement. The RASA1 and EPHB4 pathogenic variants were detected in 41 out of 59, which showed two types of variant allele frequency (VAF) distributions. VAF above 30% made RASA1 pathogenic variants more susceptible to multifocal CMs than those below 30%. CONCLUSIONS: Leading CMs in the head and neck exhibit two segmentation patterns, anterior and lateral, which may differ in ear involvement and progression. Germline RASA1 pathogenic variants increased multifocal CM risk more than the somatic variants.

Genetic Associations of Persistent Opioid Use After Surgery Point to OPRM1 but Not Other Opioid-Related Loci as the Main Driver of Opioid Use Disorder.

Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r2 < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10-5), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability.

Association of the Genetic Diversity of Killer Cell Immunoglobulin-like Receptor Genes and HLA-C Ligand in Saudi Women With Thyroid Cancer.

INTRODUCTION: Genetic diversity in the killer immunoglobulin-like receptor (KIR) gene composition and human leukocyte antigen (HLA) class I ligands, such as HLA-C, can affect the activity of natural killer cells and determine anti-cancer immunity. Specific KIR-HLA combinations can enhance cancer predisposition by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity fails, leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women. METHODS: In this retrospective study, sixteen KIR genotypes and 2 HLA-C allotypes were determined using the polymerase chain reaction-sequence-specific primer (PCR-SSP) method, and the genotypes of 50 Saudi female patients with TC were compared with those of 50 Saudi female healthy controls (HC). RESULTS: We observed a highly significant decrease in the presence of the KIR2DS2 and KIR2DS4 genes (OR = 0.15, 95% CI = 0.05-0.41, P = 0.0001; OR = 0.06, 95% CI = 0.02-0.2, P = 0.000, respectively) and in the presence of the KIR2DL5A gene (OR = 0.05, 95% CI = 0.02-0.14, P = 0.0000) in the TC group compared to the HC group. The frequency of the HLA-C2C2 allotype was significantly higher in HC compared to patients with TC (P = 0.02). The KIR haplotype group A and AB genotypes revealed a protective effect against TC (P = 0.0003 and P = 0.000, respectively), while the BB genotype showed a risk effect on TC compared to HC. Our results showed significant differences in the KIR gene combinations and KIR-HLA combinations between Saudi female TC patients and HC. CONCLUSION: These results suggest that the expression of KIR genes and their HLA-C ligands may influence the risk of TC development in Saudi women.

Genetic diversity in killer immunoglobulin-like receptors (KIR) gene composition and human leukocyte antigen class I (HLA) ligands such as HLA-C can impact the activity of natural killer cells (NK cells) and determine the results of cancer immunity. Specific KIR-HLA combinations can enhance vulnerability by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity failing leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women.

The relationship between repeated measurements of HbA1c and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study.

BACKGROUND: In the ACCORD study, participants with the haptoglobin (Hp) 2-2 phenotype and glycated hemoglobin (HbA1c) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA1c 7.0-7.9%. However, this association was not observed in participants without the Hp2-2 phenotype. The optimal glycemic target for CAD prevention for the Hp phenotypes remains uncertain and may vary based on demographic and clinical factors. OBJECTIVE: To investigate how reaching clinically relevant HbA1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA1c ≤ 11% at baseline). METHODS: Cox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA1c (< 6.5%, 6.5-6.9%, and ≥ 8.0% compared to 7.0-7.9%), updated at years 1-4, 6, 8, and 10, and incident CAD in the Hp2-2 (n = 1,587) and non-Hp2-2 (n = 2,944) phenotypes separately. Further pre-specified subgroup analyses by age, sex, history of cardiovascular disease (CVD), race, and diabetes duration were performed in each Hp phenotype group separately. RESULTS: Compared with HbA1c 7.0-7.9%, having HbA1c < 6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 phenotype (adjusted HR 0.71, 95% CI 0.55-0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 phenotype who were male (0.60, 0.44-0.83), who did not have a history of CVD (0.65, 0.47-0.90), who were aged ≥ 65 years (0.64, 0.44-0.94), who were White (0.68, 0.51-0.91), or who had diabetes duration > 10 years (0.58, 0.35-0.95). HbA1c ≥ 8.0% was associated with CAD risk only among participants with the Hp2-2 phenotype who had a history of CVD (1.79, 1.00-3.20). No associations were found between the other HbA1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups. CONCLUSION: The differences in our results compared to our previous findings may be due to variations in the study populations and factors associated with weight loss, making it difficult to draw definitive conclusions. Our current findings should be considered in the context of hypothesis generation, and ideally, will encourage additional research in this field.

