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Body conformation traits are directly associated with longevity, fertility, health, and workability in dairy cows and have been under direct genetic selection for many decades in various countries worldwide. The main objectives of this study were to perform genome-wide association studies and functional enrichment analyses for fourteen body conformation traits using imputed high-density single nucleotide polymorphism (SNP) genotypes. The traits analyzed include body condition score (BCS), body depth (BD), bone quality (BQ), chest width (CW), dairy capacity (DC), foot angle (FAN), front legs view (FLV), heel depth (HDe), height at front end (HFE), locomotion (LOC), rear legs rear view (RLRV), rear legs side view (RLSV), stature (ST), and a composite feet and legs score index (FL) of Holstein cows scored in Canada. De-regressed estimated breeding values from a dataset of 39,135 North American Holstein animals were used as pseudo-phenotypes in the genome-wide association analyses. A mixed linear model was used to estimate the SNP effects, which ranged from 239,533 to 242,747 markers depending on the trait analyzed. Genes and quantitative trait loci (QTL) located up to 100 Kb upstream or downstream of the significant SNPs previously cited in the Animal QTLdb were detected, and functional enrichment analyses were performed for the candidate genes identified for each trait. A total of 20, 60, 13, 17, 27, 8, 7, 19, 4, 10, 13, 15, 7, and 13 genome-wide statistically significant SNPs for Bonferroni correction based on independent chromosomal segments were identified for BCS, BD, BQ, CW, DC, FAN, FLV, HDe, HFE, LOC, RLRV, RLSV, ST, and FL, respectively. The significant SNPs were located across the whole genome, except on chromosomes BTA24, BTA27, and BTA29. Four markers (for BCS, BD, HDe, and RLRV) were statistically significant when considering a much stricter threshold for the Bonferroni correction for multiple tests. Moreover, the genomic regions identified overlap with various QTL previously reported for the trait groups of exterior, health, meat and carcass, milk, production, and reproduction. The functional enrichment analyses revealed 27 significant gene ontology terms. These enriched genomic regions harbor various candidate genes previously reported as linked to bone development, metabolism, as well as infectious and immunological diseases. [ABSTRACT FROM AUTHOR]

Objective: The pathogenesis of antituberculosis drug-induced liver injury (AT-DILI) remains largely unknown. The current investigation aimed to determine the genetic contribution of the nuclear receptor subfamily 1 Group I member 3 (NR1I3) and nuclear receptor subfamily 1 Group H member 4 (NR1H4) genes to the risk of AT-DILI in the Chinese population. Methods: A 1:4 matched case‒control study was conducted, and five single nucleotide polymorphisms (SNPs) in the NR1I3 and NR1H4 genes were detected and assessed. Utilizing a multivariate conditional logistic regression model, the effects of haplotype and genotype on the risk of AT-DILI were examined. Extended subgroup analysis was carried out based on sex. The distribution of the peak value of serum liver enzymes also compared among different genotypes. Results: 224 AT-DILI cases and 896 controls were included in this study. No significant difference was observed in genotypes or haplotypes frequencies between AT-DILI cases and controls. However, comparisons of liver function indicators revealed significant differences in the peak values of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) among patients with different genotypes of NR1H4 rs56163822 (GG vs. GT vs. TT, 27.1 U/L vs. 26.0 U/L vs. 23.0 U/L, p = 0.020; 34.0 U/L vs. 31.0 U/L vs. 30.6 U/L, p = 0.008; 15.5 μmol/L vs. 15.0 μmol/L vs. 13.7 μmol/L, p = 0.029, respectively), as well as in the peak values of ALT and AST among male patients with different genotypes of NR1H4 rs56163822 (29.0 U/L vs. 26.9 U/L vs. 22.6 U/L, p = 0.002; 34.0 U/L vs. 32.0 U/L vs. 30.5 U/L, p = 0.019, respectively). Conclusion: Based on this 1:4 individual-matched case‒control study, the SNP rs56163822 in the NR1H4 gene may be linked to the susceptibility to AT-DILI in Chinese patients receiving anti-TB treatment. Further studies in larger varied populations are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Introduction: Multiple linked single nucleotide polymorphisms (SNPs) have shown potential in personal identification and mixture detection. However, the limited number of marker and sequencing errors have obstructed accurate DNA typing. Methods: To develop more candidate loci, the diversity value (D-value) was introduced as a new parameter for screening the novel polymorphic multiple linked-SNP markers, referred to as multi-SNP. In this study, a "FD Multi-SNP Mixture Kit" comprising 567 multi-SNPs was developed for mixture detection. Additionally, a new computational error correction method was applied as a quality control approach for sequencing data. Results: The results demonstrated higher typing success rates than the conventional CE typing method. For single-source DNA, approximately 70-80 loci were detected with a DNA input of 0.009765625 ng. More than 65% of the minor alleles were distinguishable at 1 ng DNA with a frequency of 0.5% in 2- to 4- person mixtures. Conclusion: This study offers a polymorphic and high-resolution detection method for DNA genotyping and complex mixture detection, providing an alternative strategy for addressing challenging mixed DNA traces. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate the causal relationship between phosphatidylcholine (PC) levels and dysmenorrhea using Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis using GWAS data on PC levels and dysmenorrhea. Single nucleotide polymorphisms (SNPs) associated with PC levels were used as instrumental variables. MR-Egger regression and inverse variance weighting (IVW) were used to estimate the causal effect of PC levels on dysmenorrhea. Sensitivity analyses were performed to assess the robustness of the results. Results: The IVW analysis revealed a significant positive association between higher PC levels and dysmenorrhea (OR: 1.533, 95% CI: 1.039-2.262, P = 0.031). The MR-Egger regression did not detect pleiotropy. Sensitivity analyses confirmed the robustness of the results. Conclusion: This study provides evidence suggesting a causal link between increased PC levels and dysmenorrhea. Further research is needed to understand the biological mechanisms underlying this relationship and to explore potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Since the turn of the 21st century, genome-wide association study (GWAS) have successfully identified genetic signals associated with a myriad of common complex traits and diseases. As we transition from establishing robust genetic associations with diverse phenotypes, the central challenge is now focused on characterizing the underlying functional mechanisms driving these signals. Previous GWAS efforts have revealed multiple variants, each conferring relatively subtle susceptibility, collectively contributing to the pathogenesis of various common diseases. Such variants can further exhibit associations with multiple other traits and differ across ancestries, plus disentangling causal variants from non-causal due to linkage disequilibrium complexities can lead to challenges in drawing direct biological conclusions. Combined with cellular context considerations, such challenges can reduce the capacity to definitively elucidate the biological significance of GWAS signals, limiting the potential to define mechanistic insights. This review will detail current and anticipated approaches for functional interpretation of GWAS signals, both in terms of characterizing the underlying causal variants and the corresponding effector genes. [ABSTRACT FROM AUTHOR]

Background: Acute pancreatitis (AP) is an extraintestinal manifestation of inflammatory bowel disease (IBD). Numerous observational studies have reported an increased risk of AP in patients diagnosed with IBD. However, the causal association and directionality between IBD or its subtypes and the development of AP remains unclear due to the limitations of observational research. This study aims to explore the relationship between IBD or its subtypes and AP risk using Mendelian Randomization (MR) method. Methods: A two-sample bidirectional MR study was conducted, selecting genetic variants associated with IBD and AP as instrumental variables from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and FinnGen databases, respectively. The inverse-variance weighted (IVW) method used as the primary approach for causal inference. The Cochran Q test was employed for heterogeneity assessment. Sensitivity analyses were performed using the MR Egger intercept test, MR-Presso, and Leave-one-out method. Results: The results revealed that IBD (OR = 1.049, 95% CI = 1.010-1.090, p = 0.013) and ulcerative colitis (UC) (OR = 1.057, 95% CI = 1.013-1.102, p = 0.011) were significantly associated with an increased risk of AP. However, Crohn's disease (CD) (OR = 1.023, 95% CI = 0.993-1.055, p = 0.134) did not show a causal association with the risk of AP. Interestingly, AP was suggestively associated with a decreased risk of CD (OR = 0.797, 95% CI = 0.637-0.997, p = 0.047). Furthermore, there was no causal association between AP and the risk of IBD (OR = 0.886, 95% CI = 0.753-1.042, p = 0.144) or UC (OR = 0.947, 95% CI = 0.773-1.159, p = 0.595). Conclusion: In conclusion, this study provides genetic evidence supporting the causal influence of IBD (specifically UC) on AP, while CD does not appear to have a causal impact on AP. [ABSTRACT FROM AUTHOR]

