Preliminary study of identified novel susceptibility loci for HAPE risk in a Chinese male Han population.

High altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic pulmonary edema. In recent years, association studies have become the main method for identifying HAPE genetic loci. A genome-wide association study (GWAS) of HAPE risk-associated loci was performed in Chinese male Han individuals (164 HAPE cases and 189 healthy controls) by the Precision Medicine Diversity Array Chip with 2,771,835 loci (Applied Biosystems Axiom™). Eight overlapping candidate loci in CCNG2, RP11-445O3.2, NUPL1 and WWOX were finally selected. In silico functional analyses displayed the PPI network, functional enrichment and signal pathways related to CCNG2, NUPL1, WWOX and NRXN1. This study provides data supplements for HAPE susceptibility gene loci and new insights into HAPE susceptibility.

Novel genetic loci of inhibitory control in ADHD and healthy children and genetic correlations with ADHD.

Cumulative evidence has showed the deficits of inhibitory control in patients with attention deficit hyperactivity disorder (ADHD), which is considered as an endophenotype of ADHD. Genetic study of inhibitory control could advance gene discovery and further facilitate the understanding of ADHD genetic basis, but the studies were limited in both the general population and ADHD patients. To reveal genetic risk variants of inhibitory control and its potential genetic relationship with ADHD, we conducted genome-wide association studies (GWAS) on inhibitory control using three datasets, which included 783 and 957 ADHD patients and 1350 healthy children. Subsequently, we employed polygenic risk scores (PRS) to explore the association of inhibitory control with ADHD and related psychiatric disorders. Firstly, we identified three significant loci for inhibitory control in the healthy dataset, two loci in the case dataset, and one locus in the meta-analysis of three datasets. Besides, we found more risk genes and variants by applying transcriptome-wide association study (TWAS) and conditional FDR method. Then, we constructed a network by connecting the genes identified in our study, leading to the identification of several vital genes. Lastly, we identified a potential relationship between inhibitory control and ADHD and autism by PRS analysis and found the direct and mediated contribution of the identified genetic loci on ADHD symptoms by mediation analysis. In conclusion, we revealed some genetic risk variants associated with inhibitory control and elucidated the benefit of inhibitory control as an endophenotype, providing valuable insights into the mechanisms underlying ADHD.

Exploring silique number in Brassica napus L.: Genetic and molecular advances for improving yield.

Silique number is a crucial yield-related trait for the genetic enhancement of rapeseed (Brassica napus L.). The intricate molecular process governing the regulation of silique number involves various factors. Despite advancements in understanding the mechanisms regulating silique number in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), the molecular processes involved in controlling silique number in rapeseed remain largely unexplored. In this review, we identify candidate genes and review the roles of genes and environmental factors in regulating rapeseed silique number. We use genetic regulatory networks for silique number in Arabidopsis and grain number in rice to uncover possible regulatory pathways and molecular mechanisms involved in regulating genes associated with rapeseed silique number. A better understanding of the genetic network regulating silique number in rapeseed will provide a theoretical basis for the genetic improvement of this trait and genetic resources for the molecular breeding of high-yielding rapeseed.

Identification of Novel QTL for Mercury Accumulation in Maize Using an Enlarged SNP Panel.

Mercury (Hg) pollution not only poses a threat to the environment but also adversely affects the growth and development of plants, with potential repercussions for animals and humans through bioaccumulation in the food chain. Maize, a crucial source of food, industrial materials, and livestock feed, requires special attention in understanding the genetic factors influencing mercury accumulation. Developing maize varieties with low mercury accumulation is vital for both maize production and human health. In this study, a comprehensive genome-wide association study (GWAS) was conducted using an enlarged SNP panel comprising 1.25 million single nucleotide polymorphisms (SNPs) in 230 maize inbred lines across three environments. The analysis identified 111 significant SNPs within 78 quantitative trait loci (QTL), involving 169 candidate genes under the Q model. Compared to the previous study, the increased marker density and optimized statistical model led to the discovery of 74 additional QTL, demonstrating improved statistical power. Gene ontology (GO) enrichment analysis revealed that most genes participate in arsenate reduction and stress responses. Notably, GRMZM2G440968, which has been reported in previous studies, is associated with the significant SNP chr6.S_155668107 in axis tissue. It encodes a cysteine proteinase inhibitor, implying its potential role in mitigating mercury toxicity by inhibiting cysteine. Haplotype analyses provided further insights, indicating that lines carrying hap3 exhibited the lowest mercury content compared to other haplotypes. In summary, our study significantly enhances the statistical power of GWAS, identifying additional genes related to mercury accumulation and metabolism. These findings offer valuable insights into unraveling the genetic basis of mercury content in maize and contribute to the development of maize varieties with low mercury accumulation.