Mendelian randomization analysis on the impacts of age at menarche on adult height: A Taiwanese population study.

BACKGROUNDS: Ample evidence supports potential influence of age at menarche (AM) on adult height (AH), but multiple confounders may affect causal estimates. To address this issue, the Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on AH. METHODS: Using data (n = 57,349) from the publicly accessible Taiwan Biobank and randomly splitting them into 2 equal-size subsets, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM in the exploration subset and used these SNPs as instrumental variables to estimate the effects of instruments on AH in the validation subset based on two stage least squares (2SLS) regression. In addition, three more summary statistics-based approaches, namely inverse variance weighted (IVW), MR-Egger, and weighted median (WM) analyses, were used to verify the findings. We also performed heterogeneity and sensitivity analyses to evaluate the robustness of the results. RESULTS: We identified 4 leading SNPs associated with AM at the genome-wide significant level, whereas rs9409082 may exert some pleiotropic effects on AH. After eliminating rs9409082, the 2SLS analysis indicated that one year delay in genetically determined AM predicted 1.5 cm height gain in adulthood (ß = 1.508, 95% confidence interval [0.852, 2.163]). The causal relationship was also supported by WM (ß = 1.183, [0.329, 2.038]) and IVW (ß = 1.493, [0.523, 2.463]) methods. CONCLUSIONS: Evidence from the present MR study supports a causal relationship between later AM and taller AH.

Causal association between epilepsy and its DNA methylation profile and atrial fibrillation.

BACKGROUND: The "epileptic heart" concept is emerging, but the causal relationship between epilepsy and atrial fibrillation (AF) remains unclarified. OBJECTIVE: This study explores the genetic correlations and bidirectional causality between various epilepsy phenotypes and AF. METHODS: Genome-wide association study (GWAS) statistics for 10 epilepsy subtypes (29,944 cases, 52,538 controls) and AF (60,620 cases, 970,216 controls) were sourced from the International League Against Epilepsy (ILAE) and HGRI-EBI Catalog-GWAS, respectively. Linkage disequilibrium score regression (LDSC) and genome-wide Mendelian randomization (MR) evaluated genetic correlations and bidirectional causal relationships. Epilepsy-related DNA methylation data (N = ∼800) from Epigenome-Wide Association Study (EWAS) catalog were analyzed to identify causal CpG sites influencing risk of AF through epigenetic MR. RESULTS: LDSC revealed significant genetic correlations between 4 epilepsy subtypes and AF (correlation coefficient: rg from 0.116 to 0.241). Forward MR suggested a significant causal effect of focal epilepsy with hippocampal sclerosis (focal epilepsy [FE] with hippocampal sclerosis [HS]) on risk of AF (inverse variance weighting [IVW] and Mendelian randomized pleiotropy residual sum and outlier [MR-PRESSO]: odds ratio [OR] = 1.046, P ≤ .004), with results robust against heterogeneity, horizontal pleiotropy, and outliers. Epigenetic MR indicated that lower methylation at cg06222062 (OR = 0.994, P = 3.16E-04) mapped to PLA2G5 and cg08461451 mapped to SPPL2B gene (OR = 0.954, P = 1.19E-03), and higher cg10541930 in the C10orf143 promoter (OR = 1.043, P = 4.18E-22) increases risk of AF. Sensitivity analyses affirmed no pleiotropic bias. CONCLUSION: FE with HS significantly increases AF risk, highlighting the natural neural-cardiac connection and the need for cardiac monitoring in patients with epilepsy. Specific methylated CpG sites may serve as biomarkers and preventive targets for AF susceptibility.

Genetic Insights Into Leukemia Susceptibility in the Arab Population: A Scoping Review.