Introduction: Male pattern baldness (MPB), also known as androgenetic alopecia, represents the most prevalent form of progressive hair loss in humans. It is characterized by a distinctive pattern of hair loss progression from the scalp; however, its underlying mechanism remains elusive and is influenced by hereditary, immune, and environmental factors. Genome-wide association studies (GWASs) have uncovered numerous risk genes/loci among European individuals with MPB. However, the validation of these susceptibility genes/loci within Han Chinese men remains largely unexplored. The aim of this study was to investigate whether the 71 susceptibility loci identified in a recent GWAS among European men also confer risk for MPB in Chinese men. Methods: Forty-seven single nucleotide polymorphisms (SNPs) previously reported in GWASs of MPB were selected and genotyped in independent individuals comprising 499 Han Chinese cases and 1,489 controls using the Sequenom MassArray system. After stringent quality control measures, 25 SNPs were subjected to statistical analyses. Cochran-Armitage trend test was used to evaluate the association between SNPs and disease susceptibility. To address multiple tests, Bonferroni correction was conducted, setting the threshold for statistical significance at a p-value <2 × 10-3 (0.05/25). Results: The rs13405699 SNP located at 2q31.1 exhibited a significant association with MPB in Han Chinese men (p = 4.84 × 10-5, OR = 1.37, 95% CI: 1.18-1.59). Moreover, the difference in rs13405699 genotype distribution between MPB cases and controls was statistically significant (p = 7.00 × 10-5). Genotype-based association analysis suggested that the recessive model provided the best fit for the rs13405699 polymorphism. Conclusion: This study represents the first confirmation of the association between the rs13405699 SNP at 2q31.1 and MPB within the Han Chinese population, thereby enhancing our understanding of the genetic underpinnings of MPB. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have found associations between reproductive factors and bone density in women. However, the causal relationships are not well understood. This study aims to investigate whether various reproductive factors are causally related to bone density at different skeletal sites using both univariable and multivariable Mendelian randomization (MR) methods. Methods: The study incorporated four reproductive factors, namely, age at menarche (AAM), age at first live birth (AFB), age at menopause (ANM), and age at last live birth (ALB), as well as five distinct skeletal sites, including bone mineral density (BMD), heel calcaneus BMD, ultradistal forearm bone mineral density (FA-BMD), lumbar spine bone mineral density (LS-BMD), and femoral neck bone mineral density (FN-BMD). Univariable two-sample MR and multivariable MR analyses were conducted using data from published genome-wide association studies (GWASs). A total of 150 single nucleotide polymorphisms (SNPs) associated with the four reproductive factors were extracted from GWAS databases. The primary statistical analysis method utilized in this study was the inverse variance weighted (IVW) method. Results: In the univariate MR analysis, we observed causal connections between four reproductive factors and bone density. Specifically, AAM had a significant impact on BMD and heel calcaneus BMD. Age at first live birth was negatively associated with FA-BMD. Age at last live birth showed a negative correlation with BMD and heel calcaneus BMD. ANM exhibited positive associations with BMD, heel calcaneus BMD, FA-BMD, and LS-BMD. Subsequently, we performed a multivariable MR analysis to examine the combined effects of multiple variables, which confirmed the persistence of associations between age at menopause and bone density at various sites. Additionally, we found a negative correlation between age at last live birth and heel calcaneus BMD. Conclusion: This study offers a fresh perspective on the prevention of osteoporosis in women, explicitly stating that reproductive factors such as early menopause and late childbirth play a significant predictive role in individual bone density decline. Therefore, when developing osteoporosis screening and management protocols, reproductive factors should be included for a more comprehensive guidance of clinical practice. [ABSTRACT FROM AUTHOR]

Ethanol's anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanol's acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target specific Nin splice variants, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and found that total Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified eight differentially utilized exons and significant exon-skipping events between the strains, including three novel splicing events in the 3' end of the Nin gene that were specific to the D2 strain. Additionally, we document multiple single nucleotide polymorphisms in D2 Nin exons that are predicted to have deleterious effects on protein function. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression and function between B6 and D2 mice, thus possibly contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work adds novel information to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder. [ABSTRACT FROM AUTHOR]

The traditional single nucleotide polymorphism (SNP)-wise approach in genomewide association studies is focused on examining the marginal association between each SNP with the outcome separately and applying multiple testing adjustments to the resulting p-values to reduce false positives. However, the approach suffers a lack of power in identifying biomarkers. We design an ensemble machine learning approach to aggregate results from logistic regression models based on multiple subsamples, which helps to identify biomarkers from high-dimensional genomic data. We use different methods to analyze a genome-wide association study from the Alzheimer's Disease Neuroimaging Initiative. The SNP-wise approach does not identify any significant signal, while our novel approach provides a list of ranked SNPs associated with the cognitive functions of interests. [ABSTRACT FROM AUTHOR]

Purpose: Statins may have a protective effect against osteoarthritis (including knee osteoarthritis and hip osteoarthritis); however, the link between statins and osteoarthritis risk is incompletely established. The aim of this study was to explore the relationship between statins and osteoarthritis risk through Mendelian randomization analysis using pooled information from a large population-wide genome-wide association study (GWAS). Methods: Statin-related single-nucleotide polymorphisms (SNPs) were obtained from FinnGen's latest 9th edition database, and data on osteoarthritis, knee osteoarthritis, and hip osteoarthritis were acquired from the IEU OpenGWAS, the UK Biobank, and Arthritis Research UK Osteoarthritis Genetics (ArcOGEN) database, respectively. The inverse-variance weighting method is an important analysis method to estimate the causal effect. Weighted median method, simple median method, weighted median estimator method, and MR-Egger regression were employed to supplement the explanation. Odds ratio and 95%CI were used to evaluate the causal relationship among statins and the osteoarthritis risk, osteoarthritis in the knee, and osteoarthritis in the hip. Second, sensitivity analysis was carried out to validate the reliability of the results. Cochran's Q test was employed to test heterogeneity, MR-Egger intercept was employed to test whether horizontal pleiotropy existed, and single-nucleotide polymorphisms with potential influence were determined by the one-method analysis. Results: (1) The results of the inverse variance weighting method showed Gene prediction indicated that statins were associated with osteoarthritis (OR = 0.998, 95% CI: 0.996-0.999, P = 0.01) and knee osteoarthritis (OR = 0.964, 95% CI: knee (0.940-0.989, P = 0.005) and hip osteoarthritis risk were associated (OR = 0.928, 95% CI: 0.901-0.955, P = 4.28 × 10-7). (2) MR-Egger intercept analysis did not detect potential horizontal pleiotropy (osteoarthritis: P = 0.658; knee osteoarthritis: P = 0.600; and hip osteoarthritis: P = 0.141). (3) The findings provide evidence that statins reduce osteoarthritis risk, osteoarthritis in the knee, and osteoarthritis in the hip, as described in observational studies, and the specific mechanisms by which statins treat osteoarthritis require further investigation. Conclusion: The results of this study, at the genetic level, reveal a negative causal relationship between statins and osteoarthritis, and this causal relationship is also present in knee and hip osteoarthritis. This study provides evidence against the potential of statins in the treatment of osteoarthritis, prompting the clinical treatment of osteoarthritis to consider improving the start and compliance of statins in the future. [ABSTRACT FROM AUTHOR]

Background: The intricate relationship among gut microbiota, serum metabolites, and immunophenotypes may significantly impact myocarditis. However, direct causal links between these domains and myocarditis are not well understood. Methods: The study performed Mendelian randomization (MR) analysis using genetic data from public sources. Exposure data included 211 gut microbiota, 486 serum metabolites, and 731 immunophenotypes from Mibiogen, the Metabolomics GWAS server, and GWAS catalog databases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on established criteria. Myocarditis data from GWAS (427,911 participants, 24, 180, 570 SNPs) were used as the outcome variable. MR analysis was conducted using Inverse Variance Weighting (IVW), with Cochran's Q test for heterogeneity and Egger's intercept to assess horizontal pleiotropy. Results: 9 gut microbiota, 10 serum metabolites, and 2 immunophenotypes were negatively associated with myocarditis risk. In contrast, 5 gut microbiota, 12 serum metabolites, and 7 immunophenotypes were positively associated with myocarditis risk (all, P < 0.05). Sensitivity analyses confirmed the stability of these results. Conclusion: This MR study suggests that gut microbiota, serum metabolites, and immunophenotypes may causally influence myocarditis risk. These findings provide genetic evidence for myocarditis etiology and could inform future precision prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) represent the most prevalent form of genomic polymorphism and are extensively used in population genetics research. Using dd-RAD sequencing, a high-throughput sequencing method, we investigated the genome-level diversity, population structure, and phylogenetic relationships among three morphological forms of the widely distributed taxon Cryptotaenia japonica Hassk., which is native to East Asia. Our study aimed to assess the species status of C. japonica according to its genetic structure and genetic diversity patterns among 66 naturally distributed populations, comprising 26 C. japonica f. japonica, 36 C. japonica f. dissecta (Y. Yabe) Hara and 4 C. japonica f. pinnatisecta S. L. Liou accessions. Based on genomic SNP data generated by dd-RAD sequencing, we conducted genetic diversity, principal component, neighbor-joining (NJ) phylogenetic, admixture clustering, and population differentiation analyses. The findings revealed the following: (1) 5,39,946 unlinked, high-quality SNPs, with mean p, HO, HE and FIS values of 0.062, 0.066, 0.043 and -0.014, respectively, were generated; (2) population divergence was unaffected by isolation through distance; (3) six main distinct regions corresponding to geographic locations and exhibiting various levels of genetic diversity were identified; (4) pairwise FST analysis showed significant (P < 0.05) population differentiation in 0%-14% of populations among the six regions after sequential Bonferroni correction; and (5) three migration events (historical gene flow) indicated east? west directionality. Moreover, contemporary gene flow analysis using Jost's D, Nei's GST, and Nm values highlighted the middle latitude area of East Asia as a significant contributor to genetic structuring in C. japonica. Overall, our study elucidates the relatively low genetic differentiation and population structure of C. japonica across East Asia, further enhancing our understanding of plant lineage diversification in the Sino-Japanese Floristic Region. [ABSTRACT FROM AUTHOR]