Influences of Genetic and Environmental Factors on Chronic Migraine: A Narrative Review.

PURPOSE OF REVIEW: In this narrative review, we aim to summarize recent insights into the complex interplay between environmental and genetic factors affecting the etiology, development, and progression of chronic migraine (CM). RECENT FINDINGS: Environmental factors such as stress, sleep dysfunction, fasting, hormonal changes, weather patterns, dietary compounds, and sensory stimuli are critical triggers that can contribute to the evolution of episodic migraine into CM. These triggers are particularly influential in genetically predisposed individuals. Concurrently, genome-wide association studies (GWAS) have revealed over 100 genetic loci linked to migraine, emphasizing a significant genetic basis for migraine susceptibility. In CM, environmental and genetic factors are of equal importance and contribute to the pathophysiology of the condition. Understanding the bidirectional interactions between these elements is crucial for advancing therapeutic approaches and preventive strategies. This balanced perspective encourages continued research into the complex gene-environment nexus to improve our understanding and management of CM.

Genetic analysis of late-maturity α-amylase in twelve wheat populations.

MAIN CONCLUSION: Genetic loci, particularly those with an effect in the independent panel, could be utilised to further reduce LMA expression when used with favourable combinations of genes known to affect LMA. Late maturity α-amylase (LMA) is a grain quality defect involving elevated α-amylase within the aleurone of wheat (Triticum aestivum L.) grains. The genes known to affect expression are the reduced height genes Rht-B1 (chromosome 4B) and Rht-D1 (chromosome 4D), and an ent-copalyl diphosphate synthase gene (LMA-1) on chromosome 7B. Other minor effect loci have been reported, but these are poorly characterised and further genetic understanding is needed. In this study, twelve F4-derived populations were created through single seed descent, genotyped and evaluated for LMA. LMA-1 haplotype C and the Rht-D1b allele substantially reduced LMA expression. The alternative dwarfing genes Rht13 and Rht18 had no significant effect on LMA expression. Additional quantitative trait loci (QTL) were mapped at 16 positions in the wheat genome. Effects on LMA expression were detected for four of these QTL in a large independent panel of Australian wheat lines. The QTL detected in mapping populations and confirmed in the large independent panel provide further opportunity for selection against LMA, especially if combined with Rht-D1b and/or favourable haplotypes of LMA-1.

Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders.

Background: Anxiety disorders are prevalent and anxiety symptoms co-occur with many psychiatric disorders. We aimed to identify genomic risk loci associated with anxiety, characterize its genetic architecture, and genetic overlap with psychiatric disorders. Methods: We used the GWAS of anxiety symptoms, schizophrenia, bipolar disorder, major depression, and attention deficit hyperactivity disorder (ADHD). We employed MiXeR and LAVA to characterize the genetic architecture and genetic overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of genomic loci associated with anxiety and those shared with psychiatric disorders. Gene annotation and gene set analyses were conducted using OpenTargets and FUMA, respectively. Results: Anxiety was polygenic with 12.9k estimated genetic risk variants and overlapped extensively with psychiatric disorders (4.1-11.4k variants). MiXeR and LAVA revealed predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 114 novel loci for anxiety by conditioning on the psychiatric disorders. We also identified loci shared between anxiety and major depression (n = 47), bipolar disorder (n = 33), schizophrenia (n = 71), and ADHD (n = 20). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways and differential tissue expression in more diverse tissues than those annotated to the shared loci. Conclusions: Anxiety is a highly polygenic phenotype with extensive genetic overlap with psychiatric disorders. These genetic overlaps enabled the identification of novel loci for anxiety. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified genetic loci implicate molecular pathways that may lead to potential drug targets.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations.

Purpose: For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Design: Genetic association study. Participants: A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Methods: Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Main Outcome Measures: Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. Results: CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P < 1.67 × 10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (ß = -0.63 µm; P = 5.45 × 10-9). Pathway-specific PRSAMD for the complement cascade (ß = -0.53 µm; P = 9.42 × 10-7) and lipoprotein metabolism (ß = -0.05 µm; P = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (ß = -1.00 µm; P = 2.91 × 10-7; R2 = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Conclusions: Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Genetic Structures and Molecular Mechanisms Underlying Ear Traits in Maize (Zea mays L.).