As per the Global Cancer Observatory, the WHO Eastern Mediterranean region (which includes the Arabic countries) ranks highest for age-standardized mortality rate at 4 per 100,000, thus indicating a probable role of genetic associations. Identifying the genes associated with leukemia in the Arab population is crucial for effective preventive and treatment strategies. This scoping review aimed to determine the nature and extent of research available on the genes associated with the major types of leukemia among the Arab population. As per the scoping review guidelines, a comprehensive search was conducted in PUBMED and Google Scholar for articles published before 01/10/2023 and focused on leukemia-related genes among the Arab population. In total 119 studies, focusing on genes associated with leukemia met the inclusion criteria. On reviewing these studies, 27 genes were found to be associated with ALL, 33 genes with AML, seven genes with CLL, and 14 genes with CML. The majority of these genes were associated with an increased risk for the disease. Notably, the 119 studies covered only nine out of the 22 Arab countries, with 56 studies carried out in Egypt, exhibiting an imbalance in the regional distribution of the research landscape. Thus, indicating the inadequacy of research on leukemia genetics in the Arab region in comparison to the Western studies. This finding highlights the need for extensive research in the Middle Eastern region to gain geographically heterogeneous genetic information about the Arab population. In conclusion, this scoping study highlights the genes associated with the major types of leukemia among the Arab population and also indicates the need for comprehensive and regionally balanced research on leukemia genetics in Middle Eastern countries. Addressing this gap is essential to provide robust genetic data that can be used for targeted interventions to improve leukemia outcomes in the Middle East. Increased research efforts in all Middle Eastern countries will contribute to a greater understanding of genetic predisposition and help develop effective prevention strategies and treatments tailored to this population.

Genetic association and causal effects between inflammatory bowel disease and conjunctivitis.

Background: Inflammatory bowel disease (IBD) is often clinically associated with conjunctivitis, which may result from genetic associations and causal effects. Methods: Genetic correlations were investigated through the genome-wide association study (GWAS) data on IBD and conjunctivitis using the linkage disequilibrium score regression (LDSC) and heritability estimated in summary statistics (HESS). The causal effect analysis was performed using four methods of Mendelian randomization (MR) and the genetic risk loci common to both diseases were identified by the statistical method of conditional/conjoint false discovery rate (cond/conjFDR), followed by genetic overlap analysis. Finally, a multi-trait GWAS analysis (MTAG) was performed to validate the identified shared loci. Results: IBD (including CD and UC) and conjunctivitis showed a significant overall correlation at the genomic level; however, the local correlation of IBD and CD with conjunctivitis was significant and limited to chromosome 11. MR analysis suggested a significant positive and non-significant negative correlation between IBD (including CD and UC) and conjunctivitis. The conjFDR analysis confirmed the genetic overlap between the two diseases. Additionally, MTAG was employed to identify and validate multiple genetic risk loci. Conclusion: The present study provides evidence of genetic structure and causal effects for the co-morbidity between IBD (both CD and UC) and conjunctivitis, expanding the epidemiologic understanding of the two diseases.

The genetic architecture of substance use and its diverse correlations with mental health traits.

Although harmful substance use is common and represented by shared symptom features and high genetic correlations, the underlying genetic relationships between substance use traits have not been fully explored. We have investigated the genetic architecture of substance use traits through exploratory and confirmatory factor analyses using genomic structural equation modeling (Genomic SEM), and explored genetic correlations between different aspects of substance use and mental health-related traits. Genomic SEM was used to identify latent factors representing the relationships between 14 substance use traits (alcohol, nicotine, cannabis and opioid use), and to confirm or modify existing latent factors for 38 mental health-related traits. A bi-factor model best explained the genetic overlap between substance use traits, including a general substance use factor and two sub-factors representing genetic liability specific to alcohol use or smoking. The SNP-based heritability of these factors ranged from 2 to 7 % and each factor had 10 or more independent significant SNPs identified. Bivariate correlations revealed patterns of genetic overlap with other mental health-related factors unique to each substance use factor. Variations in the genetic overlap between psychiatric traits and different aspects of substance use can be used to further investigate the pleiotropy present between these traits, and explore commonalities in etiology.

Understanding molecular mechanisms of vertebral number of variations on Mongolian sheep using candidate genes analysis.