Introduction: Targeted single nucleotide polymorphisms (SNPs) have been used in genomic prediction methodologies to enhance the accuracy of associated genetic transmitting abilities in Holstein cows. The objective of this study was to identify and validate SNPs associated with fertility traits impacting early embryo mortality. Methods: The mRNA sequencing data from day 16 normal (n = 9) and embryo mortality (n = 6) conceptuses from lactating multiparous Holstein cows were used to detect SNPs. The selection of specific genes with SNPs as preliminary candidates was based on associations with reproductive and fertility traits. Validation of candidate SNPs and genotype-to-phenotype analyses were conducted in a separate cohort of lactating primiparous Holstein cows (n = 500). After genotyping, candidate SNPs were filtered using a quality control pipeline via PLINK software. Continuous numeric and binary models from reproductive traits were evaluated using the mixed procedure for a generalized linear model-one way ANOVA or logistic regression, respectively. Results: Sixty-nine candidate SNPs were initially identified, but only 23 passed quality control procedures. Ultimately, the study incorporated 466 observations for statistical analysis after excluding animals with missing genotypes or phenotypes. Significant (p <0.05) associations with fertility traits were identified in seven of the 23 SNPs: DSC2 (cows with the A allele were older at first calving); SREBF1 and UBD (cows with the T or G alleles took longer to conceive); DECR1 and FASN (cows with the C allele were less likely to become pregnant at first artificial insemination); SREBF1 and BOLA-DMB (cows with the T allele were less likely to be pregnant at 150 days in milk). It was also determined that two candidate SNPs within the DSC2 gene were tag SNPs. Only DSC2 SNPs had an important allele substitution effect in cows with the G allele, which had a decreased age at first calving by 10 days. Discussion: Candidate SNPs found in this study could be used to develop genetic selection tools to improve fertility traits in dairy production systems. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) has, despite significant improvements in patient survival, increasingly become associated with neurological deficits during infancy that persist into adulthood. These impairments afflict a wide range of behavioral domains including executive function, motor learning and coordination, social interaction, and language acquisition, reflecting alterations in multiple brain areas. In the past few decades, it has become clear that CHD is highly genetically heterogeneous, with large chromosomal aneuploidies and copy number variants (CNVs) as well as single nucleotide polymorphisms (SNPs) being implicated in CHD pathogenesis. Intriguingly, many of the identified loss-of-function genetic variants occur in genes important for primary cilia integrity and function, hinting at a key role for primary cilia in CHD. Here we review the current evidence for CHD primary cilia associated genetic variants, their independent functions during cardiac and brain development and their influence on behavior. We also highlight the role of environmental exposures in CHD, including stressors such as surgical factors and anesthesia, and how they might interact with ciliary genetic predispositions to determine the final neurodevelopmental outcome. The multifactorial nature of CHD and neurological impairments linked with it will, on one hand, likely necessitate therapeutic targeting of molecular pathways and neurobehavioral deficits shared by disparate forms of CHD. On the other hand, strategies for betterCHD patient stratification based on genomic data, gestational and surgical history, and CHD complexity would allow for more precise therapeutic targeting of comorbid neurological deficits. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to replicate associations of GWAS-significant loci with severe COVID-19 in the population of Central Russia, to investigate associations of the SNPs with thromboinflammation parameters, to analyze gene-gene and gene-environmental interactions. Materials and Methods: DNA samples from 798 unrelated Caucasian subjects from Central Russia (199 hospitalized COVID-19 patients and 599 controls with a mild or asymptomatic course of COVID-19) were genotyped using probe-based polymerase chain reaction for 10 GWAS-significant SNPs: rs143334143 CCHCR1, rs111837807 CCHCR1, rs17078346 SLC6A20-LLZTFL1, rs17713054 SLC6A20-LLZTFL1, rs7949972 ELF5, rs61882275 ELF5, rs12585036 ATP11A, rs67579710 THBS3, THBS3-AS1, rs12610495 DPP9, rs9636867 IFNAR2. Results: SNP rs17713054 SLC6A20-LZTFL1 was associated with increased risk of severe COVID-19 in the entire group (risk allele A, OR = 1.78, 95% CI = 1.22-2.6, p = 0.003), obese individuals (OR = 2.31, 95% CI = 1.52-3.5, p = 0.0002, (pbonf = 0.0004)), patients with low fruit and vegetable intake (OR = 1.72, 95% CI = 1.15-2.58, p = 0.01, (pbonf = 0.02)), low physical activity (OR = 1.93, 95% CI = 1.26-2.94, p = 0.0035, (pbonf = 0.007)), and nonsmokers (OR = 1.65, 95% CI = 1.11-2.46, p = 0.02). This SNP correlated with increased BMI (p = 0.006) and worsened thrombodynamic parameters (maximum optical density of the formed clot, D (p = 0.02), delayed appearance of spontaneous clots, Tsp (p = 0.02), clot size 30 min after coagulation activation, CS (p = 0.036)). SNP rs17078346 SLC6A20-LZTFL1 was linked with increased BMI (p = 0.01) and severe COVID-19 in obese individuals (risk allele C, OR = 1.72, 95% CI = 1.15-2.58, p = 0.01, (pbonf = 0.02)). SNP rs12610495 DPP9 was associated with increased BMI (p = 0.01), severe COVID-19 in obese patients (risk allele G, OR = 1.48, 95% CI = 1.09-2.01, p = 0.01, (pbonf = 0.02)), and worsened thrombodynamic parameters (time to the start of clot growth, Tlag (p = 0.01)). For rs7949972 ELF5, a protective effect against severe COVID-19 was observed in non-obese patients (effect allele T, OR = 0.67, 95% CI = 0.47-0.95, p = 0.02, (pbonf = 0.04)), improving thrombodynamic parameters (CS (p = 0.02), stationary spatial clot growth rates, Vst (p = 0.02)). Finally, rs12585036 ATP11A exhibited a protective effect against severe COVID-19 in males (protective allele A, OR = 0.51, 95% CI = 0.32-0.83, p = 0.004). SNPs rs67579710 THBS3, THBS3-AS1, rs17713054 SLC6A20-LZTFL1, rs7949972 ELF5, rs9636867 IFNAR2--were involved in two or more of the most significant G×G interactions (pperm = 0.01). The pairwise combination rs67579710 THBS3, THBS3-AS1 × rs17713054 SLC6A20-LZTFL1 was a priority in determining susceptibility to severe COVID-19 (it was included in four of the top five most significant SNP-SNP interaction models). Conclusion: Overall, this study represents a comprehensive molecular-genetic and bioinformatics analysis of the involvement of GWAS-significant loci in the molecular mechanisms of severe COVID-19, gene-gene and geneenvironmental interactions, and provides evidence of their relationship with thromboinflammation parameters in patients hospitalized in intensive care units. [ABSTRACT FROM AUTHOR]

Knowledge of past and present genetic diversity within a breed is critical for the design and optimization of breeding programs as well as the development of strategies for the conservation of genetic resources. The Polypay sheep breed was developed at the U.S. Sheep Experiment Station (USSES) in 1968 with the goal of improving productivity in Western U.S. range flocks. It has since flourished in the more intensively managed production systems throughout the U.S. The genetic diversity of the breed has yet to be documented. Therefore, the primary objective of this study was to perform a comprehensive evaluation of the genetic diversity and population structure of U.S. Polypay sheep using both pedigree- and genomic-based methods. Pedigree data from 193 Polypay flocks participating in the National Sheep Improvement Program (NSIP) were combined with pedigree records from USSES (n = 162,997), tracing back to the breed's origin. A subset of these pedigreed sheep from 32 flocks born from 2011 to 2023 were genotyped with the GGP Ovine 50K BeadChip containing 51,867 single nucleotide polymorphisms (SNPs). Four subgroups were used for the pedigree-based analyses: 1) the current generation of animals born in 2020--2022 (n = 20,701), 2) the current generation with a minimum of four generations of known ancestors (n = 12,685), 3) only genotyped animals (n = 1,856), and 4) the sires of the current generation (n = 509). Pedigree-based inbreeding for the full population was 2.2%, with a rate of inbreeding of 0.22% per generation. Pedigree-based inbreeding, Wright's inbreeding, and genomic inbreeding based on runs of homozygosity were 2.9%, 1.3%, and 5.1%, respectively, for the genotyped population. The effective population size ranged from 41 to 249 for the pedigree-based methods and 118 for the genomic-based estimate. Expected and observed heterozygosity levels were 0.409 and 0.403, respectively. Population substructure was evident based on the fixation index (FST), principal component analysis, and model-based population structure. These analyses provided evidence of differentiation from the foundation flock (USSES). Overall, the Polypay breed exhibited substantial genetic diversity and the presence of a population substructure that provides a basis for the implementation of genomic selection in the breed. [ABSTRACT FROM AUTHOR]

The most prevalent hip disease in neonates is developmental dysplasia of the hip (DDH). A timely and accurate diagnosis is required to provide the most effective treatment for pediatric patients with DDH. Heredity and gene variation have been the subject of increased attention and research worldwide as one of the factors contributing to the pathogenesis of DDH. Genome-wide association studies (GWAS), genome-wide linkage analyses (GWLA), and exome sequencing (ES) have identified variants in numerous genes and single-nucleotide polymorphisms (SNPs) as being associated with susceptibility to DDH in sporadic and DDH family patients. Furthermore, the DDH phenotype can be observed in animal models that exhibit susceptibility genes or loci, including variants in CX3CR1, KANSL1, and GDF5. The dentification of noncoding RNAs and de novo gene variants in patients with DDH-related syndrome has enhanced our understanding of the genes implicated in DDH. This article reviews the most recent molecular mechanisms and genetic factors that contribute to DDH. [ABSTRACT FROM AUTHOR]