Maize (Zea mays L.) is one of the world's staple food crops. In order to feed the growing world population, improving maize yield is a top priority for breeding programs. Ear traits are important determinants of maize yield, and are mostly quantitatively inherited. To date, many studies relating to the genetic and molecular dissection of ear traits have been performed; therefore, we explored the genetic loci of the ear traits that were previously discovered in the genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping studies, and refined 153 QTL and 85 quantitative trait nucleotide (QTN) clusters. Next, we shortlisted 19 common intervals (CIs) that can be detected simultaneously by both QTL mapping and GWAS, and 40 CIs that have pleiotropic effects on ear traits. Further, we predicted the best possible candidate genes from 71 QTL and 25 QTN clusters that could be valuable for maize yield improvement.

Molecular Mapping to Discover Reliable Salinity-Resilient QTLs from the Novel Landrace Akundi in Two Bi-Parental Populations Using SNP-Based Genome-Wide Analysis in Rice.

Achieving high-yield potential is always the ultimate objective of any breeding program. However, various abiotic stresses such as salinity, drought, cold, flood, and heat hampered rice productivity tremendously. Salinity is one of the most important abiotic stresses that adversely affect rice grain yield. The present investigation was undertaken to dissect new genetic loci, which are responsible for salt tolerance at the early seedling stage in rice. A bi-parental mapping population (F2:3) was developed from the cross between BRRI dhan28/Akundi, where BRRI dhan28 (BR28) is a salt-sensitive irrigated (boro) rice mega variety and Akundi is a highly salinity-tolerant Bangladeshi origin indica rice landrace that is utilized as a donor parent. We report reliable and stable QTLs for salt tolerance from a common donor (Akundi) irrespective of two different genetic backgrounds (BRRI dhan49/Akundi and BRRI dhan28/Akundi). A robust 1k-Rice Custom Amplicon (1k-RiCA) SNP marker genotyping platform was used for genome-wide analysis of this bi-parental population. After eliminating markers with high segregation distortion, 886 polymorphic SNPs built a genetic linkage map covering 1526.5 cM of whole rice genome with an average SNP density of 1.72 cM for the 12 genetic linkage groups. A total of 12 QTLs for nine different salt tolerance-related traits were identified using QGene and inclusive composite interval mapping of additive and dominant QTL (ICIM-ADD) under salt stress on seven different chromosomes. All of these 12 new QTLs were found to be unique, as no other map from the previous study has reported these QTLs in the similar chromosomal location and found them different from extensively studied Saltol, SKC1, OsSalT, and salT locus. Twenty-eight significant digenic/epistatic interactions were identified between chromosomal regions linked to or unlinked to QTLs. Akundi acts like a new alternate donor source of salt tolerance except for other usually known donors such as Nona Bokra, Pokkali, Capsule, and Hasawi used in salt tolerance genetic analysis and breeding programs worldwide, including Bangladesh. Integration of the seven novel, reliable, stable, and background independent salinity-resilient QTLs (qSES1, qSL1, qRL1, qSUR1, qSL8, qK8, qK1) reported in this investigation will expedite the cultivar development that is highly tolerant to salt stress.

Genome-wide association study of multiyear dynamic growth traits in hybrid Liriodendron identifies robust genetic loci associated with growth trajectories.

The genetic factors underlying growth traits differ over time points or stages. However, most current studies of phenotypes at single time points do not capture all loci or explain the genetic differences underlying growth trajectories. Hybrid Liriodendron exhibits obvious heterosis and is widely cultivated, although its complex genetic mechanism underlying growth traits remains unknown. A genome-wide association study (GWAS) is an effective method for elucidating the genetic architecture by identifying genetic loci underlying complex quantitative traits. In the present study, using a GWAS, we identified robust loci associated with growth trajectories in hybrid Liriodendron populations. We selected 233 hybrid progenies derived from 25 crosses for resequencing, and measured their tree height (H) and diameter at breast height (DBH) for 11 consecutive years; 192 972 high-quality single nucleotide polymorphisms (SNPs) were obtained. The dynamics of the multiyear single-trait GWAS showed that year-specific SNPs predominated, and only five robust SNPs for DBH were identified in at least three different years. Multitrait GWAS analysis with model parameters as latent variables also revealed 62 SNPs for H and 52 for DBH associated with the growth trajectory, displaying different biomass accumulation patterns, among which four SNPs exerted pleiotropic effects. All identified SNPs also exhibited temporal variations in effect sizes and inheritance patterns potentially related to different growth and developmental stages. The haplotypes resulting from these significant SNPs might pyramid favorable loci, benefitting the selection of superior genotypes. The present study provides insights into the genetic architecture of dynamic growth traits and lays a basis for future molecular-assisted breeding.