Objective: This study aimed to investigate the genetic link between variations in vertebral number and meat production traits, such as body weight and body measurements (body length, body height, heart girth, and shin width) in Mongolian (Bayantsagaan) sheep. Additionally, we examined the association of single-nucleotide polymorphisms (SNPs) in candidate genes, particularly Vertnin (VRTN), Nuclear receptor subfamily 6, group A, member 1 (NR6A1), and synapse differentiation-inducing 1-like (SYNDIG1L), with vertebral number variations and their potential impact on meat production traits. Materials and Methods: The study involved 220 Bayantsagaan sheep from Bayantsagaan soum, Tov province, Mongolia, including 104 sheep with extra vertebrae group and 116 individuals with typical vertebral number as the control group. Morphological data, including body weight and body measurements, were collected, and genetic samples were obtained. The impact of vertebral number on morphological traits was estimated using a general linear model. SNPs in the VRTN, NR6A1, and SYNDIG1L genes were sequenced, and their association with vertebral number was analyzed using one-way ANOVA. Results: Bayantsagaan sheep with extra vertebrae were, on average, 4.45 kg heavier and exhibited higher variability in body size traits compared to the control group. Four polymorphic sites were identified at the VRTN gene, with one polymorphic locus (VRTN1716) showing a significant association with vertebrae number and body size. Sheep with C/C genotype at VRTN1716 locus, had more vertebrae and larger body size compared to other genotypes. Conclusion: The findings suggest that variations in vertebral number and VRTN gene polymorphisms are linked to favorable meat production traits in Bayantsagaan sheep. The identified SNP (VRTN1716) associated with vertebral number and body size offers the potential for marker-assisted selection in breeding programs. These results provide valuable insights into the genetic basis of meat production traits in Bayantsagaan sheep and may contribute to the development of more efficient breeding strategies.

Genetic association between post-traumatic stress disorder and cardiovascular disease: A scoping review.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder associated with adverse long-term health outcomes, including cardiovascular disease (CVD). Despite growing evidence that PTSD is positively associated with CVD, the biological mechanisms underlying this association are poorly understood. This review provides an overview of the current state of science on the genetic association between PTSD and CVD. MATERIAL AND METHODS: This scoping review identified studies from Pubmed, Embase, PsycINFO, and Web of Science. The search terms were a combination of PTSD, CVD/CVD-related traits, and a set of genetic molecules and related terms. This review followed the PRISMA Extension for Scoping Reviews guidelines. Eligible criteria included original studies that have genetic factors related to PTSD or CVD, conducted in humans, written in English, and published between 2003 and 2023 in peer-reviewed journals. RESULTS: A total of twenty-three studies were included; PTSD correlated with genetic variants in CVD-related traits and gene expression in regulatory pathways contributing to CVD development. Common CVD-related traits involved in genetic associations with PTSD were inflammation, cellular aging, increased blood pressure, hypothalamus-pituitary-adrenal axis dysregulation, metabolic syndrome, and oxidative stress. These traits may explain potential underlying mechanisms between PTSD and CVD. Evidence of a causal relationship between the two diseases was insufficient. DISCUSSION: PTSD and CVD/CVD-related traits are genetically associated. Further research is needed to comprehensively explore gene-environment interactions and the cumulative impact of behavioral and psychological factors on the pathophysiological mechanisms between PTSD and CVD.

Genetic Variations and Nonalcoholic Fatty Liver Disease: Field Synopsis, Systematic Meta-Analysis, and Epidemiological Evidence.

Objective: To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease (NAFLD). Methods: Literature from Web of Science, PubMed, and Embase between January 1980 and September 2022 was systematically searched. Meta-analyses of the genetic variants were conducted using at least five data sources. The epidemiologic credibility of the significant associations was graded using the Venice criteria. Results: Based on literature screening, 399 eligible studies were included, comprising 381 candidate gene association, 16 genome-wide association, and 2 whole-exome sequencing studies. We identified 465 genetic variants in 173 genes in candidate gene association studies, and 25 genetic variants in 17 genes were included in the meta-analysis. The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD, with cumulative epidemiological evidence of an association graded as strong for two variants in two genes ( HFE, TNF), moderate for four variants in three genes ( TM6SF2, GCKR, and ADIPOQ), and weak for five variants in five genes ( MBOAT7, PEMT, PNPLA3, LEPR, and MTHFR). Conclusion: This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD, which may help understand the genetic architecture of NAFLD risk.

Association of rare single nucleotide variant MUC5B rs35705950 with interstitial lung disease in Japanese rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. METHODS: Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. RESULTS: MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. CONCLUSIONS: MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.

Impact of multiple obesity metrics on hypertensive disorders of pregnancy: a meta-analysis and Mendelian randomisation study.