Members of the genus Hemerocallis have significant value as ornamental, edible, and medicinal plants, particularly in China, where they have been utilized for thousands of years as both a vegetable and Traditional Chinese Medicine. Hemerocallis species exhibit strict control over flowering time, with individuals flowering either diurnally or nocturnally. However, our understanding of the evolutionary history of this genus, especially concerning important horticultural traits, remains limited. In this study, sequencing and assembly efforts were conducted on 73 samples within the Hemerocallis genus. All accessions were classified into two distinct groups based on their diurnal (daylilies) or nocturnal (nightlilies) flowering habits. Comparative analysis of the chloroplast genomes from these two groups identified fifteen variant hotspot regions, including fourteen SNPs and one deletion, which hold promise for the development of molecular markers for interspecific identification. Phylogenetic trees, generated through both maximum-likelihood and Bayesian inference methods using 76 shared protein-coding sequences, revealed that diurnal flowering evolved prior to nocturnal flowering. The divergence between the two groups is estimated to have occurred approximately 0.82 MYA (95% CI: 0.35-1.45 MYA). The ancestral state of Hemerocallis is hypothesized to have featured diurnal flowering with orange yellow petals. This study marks the first reconstruction of the evolutionary history and ancestral state of the genus Hemerocallis. The findings contribute significantly to our understanding of the adaptation and speciation history within the genus. [ABSTRACT FROM AUTHOR]

Background: Benign prostatic hyperplasia (BPH) is a common disease occurring in elderly and middle-aged men, and cardiovascular diseases (CVDs) are one of the major causes of death worldwide. Many observational studies examined have found a strong association between BPH and CVDs, but the causal relationship between them is unclear. The aim of this study was to determine the causal relationship between BPH and CVDs, specifically five diseases: stroke, coronary heart disease (CHD), heart failure, myocardial infarction (MI), and atrial fibrillation (AF). Methods: In this study, we obtained single nucleotide polymorphisms (SNPs) of patients with BPH from the UK Biobank database and patients with CVDs from the UK Biobank, the HERMES Consortium, and the FinnGen Genome Database, each used as a genetic tool for a Mendelian randomization (MR) study. We used conventional MR analysis to assess potential causal direction between BPH and CVDs, as well as MR-Egger, MR-PRESSO, model-based estimation (MBE) and weighted median methods for sensitivity analysis. Results: Using a bidirectional two-sample MR study, we found that BPH patients had an increased risk of developing CHD (ConMix OR = 1.152, 95% CI: 1.011-1.235, p = 0.035) and MI (ConMix OR = 1.107.95% CI: 1.022-1.164, p = 0.013), but a decreased risk of stroke (ConMix OR = 0.872, 95% CI: 0.797-0.926, p = 0.002). The reverse study was not statistically significant and further research may be needed. Conclusion: Our study suggests a potential causal relationship between BPH and CVDs. BPH appears to be a risk factor for CHD and MI, but it may be protective against stroke. There was no evidence of a causal association in the reverse study, and a larger sample size was needed in follow-up to further explore the potential association. [ABSTRACT FROM AUTHOR]

Background: Significant evidence has been documented regarding the intricate connection between the development of anal fistula (AF) and the composition of Body Mass Index (BMI). Nevertheless, due to the inherent limitations of reverse causality and confounders inherent in observational studies, this relationship remains unclarified. Our study aims to reveal the causal impact between BMI and AF, as well as identify its associated risk factors, thereby providing a more comprehensive understanding of this complex interaction. Methods: Single nucleotide polymorphisms (SNPs) identified through genomewide association study (GWAS) databases were used as instrumental variables for analysis. BMI served as the exposure variable, with six pooled GWAS datasets included. AF was the outcome variable. The Inverse Variance Weighted (IVW) method was used as the primary analytical technique, with MR-Egger regression, Weighted Median (WME) estimation, and Multiplicity Residual Sum and Outlier (MR-PRESSO) tests serving as secondary validations of the IVW results. Odds ratios (OR) were utilized as indicators to evaluate the causal relationship between BMI and AF. Results: A total of 738 SNPs strongly associated with the exposure were identified as instrumental variables. The IVW results demonstrated a positive correlation between BMI and the risk of AF. The MR-Egger analysis yielded p-values greater than 0.05, indicating no pleiotropic effects among the selected SNPs. Cochran's Q test also resulted in p-values greater than 0.05, suggesting no significant heterogeneity among the instrumental variables. The MR-PRESSO analysis revealed no horizontal pleiotropy or outliers potentially violating the causal assumption (p > 0.05). Conclusion: High BMI is positively associated with the risk of AF, and correcting BMI levels may have a preventive effect on the incidence of AF. [ABSTRACT FROM AUTHOR]

A dicentric chromosome is an abnormal chromosome with two centromeres on the same chromosome. It has been reported that dicentric chromosomes are specific biomarkers of radiation exposure, but dicentric chromosomes are rarely identified in newborns with multiple congenital anomalies. At 16 weeks of gestation, a 39-year-old pregnant woman (gravida 2, para 1) was referred to the prenatal diagnosis center for genetic counseling. The fetal ultrasonography indicated multiple anomalies. Subsequently, amniocentesis was performed, and the G-banding karyotype analysis showed a rare type of mosaicism. The C-banding karyotype analysis indicated a pseudo-dicentric chromosome X [psu dic (X; 18) (p11.2; p11.2)]. A single-nucleotide polymorphism array (SNP array) revealed three pathogenic copy number variations (CNVs). After genetic counseling, the parents chose to terminate this pregnancy. This study provides new evidence for a better understanding of the diagnosis of dicentric chromosomes and emphasizes on the importance of genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWASs) have identified 38 loci associated with ulcerative colitis (UC) susceptibility, but the risk genes and their biological mechanisms remained to be comprehensively elucidated. Methods: Multi-marker analysis of genomic annotation (MAGMA) software was used to annotate genes on GWAS summary statistics of UC from FinnGen database. Genetic analysis was performed to identify risk genes. Cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signatures (UTMOST) was performed to compare GWAS summary statistics with gene expression matrix (from Genotype-Tissue Expression Project) for data integration. Subsequently, we used FUSION software to select key genes from the individual tissues. Additionally, conditional and joint analysis was conducted to improve our understanding on UC. Fine-mapping of causal gene sets (FOCUS) software was employed to accurately locate risk genes. The results of the four genetic analyses (MAGMA, UTMOST, FUSION and FOCUS) were combined to obtain a set of UC risk genes. Finally, Mendelian randomization (MR) analysis and Bayesian colocalization analysis were conducted to determine the causal relationship between the risk genes and UC. To test the robustness of our findings, the same approaches were taken to verify the GWAS data of UC on IEU. Results: Multiple correction tests screened PIM3 as a risk gene for UC. The results of Bayesian colocalization analysis showed that the posterior probability of hypothesis 4 was 0.997 and 0.954 in the validation dataset. MR was conducted using the inverse variance weighting method and two single nucleotide polymorphisms (SNPs, rs28645887 and rs62231924) were included in the analysis (p < 0.001, 95%CI: 1.45-1.89). In the validation dataset, MR result was p < 0.001, 95%CI: 1.19-1.72, indicating a clear causal relationship between PIM3 and UC. Conclusion: Our study validated PIM3 as a key risk gene for UC and its expression level may be related to the risk of UC, providing a novel reference for further improving the current understanding on the genetic structure of UC. [ABSTRACT FROM AUTHOR]

Grain chalkiness directly affects the commercial value of rice. Genes related to chalkiness reported thus far have been discovered in mutants, but it has not been identified whether these genes can be used to improve rice quality by breeding. Therefore, discovering more quantitative trait loci (QTLs) or genes related to chalkiness in the rice germplasm is necessary. This study entails a genome-wide association study on the degree of endosperm chalkiness (DEC) and percentage of grains with chalkiness (PGWC) by combining 1.2 million single-nucleotide polymorphisms (SNPs) with the phenotypic data of 173 rice accessions. Thirteen QTLs for DEC and nine for PGWC were identified, of which four were detected simultaneously for both DEC and PGWC; further, qDEC11/qPGWC11 was identified as the major QTL. By combining linkage disequilibrium analysis and SNP information, LOC_Os11g10170 was identified as the candidate gene for DEC. There were significant differences among the haplotypes of LOC_Os11g10170, and the Hap 1 of LOC_Os11g10170 was observed to reduce the DEC by 6.19%. The qRT-PCR results showed that the gene expression levels in accessions with high DEC values were significantly higher than those in accessions with low DEC values during days 21-42 after flowering, with a maximum at 28 days. These results provide molecular markers and germplasm resources for genetic improvement of the chalkiness-related traits in rice. [ABSTRACT FROM AUTHOR]

The burden of Type 1 diabetes (T1D) is vast and as of 2021, an estimated 8.4 million people were living with the disease worldwide. Predictably, this number could increase to 17.4 million people by 2040. Despite nearly a century of insulin therapy for the management of hyperglycemia in T1D, no therapies exist to treat its underlying etiopathology. Adequate dietary intake of omega-3 fatty acids (ω-3) has been reported in observational studies and Randomized Controlled Trials to be associated with reduced risk of developing T1D but results have been inconclusive. We conducted a Mendelian randomization (MR) study to explore the relationship between ω-3 intake and T1D. We performed a two-sample MR analysis using single nucleotide polymorphisms associated with ω-3 levels in a sample of 114,999 Europeans and their effects on T1D from a genome-wide association study meta-analysis of 24,840 European participants. A main MR analysis using the Inverse-variance weighted (IVW) method was conducted and validated using MR-Egger, Weighted median, and Weighted mode methods. Sensitivity analyses excluding potentially pleiotropic single nucleotide polymorphisms were also performed. Main MR analysis using the IVW method showed no evidence of a causal relationship between ω-3 levels and T1D risk (OR: 0.92, 95% CI: 0.56-1.51, p = 0.745). MREgger and Weighted mode methods showed similar results while Weighted median showed a marginally significant association (OR: 1.15, CI: 1.00-1.32, p = 0.048). Sensitivity analysis revealed heterogeneity in the main analysis MR estimates (IVW Q > 100, p < 0.0001) and no directional pleiotropy (Egger intercept: -0.032, p = 0.261). Our study found limited evidence of a causal association between ω-3 and T1D, with only a marginally significant association observed in one of the four MR methods. This challenges the proposition that ω-3-rich diets are of substantial benefit for the prevention and management of T1D. [ABSTRACT FROM AUTHOR]