Genomic approaches to identify and investigate genes associated with atrial fibrillation and heart failure susceptibility.

Atrial fibrillation (AF) and heart failure (HF) contribute to about 45% of all cardiovascular disease (CVD) deaths in the USA and around the globe. Due to the complex nature, progression, inherent genetic makeup, and heterogeneity of CVDs, personalized treatments are believed to be critical. To improve the deciphering of CVD mechanisms, we need to deeply investigate well-known and identify novel genes that are responsible for CVD development. With the advancements in sequencing technologies, genomic data have been generated at an unprecedented pace to foster translational research. Correct application of bioinformatics using genomic data holds the potential to reveal the genetic underpinnings of various health conditions. It can help in the identification of causal variants for AF, HF, and other CVDs by moving beyond the one-gene one-disease model through the integration of common and rare variant association, the expressed genome, and characterization of comorbidities and phenotypic traits derived from the clinical information. In this study, we examined and discussed variable genomic approaches investigating genes associated with AF, HF, and other CVDs. We collected, reviewed, and compared high-quality scientific literature published between 2009 and 2022 and accessible through PubMed/NCBI. While selecting relevant literature, we mainly focused on identifying genomic approaches involving the integration of genomic data; analysis of common and rare genetic variants; metadata and phenotypic details; and multi-ethnic studies including individuals from ethnic minorities, and European, Asian, and American ancestries. We found 190 genes associated with AF and 26 genes linked to HF. Seven genes had implications in both AF and HF, which are SYNPO2L, TTN, MTSS1, SCN5A, PITX2, KLHL3, and AGAP5. We listed our conclusion, which include detailed information about genes and SNPs associated with AF and HF.

Sex differences in the influence of type 2 diabetes (T2D)-related genes, parental history of T2D, and obesity on T2D development: a case-control study.

BACKGROUND: This study investigated the effect of sex and age at type 2 diabetes (T2D) diagnosis on the influence of T2D-related genes, parental history of T2D, and obesity on T2D development. METHODS: In this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤ 45 years; late, ≥ 46 years). Sixty-nine T2D-associated single nucleotide polymorphisms were explored and the percentage contribution (R2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist-hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models. RESULTS: T2D-related genes influenced T2D development most in males who were diagnosed early (R2 = 23.5%; females, R2 = 13.5%; males and females diagnosed late, R2 = 11.9% and R2 = 7.3%, respectively). With an early diagnosis, insulin production-related genes were more influential in males (76.0% of R2) while peripheral insulin resistance-associated genes were more influential in females (52.3% of R2). With a late diagnosis, insulin production-related genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and genes associated with inflammation and other processes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males. CONCLUSIONS: The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.

The prevalence of diabetes worldwide is slightly higher in men than in women, particularly in those aged 50 or younger (16.5% for men versus 13.5% for women). This suggests that hormonal differences could be critical in early development of Type 2 diabetes. Some known factors previously associated with T2D, such as genes, parental history of diabetes and obesity, could have a differential influence between both sexes for the development of T2D. We compared these factors between 1008 healthy individual and 1012 TD2 patients. In this comparison, we calculated the percentage of variability of the disease explained by each factor. As expected, the most noticeable differences between men and women were observed in T2D diagnoses before age 46. Genes had a greater effect in men than in women (23.5% vs. 13.5%). While genes involved in insulin production have a greater influence on men, genes involved in peripheric insulin resistance have a greater influence on women. The overall parental history of T2D influences similarly in males (19.9%) and females (17.5%), however, the unilateral genetic influence of the mother was much greater in males than in females. The influence of global and abdominal obesity played a greater role in men than in women. In T2D diagnoses after age of 45, the influence of genes and parental history of diabetes decreases markedly, and the relative influence of global obesity augments. However, while genes linked to insulin resistance and inflammation predominate in females, genes linked to insulin secretion predominate in males.

Risk Genetic Variants (IL-10) for Osteoporosis in Han Population from Northwest China.