BACKGROUND: The relationships between various obesity measures and hypertensive disorders of pregnancy (HDP) remain inadequately explored, and their causal links are not well understood. This study aims to clarify these associations and investigate the mediating role of triglycerides. METHODS: We conducted a comprehensive meta-analysis of observational studies alongside Mendelian randomisation (MR) analysis to assess the impact of 10 obesity measures on HDP risk. Additionally, we evaluated the mediating effect of triglycerides. RESULTS: Our meta-analysis revealed significant associations between maternal prepregnancy overweight/obesity and increased risks of gestational hypertension (GH) (overweight: OR=1.98, 95% CI 1.83 to 2.15; obesity: OR=3.77, 95% CI 3.45 to 4.13) and pre-eclampsia (overweight: OR=1.78, 95% CI 1.67 to 1.90; obesity: OR=3.46, 95% CI 3.16 to 3.79). Higher maternal waist circumference (WC) was also linked to increased pre-eclampsia risk (OR=1.45, 95% CI 1.14 to 1.83). MR analyses indicated that each 1-SD increase in genetically predicted obesity measures (whole body fat mass, body fat percentage, trunk fat mass, trunk fat percentage, body mass index, WC, hip circumference) was associated with higher risks of GH and pre-eclampsia. Triglycerides mediated 4.3%-14.1% of the total genetic effect of these obesity measures on GH and pre-eclampsia risks. CONCLUSIONS: This study demonstrates that various obesity measures are causally linked to increased HDP risk and highlights the mediating role of triglycerides. These findings could inform clinical practices and public health strategies aimed at reducing HDP through targeted obesity and triglyceride management.

Establishing causal relationships between insomnia and gestational diabetes mellitus using Mendelian randomization.

Background: Gestational diabetes mellitus (GDM) is a common condition observed globally, and previous studies have suggested a link between GDM and insomnia. The objective of this study was to elucidate the causative relationship between insomnia and GDM, and to investigate the influence of factors related to insomnia on GDM. Methods: We performed bidirectional Mendelian randomization (MR) analyses using single nucleotide polymorphisms (SNPs) as genetic instruments for exposure and mediators, thereby minimizing bias due to confounding and reverse causation. The Cochran Q test was utilized for heterogeneity analysis, MR-Egger regression for pleiotropy assessment, and the leave-one-out method for evaluating the robustness of the results. Additionally, we determined the causal relationships between GDM and other factors such as coffee consumption, alcohol intake, and household income. Results: Insomnia was positively associated with GDM, as indicated by 39 SNPs (OR = 1.27, 95 % CI 1.12-1.439, P-value = 0.008). Conversely, the MR analysis did not reveal any causal relationship between GDM and insomnia (OR = 1.032, 95 % CI 0.994-1.071, P-value = 0.99). Additionally, no causal relationship was observed between coffee consumption, alcohol intake, household income, and GDM (all P-values >0.05). Conclusion: Our study indicates that insomnia elevates the risk of GDM, thereby establishing a causal link with GDM, independent of coffee consumption, alcohol intake, and household income.

How should we measure population-level inbreeding depression? Impacts of standing genetic associations between selfing rate and deleterious mutations.

Inbreeding depression (ID) is a major selective force during mating system evolution primarily contributed by highly to partially recessive deleterious mutations. Theories suggest that transient genetic association with fitness alleles can be important in affecting the evolution of alleles that modify the selfing rate during its sweep. Nevertheless, empirical tests often focus on the pre-existing genetic association between selfing rate and ID maintained under mutation-selection balance. Therefore, how this standing genetic association is affected by key factors and its impacts on the evolution of selfing remain unclear. I show that as the selection coefficient of deleterious mutations increases, the association between selfing rate and ID declines from positive to negative. These results predict that association between selfing and ID tends to be negative in populations with low selfing rates, while positive in highly selfing populations. Using population genetic and quantitative genetic models, I show that standing genetic associations between selfing rate and fitness alleles can significantly impact the evolution of the mean selfing rate of a population. I present better metrics of population-level ID, which can be calculated based on the correlation coefficient between individual selfing rate and the fitness of selfed and outcrossed offspring.

CWAS-Plus: estimating category-wide association of rare noncoding variation from whole-genome sequencing data with cell-type-specific functional data.