Introduction: Observational investigations have examined the impact of glucosamine use on the risk of cancer and non-neoplastic diseases. However, the findings from these studies face limitations arising from confounding variables, reverse causation, and conflicting reports. Consequently, the establishment of a causal relationship between habitual glucosamine consumption and the risk of cancer and non-neoplastic diseases necessitates further investigation. Methods: For Mendelian randomization (MR) investigation, we opted to employ single-nucleotide polymorphisms (SNPs) as instruments that exhibit robust associations with habitual glucosamine consumption. We obtained the corresponding effect estimates of these SNPs on the risk of cancer and nonneoplastic diseases by extracting summary data for genetic instruments linked to 49 varied cancer types amounting to 378,284 cases and 533,969 controls, as well as 20 non-neoplastic diseases encompassing 292,270 cases and 842,829 controls. Apart from the primary analysis utilizing inverse-variance weighted MR, we conducted two supplementary approaches to account for potential pleiotropy (MR-Egger and weighted median) and assessed their respective MR estimates. Furthermore, the results of the leave-one-out analysis revealed that there were no outlying instruments. Results: Our results suggest divergence from accepted biological understanding, suggesting that genetically predicted glucosamine utilization may be linked to an increased vulnerability to specific illnesses, as evidenced by increased odds ratios and confidence intervals (95% CI) for diseases, such as malignant neoplasm of the eye and adnexa (2.47 [1.34-4.55]), benign neoplasm of the liver/bile ducts (2.12 [1.32-3.43]), benign neoplasm of the larynx (2.01 [1.36-2.96]), melanoma (1.74 [1.17-2.59]), follicular lymphoma (1.50 [1.06-2.11]), autoimmune thyroiditis (2.47 [1.49-4.08]), and autoimmune hyperthyroidism (1.93 [1.17-3.18]). In contrast to prior observational research, our genetic investigations demonstrate a positive correlation between habitual glucosamine consumption and an elevated risk of sigmoid colon cancer, lung adenocarcinoma, and benign neoplasm of the thyroid gland. Conclusion: Casting doubt on the purported purely beneficial association between glucosamine ingestion and prevention of neoplastic and non-neoplastic diseases, habitual glucosamine ingestion exhibits dichotomous effects on disease outcomes. Endorsing the habitual consumption of glucosamine as a preventative measure against neoplastic and non-neoplastic diseases cannot be supported. [ABSTRACT FROM AUTHOR]

Purpose: Major depressive disorder (MDD) and venous thromboembolism (VTE) may be linked in observational studies. However, the causal association remains ambiguous. Therefore, this study investigates the causal associations between them. Methods: We performed a two-sample univariable and multivariable bidirectional Mendelian randomization (MR) analysis to evaluate the associations between MDD and VTE. The summary genetic associations of MDD statistics were obtained from the Psychiatric Genomics Consortium and UK Biobank. Information on VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE) were obtained from the FinnGen Biobank. Inverse-variance weighting was used as the main analysis method. Other methods include weighted median, MR- Egger, Simple mode, and Weighted mode. Results: Univariable MR analysis revealed no significant associations between MDD and VTE risk (odds ratio (OR): 0.936, 95% confidence interval (CI): 0.736-1.190, p = 0.590); however, after adjusting the potential relevant polymorphisms of body mass index and education, the multivariable MR analysis showed suggestive evidence of association between them (OR: 1.163, 95% CI: 1.004-1.346, p = 0.044). Univariable MR analysis also revealed significant associations between MDD and PE risk (OR: 1.310, 95% CI: 1.073-1.598, p = 0.008), but the association between them was no longer significant in MVMR analysis (p = 0.072). We found no significant causal effects between MDD and DVT risk in univariable or multivariable MR analyses. There was also no clear evidence showing the causal effects between VTE, PE, or DVT and MDD risk. Conclusion: We provide suggestive genetic evidence to support the causal association between MDD and VTE risk. No causal associations were observed between VTE, PE, or DVT and MDD risk. Further validation of these associations and investigations of potential mechanisms are required. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested a potential relationship between birthweight and telomere length. However, the causal link between these two parameters remains undefined. In this study, we use Mendelian Randomization (MR). This method employs genetic variants as instrumental variables, to explore the existence of causal associations and elucidate the causal relationship between birth weight and telomere length. Methods: We used 35 single nucleotide polymorphisms (SNPs) as instrumental variables for birth weight. These SNPs were identified from a meta-analysis involving 153,781 individuals. Furthermore, we obtained summary statistics for telomere length from a study conducted on 472,174 United Kingdom Biobank participants. To evaluate the causal estimates, we applied the random effect inverse variance weighted method (IVW) and several other MR methods, such as MR-Egger, weighted median, and MR-PRESSO, to verify the reliability of our findings. Results: Our analysis supports a significant causal relationship between genetically predicted birth weight and telomer3e length. The inverse variance weighted analysis results for birth weight (Beta = 0.048; 95%CI = 0.023 to 0.073; p < 0.001) corroborate this association. Conclusion: Our study provides robust evidence supporting a causal link between higher birth weight and longer telomere length. [ABSTRACT FROM AUTHOR]

Background: Intracerebral hemorrhage (ICH) is a severe form of stroke with high mortality and limited treatment options. While traditional risk factors like hypertension have been well-studied, the role of emotional states as acute triggers for ICH remains unclear. This study employs Mendelian Randomization (MR) to investigate the causal relationship between emotional traits of worry and anxiety and the incidence of ICH. Methods: We used a two-sample MR approach, leveraging summary-level data from genome-wide association studies (GWAS) for emotional traits and ICH. The primary analysis was conducted using the Inverse-Variance Weighted (IVW) method, supplemented by multiple sensitivity analyses including Maximum Likelihood and MR PRESSO methods. Results: Our MR analysis revealed a robust and significant causal relationship between the emotional trait "Worrier/anxious feelings" and ICH, supported by 195 instrumental variables (SNPs). The odds ratio (OR) was 2.98 (95% CI: 1.16, 7.61) with a p-value of 0.0229. Sensitivity analyses corroborated these findings, enhancing the reliability of our results. In contrast, other emotional traits such as "Nervous feelings" and "Sensitivity/hurt feelings" did not show significant associations, reinforcing the specificity of our primary finding. Conclusion: Our study provides compelling evidence for a causal relationship between the emotional traits of worry and anxiety and the incidence of ICH, offering a new dimension in our understanding of this devastating condition and paving the way for more nuanced risk stratification and preventive strategies. [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have found a correlation between the consumption of tobacco and alcohol and the likelihood of developing renal cell carcinoma. However, whether these associations indicate causal relationships is unclear. Methods: To establish if these connections indicate causal relationships, we performed a Mendelian Randomization (MR) analysis using a two-sample approach. For the number of daily cigarettes, lifetime smoking index, smoking initiation, and weekly drinking, we employed 44, 108, 174, and 76 single nucleotide polymorphisms (SNPs) as instrumental variables. Outcome data were obtained from the FinnGen Alliance, which included a combined total of 429,290 individuals. The MR analysis was conducted using the inverse-variance weighted (IVW) method to estimate causal effects. To address potential violations of MR assumptions due to directional pleiotropy, we performed MR-Egger regression and MRPRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) analysis. Results: Genetically influenced smoking initiation was directly associated with the risk of developing renal cell carcinoma (OR = 1.55, 95% CI: 1.04-2.33; p = 0.03). No causal relationship was found between daily cigarette consumption and lifetime smoking index with the risk of renal cell cancer. Genetic predisposition for weekly alcohol consumption showed a reduced risk of renal cell cancer (OR = 0.45, 95% CI: 0.26-0.81; p = 0.007). Discussion: Our study suggests a potential causal relationship between alcohol consumption and reduced risk of renal cell cancer, while no such association was observed with smoking. Further research is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

In modern breeding practices, genomic prediction (GP) uses high-density single nucleotide polymorphisms (SNPs) markers to predict genomic estimated breeding values (GEBVs) for crucial phenotypes, thereby speeding up selection breeding process and shortening generation intervals. However, due to the characteristic of genotype data typically having far fewer sample numbers than SNPs markers, overfitting commonly arise during model training. To address this, the present study builds upon the Least Squares Twin Support Vector Regression (LSTSVR) model by incorporating a Lasso regularization term named ILSTSVR. Because of the complexity of parameter tuning for different datasets, subtraction average based optimizer (SABO) is further introduced to optimize ILSTSVR, and then obtain the GP model named SABO-ILSTSVR. Experiments conducted on four different crop datasets demonstrate that SABO-ILSTSVR outperforms or is equivalent in efficiency to widely-used genomic prediction methods. Source codes and data are available at: https://github.com/MLBreeding/SABO-ILSTSVR. [ABSTRACT FROM AUTHOR]

Introduction: Pubertal attainment is critical to reproductive longevity in heifers. Previously, four heifer pubertal classifications were identified according to attainment of blood plasma progesterone concentrations > 1 ng/ml: 1) Early; 2) Typical; 3) Start-Stop; and 4) Non-Cycling. Early and Typical heifers initiated and maintained cyclicity, Start-Stop started and then stopped cyclicity and Non-Cycling never initiated cyclicity. Start-Stop heifers segregated into Start-Stop-Discontinuous (SSD) or Start-Stop-Start (SSS), with SSD having similar phenotypes to Non-Cycling and SSS to Typical heifers. We hypothesized that these pubertal classifications are heritable, and loci associated with pubertal classifications could be identified by genome wide association studies (GWAS). Methods: Heifers (n = 532; 2017 - 2022) genotyped on the Illumina Bovine SNP50 v2 or GGP Bovine 100K SNP panels were used for variant component estimation and GWAS. Heritability was estimated using a univariate Bayesian animal model. Results: When considering pubertal classifications: Early, Typical, SSS, SSD, and Non-Cycling, pubertal class was moderately heritable (0.38 ± 0.08). However, when heifers who initiated and maintained cyclicity were compared to those that did not cycle (Early+Typical vs. SSD+Non-Cycling) heritability was greater (0.59 ± 0.19). A GWAS did not identify single nucleotide polymorphisms (SNPs) significantly associated with pubertal classifications, indicating puberty is a polygenic trait. A candidate gene approach was used, which fitted SNPs within or nearby a set of 71 candidate genes previously associated with puberty, PCOS, cyclicity, regulation of hormone secretion, signal transduction, and methylation. Eight genes/regions were associated with pubertal classifications, and twentytwo genes/regions were associated with whether puberty was attained during the trial. Additionally, whole genome sequencing (WGS) data on 33 heifers were aligned to the reference genome (ARS-UCD1.2) to identify variants in FSHR, a gene critical to pubertal attainment. Fisher's exact test determined if FSHR SNPs segregated by pubertal classification. Two FSHR SNPs that were not on the bovine SNP panel were selected for additional genotyping and analysis, and one was associated with pubertal classifications and whether they cycled during the trial. Discussion: In summary, these pubertal classifications are moderately to highly heritable and polygenic. Consequently, genomic tools to inform selection/management of replacement heifers would be useful if informed by SNPs associated with cyclicity and early pubertal attainment. [ABSTRACT FROM AUTHOR]

Introduction: The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: LGALS3), specifying the variant proline (P64) to histidine (H64), is known to affect the protein’s functions and has been associated with the risk of several types of cancer, including differentiated thyroid carcinoma (DTC). Materials and methods: To deepen our understanding of the biological effects of this SNP, we analyzed the proteome of two isogenic cell lines (NC-P64 vs. NA-H64) derived from the immortalized non-malignant thyrocyte cell line Nthy-Ori, generated through the CRISPR-Cas9 technique to differ by rs4644 genotype. We compared the proteome of these cells to detect differentially expressed proteins and studied their proteome in relation to their transcriptome. Results: Firstly, we found, consistently with previous studies, that gal-3- H64 could be detected as a monomer, homodimer, and heterodimer composed of one cleaved and one uncleaved monomer, whereas gal-3- P64 could be found only as a monomer or uncleaved homodimer. Moreover, results indicate that rs4644 influences the expression of several proteins, predominantly upregulated in NA-H64 cells. Overall, the differential protein expression could be attributed to the altered mRNA expression, suggesting that rs4644 shapes the function of gal-3 as a transcriptional co-regulator. However, this SNP also appeared to affect post-transcriptional regulatory mechanisms for proteins whose expression was oppositely regulated compared to mRNA expression. It is conceivable that the rs4644-dependent activities of gal-3 could be ascribed to the different modalities of self-dimerization. Conclusion: Our study provided further evidence that rs4644 could affect the gal-3 functions through several routes, which could be at the base of differential susceptibility to diseases, as reported in case-control association studies. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) is typically diagnosed by evaluating bone mineral density (BMD), and it frequently results in fractures. Here, we investigated the causal relationships between diet-derived circulating antioxidants and the risk of OP using Mendelian randomization (MR). Methods: Published studies were used to identify instrumental variables related to absolute levels of circulating antioxidants like lycopene, retinol, ascorbate, and β-carotene, as well as antioxidant metabolites such as ascorbate, retinol, αtocopherol, and γ-tocopherol. Outcome variables included BMD (in femoral neck, lumbar spine, forearm, heel, total body, total body (age over 60), total body (age 45–60), total body (age 30–45), total body (age 15–30), and total body (age 0–15)), fractures (in arm, spine, leg, heel, and osteoporotic fractures), and OP. Inverse variance weighted or Wald ratio was chosen as the main method for MR analysis based on the number of single nucleotide polymorphisms (SNPs). Furthermore, we performed sensitivity analyses to confirm the reliability of the findings. Results: We found a causal relationship between absolute retinol levels and heel BMD (p = 7.6E-05). The results of fixed effects IVW showed a protective effect of absolute retinol levels against heel BMD, with per 0.1 ln-transformed retinol being associated with a 28% increase in heel BMD (OR: 1.28, 95% CI: 1.13–1.44). In addition, a sex-specific effect of the absolute circulating retinol levels on the heel BMD has been observed in men. No other significant causal relationship was found. Conclusion: There is a positive causal relationship between absolute retinol levels and heel BMD. The implications of our results should be taken into account in future studies and in the creation of public health policies and OP prevention tactics. [ABSTRACT FROM AUTHOR]

Background: An association between depression and migraine has been reported in observational studies; however, conventional observational studies are prone to bias. This study aims to investigate the causal relationship between depression and migraine and to quantify the mediating effects of known risk factors. Methods: We applied two-sample Mendelian randomization and utilized single nucleotide polymorphisms as genetic instruments for exposure (depression) and mediators (sleep traits). We utilized summary data on genome-wide association studies for depression, sleep-related traits mediators and migraine. For depression, genome-wide association studies (depression) were utilized as a test cohort for the primary analysis. Moreover, genome-wide association studies (major depressive disorder) were utilized to test the stability of the results for the validation cohort. IVW and MR-Egger regression were applied to test the heterogeneity, and Cochran's Q statistics were calculated to quantitatively evaluate the heterogeneity. MR-PRESSO analyses were utilized to examine and correct possible horizontal pleiotropy through removing outliers, and leave-one-out analyses were utilized to identify outlier SNPs. Results: Genetically predicted depression was associated with migraine (OR = 1.321, 95% CI: 1.184-1.473, p < 0.001). Furthermore, risk factors insomnia was associated with migraine risk (OR = 1.766, 95% CI: 1.120-2.784, p = 0.014). The mediator insomnia accounted for 19.5% of the total effect of depression on migraine. Conclusion: These results support a potential causal effect of depression on migraine, partly mediated by insomnia. Therefore, the enhancement of sleep quality and difficulty in falling asleep may reduce the migraine burden occasioned by depression. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum malaria is still a leading cause of child mortality in sub-Saharan Africa. The clinical manifestations of malaria range from asymptomatic infection to severe disease. The variation in clinical presentation is partly attributed to host genetic factors with estimated narrow-sense heritability of 23%. Here, we investigate the associations between candidate gene polymorphisms and the likelihood of severe malaria (SM) in a cohort of Malian children. Methods: Based on our previous genome-wide association studies (GWAS) analysis, candidate genes were selected for in-depth analysis using several criteria including gene-level GWAS scores, functional overlap with malaria pathogenesis, and evidence of association with protection or susceptibility to other infectious or inflammatory diseases. Single Nucleotide Polymorphisms (SNPs) residing within these genes were selected mainly based on p-values from previous severe malaria susceptibility GWAS studies and minor allele frequency (MAF) in West African populations. Results: Of 182 candidate genes reported in our previous study, 11 genes and 22 SNPs residing in these genes were selected. The selected SNPs were genotyped using KASP technology in 477 DNA samples (87 SM and 390 controls). Logistic regression analysis revealed that a common intron variant, rs13340578 in CUB and Sushi Multi Domain (CSMD1) gene, is associated with increased odds of SM in recessive mode of inheritance (MAF = 0.42, OR = 1.8, 95% CI = [1.78, 1.84], p = 0.029). The SNP is in linkage disequilibrium (LD) with multiple variants with regulatory features. Conclusion: Taken together, the current study showed that an intron variant rs13340578, residing in CSMD1 gene, is associated with increased susceptibility to malaria. This finding suggests that modified regulation of complement may contribute to malaria disease severity. Further studies are needed to identify the causal variants and the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: While clinical research has indicated a potential link between Helicobacter pylori infection and the onset of glaucoma, the causality of this association remains uncertain due to the susceptibility of observational studies to confounding factors and reverse causation. Methods: A comprehensive two-sample bidirectional Mendelian randomization (MR) analysis was conducted to assess the causal connection between H. pylori infection and glaucoma. Glaucoma was categorized into primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and pseudo-exfoliation glaucoma (PEG). Various methods, including inverse variance weighted, MREgger regression, weighted median, and mode-based estimator, were employed for effect estimation and pleiotropy testing. To enhance result robustness, a sensitivity analysis was performed by excluding proxy single nucleotide polymorphisms. Results: Genetic predisposition for H. pylori infection has no causal effect on glaucoma: (OR 1.00; 95% CI 0.95-1.06, p = 0.980), (OR 0.97; 95% CI 0.86-1.09, p = 0.550), and (OR 0.99; 95% CI 0.90-1.08, p = 0.766) with POAG, NTG, and PEG, respectively. An inverse MR showed no causal effect of POAG, NTG, and PEG on H. pylori infection (OR 1.01; 95% CI 0.97-1.05, p = 0.693), (OR 1.00; 95% CI 0.98-1.03, p = 0.804), and (OR 0.99; 95% CI 0.96-1.01, p = 0.363), respectively. Heterogeneity (p > 0.05) and pleiotropy (p > 0.05) analysis confirmed the robustness of MR results. Conclusion: These results indicated that there was no genetic evidence for a causal link between H. pylori and glaucoma, suggesting that the eradication or prevention of H. pylori infection might not benefit glaucoma and vice versa. [ABSTRACT FROM AUTHOR]