Variants in cis-regulatory elements link the noncoding genome to human pathology; however, detailed analytic tools for understanding the association between cell-level brain pathology and noncoding variants are lacking. CWAS-Plus, adapted from a Python package for category-wide association testing (CWAS), enhances noncoding variant analysis by integrating both whole-genome sequencing (WGS) and user-provided functional data. With simplified parameter settings and an efficient multiple testing correction method, CWAS-Plus conducts the CWAS workflow 50 times faster than CWAS, making it more accessible and user-friendly for researchers. Here, we used a single-nuclei assay for transposase-accessible chromatin with sequencing to facilitate CWAS-guided noncoding variant analysis at cell-type-specific enhancers and promoters. Examining autism spectrum disorder WGS data (n = 7280), CWAS-Plus identified noncoding de novo variant associations in transcription factor binding sites within conserved loci. Independently, in Alzheimer's disease WGS data (n = 1087), CWAS-Plus detected rare noncoding variant associations in microglia-specific regulatory elements. These findings highlight CWAS-Plus's utility in genomic disorders and scalability for processing large-scale WGS data and in multiple-testing corrections. CWAS-Plus and its user manual are available at https://github.com/joonan-lab/cwas/ and https://cwas-plus.readthedocs.io/en/latest/, respectively.

Detection of Polymorphisms in FASN, DGAT1, and PPARGC1A Genes and Their Association with Milk Yield and Composition Traits in River Buffalo of Bangladesh.

This study aimed to identify SNPs in the intron, exon, and UTR regions of the FASN, DGAT1, and PPARGC1A genes and to investigate their possible association with milk yield and composition traits in the riverine buffalo of Bangladesh. A total of 150 DNA samples from riverine buffalo were used for PCR amplification with five pairs of primers, followed by association studies using a generalized linear model in R. SNP genotyping was performed by direct sequencing of the respective amplicon. Traits analyzed included DMY, fat%, protein%, and SNF%. This study identified 8 SNPs in FASN (g.7163G>A and g.7271C>T), DGAT1 (g.7809C>T and g.8525C>T) and PPARGC1A (g.387642C>T, g.387758A>G, g.409354A>G, and g.409452G>A). Genotypic and allelic frequencies differed significantly for each SNP genotype and did not follow the Hardy-Weinberg principle (p < 0.01 or p < 0.001) in most cases. The g.7163G>A and g.7271C>T SNP genotypes of the FASN gene were significantly associated with milk fat%, with the latter also significantly associated with SNF%. The g.8525C>T polymorphism of the DGAT1 gene significantly affected protein% (p < 0.01). Additionally, PPARGC1A gene polymorphisms showed significant associations: g.387642C>T with fat% (p < 0.05); g.387758A>G and g.409354A>G with protein% (p < 0.001) and SNF% (p < 0.01); and g.409452G>A with DMY (p < 0.001), fat% (p < 0.05), and protein% (p < 0.01). Reconstructed haplotypes of the PPARGC1A gene were significantly associated (p < 0.01) with all traits except SNF%. These findings suggest that polymorphisms in these three candidate genes have the potential as molecular markers for improving milk yield and composition traits in the riverine buffalo of Bangladesh.

Genetic and Epigenetic Association of FOXP3 with Papillary Thyroid Cancer Predisposition.

Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy with an increased female incidence ratio. The specific traits of X chromosome inheritance may be implicated in gender differences of PTC predisposition. The aim of this study was to investigate the association of two X-linked genes, Forkhead Box P3 (FOXP3) and Protein Phosphatase 1 Regulatory Subunit 3F (PPP1R3F), with PTC predisposition and gender disparity. One hundred thirty-six patients with PTC and an equal number of matched healthy volunteers were enrolled in the study. Genotyping for rs3761548 (FOXP3) and rs5953283 (PPP1R3F) was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). The methylation status of FOXP3 was assessed using the combined bisulfite restriction analysis (COBRA) method. The SPSS software was used for statistical analyses. Gender stratification analysis revealed that the CA and AA genotypes and the A allele of FOXP3 rs3761548 variant are associated with PTC predisposition only in females. Moreover, different methylation status was observed up to the promoter locus of FOXP3 between PTC female patients, carrying the CA and CC genotype, and controls. Both revealed associations may explain the higher PTC incidence in females through reducing FOXP3 expression as reported in immune related blood cells.

Assessment tools for cognitive performance in Parkinson's disease and its genetic contributors.

Background: We have shown that genetic factors associating with motor progression of Parkinson's disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better. Methods: Data were obtained from the Parkinson's Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD. Results: SDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323. Conclusion: SDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.