BackgroundColorectal cancer (CRC) poses a significant global health burden, with high incidence and mortality rates. Despite advances in diagnostic and therapeutic modalities, early diagnosis remains critical for improved outcomes. Recent research has realized the important role of gut microbiota in CRC development, highlighting the need to elucidate potential relationships.MethodsIn this study, we employed Mendelian randomization (MR) to establish a robust potential link between gut microbial genera and CRC. Data from the MiBioGen database provided curated genome-wide association study (GWAS) summary datasets for microbial genera, while the Finngen database provided CRC outcome data. Instrumental variables (IVs) were identified based on genetic variants associated with gut microbiota. Various MR methods, including Inverse Variance Weighted (IVW), Weighted Median, Weighted Mode, Simple Mode, and MR-Egger, were employed to estimate potential effects. Functional analysis of genes near single nucleotide polymorphisms (SNPs) was performed to unravel potential pathways.ResultsAnalysis of microbial genera identified five potentially associated with CRC: Eubacterium fissicatena group, Anaerofilum, Defluviitaleaceae UCG011, Ruminococcus 2, and Sutterella. Notably, Defluviitaleaceae UCG011 emerged as the only risk factor. Gene analysis revealed hub genes PTPRD and DSCAM near Defluviitaleaceae UCG011 associated SNPs. Expression analysis showed that PTPRD decreased in colon cancer and DSCAM decreased in rectal cancer. The methylation status of the PTPRD gene promoter region indicated potential regulatory alterations.ConclusionThis study establishes a potential relationship between five specific gut microbial genera, particularly Defluviitaleaceae UCG011, and CRC. Hub genes PTPRD and DSCAM provide insights into potential molecular mechanisms, suggesting the potential role of Defluviitaleaceae UCG011 in modulating the initiation and progression of CRC. Further research is essential to validate these associations and delve deeper into therapeutic implications.

The editorial discusses the clinical utility of long read sequencing (LRS) in improving diagnostic yield and uncovering biological mechanisms in rare genetic diseases. LRS technology overcomes limitations of short read sequencing and other techniques, allowing for precise identification of structural variants and novel disease-associated tandem repeats. While LRS is primarily used in research, efforts are being made to promote its application in clinical settings, particularly for rare diseases with challenging molecular mechanisms. The article highlights the potential of LRS in advancing diagnostic testing for various diseases, including cancer and rare genetic disorders. [Extracted from the article]

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations. [ABSTRACT FROM AUTHOR]

Motivation: Genomic structural variation refers to chromosomal level variations such as genome rearrangement or insertion/deletion, which typically involve larger DNA fragments compared to single nucleotide variations. Deletion is a common type of structural variants in the genome, whichmay lead to mangy diseases, so the detection of deletions can help to gain insights into the pathogenesis of diseases and provide accurate information for disease diagnosis, treatment, and prevention. Many tools exist for deletion variant detection, but they are still inadequate in some aspects, and most of them ignore the presence of chimeric variants in clustering, resulting in less precise clustering results. Results: In this paper, we present LcDel, which can detect deletion variation based on clustering and long reads. LcDel first finds the candidate deletion sites and then performs the first clustering step using two clustering methods (sliding windowbased and coverage-based, respectively) based on the length of the deletion. After that, LcDel immediately uses the second clustering by hierarchical clustering to determine the location and length of the deletion. LcDel is benchmarked against some other structural variation detection tools onmultiple datasets, and the results show that LcDel has better detection performance for deletion. The source code is available in https://github.com/cyq1314woaini/LcDel. [ABSTRACT FROM AUTHOR]

Cercospora leaf blight (CLB), caused by Cercospora cf. flagellaris, C. kikuchii, and C. cf. sigesbeckiae, is a significant soybean [Glycine max (L.) Merr.] disease in regions with hot and humid conditions causing yield loss in the United States and Canada. There is limited information regarding resistant soybean cultivars, and there have been marginal efforts to identify the genomic regions underlying resistance to CLB. A Genome-Wide Association Study was conducted using a diverse panel of 460 soybean accessions from maturity groups III to VII to identify the genomic regions associated to the CLB disease. These accessions were evaluated for CLB in different regions of the southeastern United States over 3 years. In total, the study identified 99 Single Nucleotide Polymorphism (SNPs) associated with the disease severity and 85 SNPs associated with disease incidence. Across multiple environments, 47 disease severity SNPs and 23 incidence SNPs were common. Candidate genes within 10 kb of these SNPs were involved in biotic and abiotic stress pathways. This information will contribute to the development of resistant soybean germplasm. Further research is warranted to study the effect of pyramiding desirable genomic regions and investigate the role of identified genes in soybean CLB resistance. [ABSTRACT FROM AUTHOR]

Background: Several observational cohort studies suggested a close correlation between inflammatory bowel disease and erectile dysfunction. Nevertheless, whether there was a causal effect between them remained debatable. In this study, we aimed to detect the underlying causal links between genetically predicted inflammatory bowel disease and the risk of erectile dysfunction. Methods: A bidirectional Mendelian randomization (MR) study was performed to assess the causal link between inflammatory bowel disease and erectile dysfunction. Inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode were utilized to estimate the causality. The top single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease cases (n = 25,800) and erectile dysfunction cases (n = 1,154) were extracted from the summary genome-wide association study (GWAS) data obtained from a publicly attainable database. MR-PRESSO global outlier test and MR-Egger regression were utilized to explore the horizontal pleiotropy and outlier instrumental variables. Cochran's Q statistic was utilized to detect the heterogeneity. Results: In the forward MR study, the IVW approach demonstrated that genetically determined inflammatory bowel disease exhibited a suggestively causal association with an increased risk of erectile dysfunction (OR: 1.11, 95% CI: 1.02-1.21, p = 0.019), and also the genetically determined Crohn's disease was found to be causally associated with an increased risk of erectile dysfunction (OR: 1.09, 95% CI: 1.02-1.17, p = 0.014). However, the MR analysis results showed no significant evidence supporting a causal effect of ulcerative colitis with erectile dysfunction (OR: 1.02, 95% CI: 0.92-1.14, p = 0.679). Furthermore, the reverse MR analysis showed no causal effects of genetically determined erectile dysfunction on inflammatory bowel disease. Additionally, sensitivity analysis demonstrated no pleiotropy and heterogeneity. Conclusion: Our MR analysis substantiated causal links of inflammatory bowel disease and Crohn's disease on erectile dysfunction, which may further elucidate how inflammatory bowel disease impacted the initiation and development of erectile dysfunction, and facilitated the prevention and clinical management of inflammatory bowel disease in individuals with erectile dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Acetyl-Coenzyme A Acyltransferase-1 (ACAA1) is a peroxisomal acyltransferase involved in fatty acid metabolism. Current evidence does not precisely reveal the effect of the ACAA1 gene on pig growth performance. Methods: The present study assessed the mRNA expression levels of the ACAA1 gene in the heart, liver, spleen, lung, kidney of 6-month-old Xiangsu pigs and in the longissimus dorsi muscle at different growth stages (newborn, 6 months and 12 months of age) using RT-qPCR. The relationship between single-nucleotide polymorphisms (SNPs) of ACAA1 gene and growth traits in 6-month-old and 12-month-old Xiangsu pigs was investigated on 184 healthy Xiangsu pigs using Sanger sequencing. Results: The ACAA1 gene was expressed in heart, liver, spleen, lung, kidney, and longissimus dorsi muscle of 6-month-old pigs, with the highest level of expression in the liver. ACAA1 gene expression in the longissimus dorsi muscle decreased with age (p < 0.01). In addition, four SNPs were identified in the ACAA1 gene, including exon g.48810 A>G (rs343060194), intron g.51546 T>C (rs319197012), exon g.55035 T>C (rs333279910), and exon g.55088 C>T (rs322138947). Hardy-Weinberg equilibrium (p > 0.05) was found for the four SNPs, and linkage disequilibrium (LD) analysis revealed a strong LD between g.55035 T>C (rs333279910) and g.55088 C>T (rs322138947) (r2 = 1.000). Association analysis showed that g.48810 A>G (rs343060194), g.51546 T>C (rs319197012), g.55035 T>C (rs333279910), and g.55088 C>T (rs322138947) varied in body weight, body length, body height, abdominal circumference, leg and hip circumference and living backfat thickness between 6-month-old and 12-month-old Xiangsu pigs. Conclusion: These findings strongly demonstrate that the ACAA1 gene can be exploited for marker-assisted selection to improve growth-related phenotypes in Xiangsu pigs and present new candidate genes for molecular pig breeding. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided and right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, and prognosis. Methods: This study employed single-cell transcriptomic data and various bioinformatics approaches, such as two-sample Mendelian randomization, reverse Mendelian randomization, colocalization analysis, directed filtering, pseudotime analysis, and intercellular communication analysis. It analyzed cellular-level disparities between left-sided and right-sided CRC, identifying distinct subpopulations with characteristic variations. For these cells, two-sample Mendelian randomization was utilized to explore gene-to-one-sided CRC causality. Results: LUCAT1 was enriched in high-abundance monocyte subpopulations in right-sided CRC and demonstrated potential risk factor status through Mendelian randomization analysis. The specific single-nucleotide polymorphism (SNP) rs10774624 was associated with an increased risk of CRC. Moreover, metabolic pathway analysis revealed that LUCAT1+ monocytes exhibit lower communication activity in the tumor microenvironment and heightened activity in metabolic functions like glycosaminoglycan degradation. Its biological functions are related to the positive regulation of interleukin-6 production and NF-kappa B signaling, among others. Conclusion: This study confirmed a potential causal relationship between LUCAT1 and right-sided CRC risk through Mendelian randomization analysis. These findings provide novel insights into the pathogenesis of right-sided CRC and may aid in developing early detection and treatment strategies for right-sided CRC. [ABSTRACT FROM AUTHOR]

Introduction: Frailty is the most common medical condition affecting the aging population, and its prevalence increases in the population aged 65 or more. Frailty is commonly diagnosed using the frailty index (FI) or frailty phenotype (FP) assessments. Observational studies have indicated the association of frailty with Alzheimer's disease (AD). However, the shared genetic and biological mechanism of these comorbidity has not been studied. Methods: To assess the genetic relationship between AD and frailty, we examined it at single nucleotide polymorphism (SNP), gene, and pathway levels. Results: Overall, 16 genome-wide significant loci (15 unique loci) (pmeta-analysis < 5 × 10-8) and 22 genes (21 unique genes) were identified between AD and frailty using cross-trait meta-analysis. The 8 shared loci implicated 11 genes: CLRN1-AS1, CRHR1, FERMT2, GRK4, LINC01929, LRFN2, MADD, RP11-368P15.1, RP11-166N6.2, RNA5SP459, and ZNF652 between AD and FI, and 8 shared loci between AD and FFS implicated 11 genes: AFF3, C1QTNF4, CLEC16A, FAM180B, FBXL19, GRK4, LINC01104, MAD1L1, RGS12, ZDHHC5, and ZNF521. The loci 4p16.3 (GRK4) was identified in both meta-analyses. The colocalization analysis supported the results of our meta-analysis in these loci. The gene-based analysis revealed 80 genes between AD and frailty, and 4 genes were initially identified in our meta-analyses: C1QTNF4, CRHR1, MAD1L1, and RGS12. The pathway analysis showed enrichment for lipoprotein particle plasma, amyloid fibril formation, protein kinase regulator, and tau protein binding. Conclusion: Overall, our results provide new insights into the genetics of AD and frailty, suggesting the existence of non-causal shared genetic mechanisms between these conditions. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa, 80% of poultry production is on smallholder village farms, where chickens are typically reared outdoors in free-ranging conditions. There is limited knowledge on chickens' phenotypic characteristics and genetics under these conditions. Objective: The present is a large-scale study set out to phenotypically characterise the performance of tropically adapted commercial chickens in typical smallholder farm conditions, and to examine the genetic profile of chicken phenotypes associated with growth, meat production, immunity, and survival. Methods: A total of 2,573 T451A dual-purpose Sasso chickens kept outdoors in emulated free-ranging conditions at the poultry facility of the International Livestock Research Institute in Addis Ababa, Ethiopia, were included in the study. The chickens were raised in five equally sized batches and were individually monitored and phenotyped from the age of 56 days for 8 weeks. Individual chicken data collected included weekly body weight, growth rate, body and breast meat weight at slaughter, Newcastle Disease Virus (NDV) titres and intestinal Immunoglobulin A (IgA) levels recorded at the beginning and the end of the period of study, and survival rate during the same period. Genotyping by sequencing was performed on all chickens using a low-coverage and imputation approach. Chicken phenotypes and genotypes were combined in genomic association analyses. Results: We discovered that the chickens were phenotypically diverse, with extensive variance levels observed in all traits. Batch number and sex of the chicken significantly affected the studied phenotypes. Following quality assurance, genotypes consisted of 2.9 million Single Nucleotide Polymorphism markers that were used in the genomic analyses. Results revealed a largely polygenic mode of genetic control of all phenotypic traits. Nevertheless, 15 distinct markers were identified that were significantly associated with growth, carcass traits, NDV titres, IgA levels, and chicken survival. These markers were located in regions harbouring relevant annotated genes. Conclusion: Results suggest that performance of chickens raised under smallholder farm conditions is amenable to genetic improvement and may inform selective breeding programmes for enhanced chicken productivity in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Leigh syndrome French Canadian type (LSFC) is a recessive neurodegenerative disease characterized by tissue-specific deficiency in cytochrome c oxidase (COX), the fourth complex in the oxidative phosphorylation system. LSFC is caused by mutations in the leucine rich pentatricopeptide repeat containing gene (LRPPRC). Most LSFC patients in Quebec are homozygous for an A354V substitution that causes a decrease in the expression of the LRPPRC protein. While LRPPRC is ubiquitously expressed and is involved in multiple cellular functions, tissue-specific expression of LRPPRC and COX activity is correlated with clinical features. In this proof-of-principle study, we developed human induced pluripotent stem cell (hiPSC)-based models from fibroblasts taken from a patient with LSFC, homozygous for the LRPPRC*354V allele, and from a control, homozygous for the LRPPRC*A354 allele. Specifically, for both of these fibroblast lines we generated hiPSC, hiPSC-derived cardiomyocytes (hiPSC-CMs) and hepatocyte-like cell (hiPSC-HLCs) lines, as well as the three germ layers. We observed that LRPPRC protein expression is reduced in all cell lines/layers derived from LSFC patient compared to control cells, with a reduction ranging from ~70% in hiPSC-CMs to undetectable levels in hiPSC-HLC, reflecting tissue heterogeneity observed in patient tissues. We next performed exploratory analyses of these cell lines and observed that COX protein expression was reduced in all cell lines derived from LSFC patient compared to control cells. We also observed that mutant LRPPRC was associated with altered expression of key markers of endoplasmic reticulum stress response in hiPSC-HLCs but not in other cell types that were tested. While this demonstrates feasibility of the approach to experimentally study genotype-based differences that have tissue-specific impacts, this study will need to be extended to a larger number of patients and controls to not only validate the current observations but also to delve more deeply in the pathogenic mechanisms of LSFC. [ABSTRACT FROM AUTHOR]

The high prevalence of obesity in Mexico starting from the early stages of life is concerning and represents a major public health problem. Genetic association studies have reported that single nucleotide variants (SNVs) in SIRT1, an NAD+- dependent deacetylase that plays an important role in the regulation of metabolic cellular functions, are associated with multiple metabolic disorders and the risk of obesity. In the present study, we analyzed the effect that the SNVs rs1467568 and rs7895833 of the SIRT1 gene may have on cardiometabolic risk factors in a young adult population from Mexico. A cross-sectional study was carried out with young adults between the ages of 18 and 25 who had a body mass index (BMI) greater than 18.5 kg/m2. This study included 1122 young adults who were classified into the normal weight (n = 731), overweight group (n = 277), and obesity group (n = 114) according to BMI of whom 405 and 404 volunteers were genotyped for rs1467568 and rs7895833 respectively using TaqMan probes through allelic discrimination assays. We found that the male sex carrying the G allele of rs7895833 had slightly lower BMI levels (p = 0.009). Furthermore, subjects carrying rs1467568 (G allele) showed a 34% lower probability of presenting with hyperbetalipoproteinemia where female carrying rs1467568 had lower levels of total cholesterol (p = 0.030), triglycerides (p = 0.026) and LDL cholesterol (p = 0.013). In conclusion, these findings suggest that the presence of both SNVs could have a non-risk effect against dyslipidemia in the Mexican population. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is common in patients with autoimmune diseases (ADs); however, the causal associations between ADs and sarcopenia remain unclear. Therefore, this study investigated the causal associations using bi-directional Mendelian randomization analysis. Methods: Exposure-related single-nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWASs). GWAS statistics for common ADs [Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis (PSO), and multiple sclerosis (MS)] and sarcopenia-related traits [hand grip strength (HGS), appendicular fatfree mass (FFM), and walking pace] were obtained from public datasets. Inverse-variance weighting as the main method was used to evaluate the causal effect. Results: Genetically predicted CD had causal effects on whole-body FFM (β = -0.005, p = 0.001), leg FFM (βleft = -0.006, p = 1.8E-4; βright = -0.007, p = 2.0E-4), and arm FFM (βleft = -0.005, p = 0.005; βright = -0.005, p = 0.001), while RA had causal effects on 8 sarcopenia-related traits, namely, HGS (βleft = -2.06, p = 2.8E-38; βright = -2.311, p = 2E-20), whole-body FFM (β = -0.842, p = 4.7E-10), leg FFM (βleft = -0.666, p = 2.6E-6; βright = -0.073, p = 2.1E-3), arm FFM (βleft = -0.63, p = 4.4E-6; βright = -0.736, p = 4.4E-8), and walking pace (β = -1.019, p = 6.2E-14). In the reverse direction, HGS (odds ratio [OR]left = 10.257, p = 3.6E-5; ORright = 16.445, p = 3.7E-7) had causal effects on CD, while HGS (ORleft = 0.994, p = 0.004; ORright = 0.993, p = 1.4E-4), leg FFM (ORleft = 1.003, p = 0.005; ORright = 1.005, p = 1.9E-4), and walking pace (OR = 0.985, p = 5.7E-5) were causally associated with RA. No evidence showed causal associations of UC, SLE, PSO, or MS with sarcopenia-related traits. Conclusion: Our study demonstrated that the genetic susceptibility to CD and RA was associated with high risk of sarcopenia, and some sarcopenia-related traits had causal effects on CD or RA. [ABSTRACT FROM AUTHOR]