Background: Osteoporosis (OP) is a common metabolic bone disease characterized by loss of bone mass. IL-10 is considered to be a powerful immune and inflammatory suppressor. This study aimed to assess association between genetic loci in IL-10 and susceptibility to OP. Methods: Association analysis between IL-10 genetic loci and OP risk through SNPStats online software. FPRP analysis (false-positive report probability) verified whether the positive results were noteworthy findings. Linkage disequilibrium (LD) and haplotype analysis were completed by Haploview 4.2 and SNPStats. Multi-factor dimensionality reduction (MDR) was used to assess interaction of SNP-SNP in susceptibility to OP. Results: Allele "G" of IL-10-rs1554286 (OR = 1.21, p = 0.013), allele "C" of IL-10-rs1518111 (OR = 1.22, p = 0.011), allele "C" of IL-10-rs3024490 (OR = 1.20, p = 0.018), and allele "G" of IL-10-rs1800871 (OR = 1.21, p = 0.015) were risk factors for OP. In females, smoking, drinking, or aging ≤60 years old participants, the above genetic loci are also significantly associated with the increased risk of OP. FPRP analysis showed that all positive results are noteworthy findings. There are significant differences in serum levels of uric acid, mean hemoglobin concentration, or mean hemoglobin among different genotypes of IL-10 gene loci. MDR showed that four loci model composed rs1554286, rs1518111, rs3021094, and rs1800871 is the best model for predicting OP risk. Conclusion: IL-10-rs1554286, -rs1518111, -rs3021094, and -rs1800871 are risk factors for susceptibility to OP.

A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers.

Breast, ovarian, prostate, lung, and head/neck cancers are five solid cancers with complex interrelationships. However, the shared genetic factors of the five cancers were often revealed either by the combination of individual genome-wide association study (GWAS) approach or by the fixed-effect model-based meta-analysis approach with practically impossible assumptions. Here, we presented a random-effect model-based cross-cancer meta-analysis framework for identifying the genetic variants jointly influencing the five solid cancers. A comprehensive genetic correlation analysis (genome-wide, partitioned, and local) approach was performed by using GWAS summary statistics of the five cancers, and we observed three cancer pairs with significant genetic correlation: breast-ovarian cancer (r g = 0.221, p = 0.0003), breast-lung cancer (r g = 0.234, p = 7.6 × 10-6), and lung-head/neck cancer (r g = 0.652, p = 0.010). Furthermore, a random-effect model-based cross-trait meta-analysis was conducted for each significant cancer pair, and we found 27 shared genetic loci between breast and ovarian cancers, 18 loci between breast and lung cancers, and three loci between lung and head/neck cancers. Functional analysis indicates that the shared genes are enriched in human T-cell leukemia virus 1 infection (HTLV-1) and antigen processing and presentation (APP) pathways. Our study investigates the shared genetic links across five solid cancers and will help to reveal their potential molecular mechanisms.

Genetic loci, rs17817449 and rs6567160, known for obesity and the risk of stroke events among middle-aged and older Chinese people.

Background: Fat Mass and Obesity-Associated (FTO) and the Melanocortin-4 Receptor (MC4R) genes are strongly associated with obesity, an established risk factor for stroke. We aimed to assess the associations between rs17817449 at the FTO and rs6567160 at the MC4R and the risk of stroke events in middle-aged and older Chinese people. Materials and methods: Study data were obtained from the Guangzhou Biobank Cohort Study; a total of 148 participants with a self-reported history of stroke and an equal volume of age- and sex-matched participants were selected as the cases and the controls in a case-control study; a total of 13,967 participants at the first follow-up and all participants with fatal stroke (up to April 2021) were included in a retrospective cohort study. Conditional logistic regression and the Cox proportional hazards regression analyses were used to assess the associations of the two genetic loci with the risk of stroke events. Results: After adjusting for age, sex, education, job, smoking, alcohol consumption, body mass index, physical activity, hypertension, diabetes, and dyslipidemia, rs17817449 and rs6567160 shared minor alleles G and C, respectively, in the case-control analyses. The genotypes GG+GT of rs17817449 at the FTO were significantly associated with a decreased risk of fatal stroke occurrence, with fatal all strokes having an adjusted hazard ratio (aHR) of 0.71 (95% confidence intervals (CI) 0.52-0.97, P = 0.04) and fatal ischemic stroke having an aHR of 0.64 (95% CI 0.41-1.00, P = 0.05), when the genotype TT was taken as a reference and a series of multiplicities were adjusted; the risk of fatal all strokes was lowered by dyslipidemia (aHR = 0.63, 95% CI 0.39-1.00, P = 0.05) and non-diabetes (aHR = 0.68, 95% CI 0.46-0.99, P = 0.049) in the retrospective cohort analyses. Significances were observed neither in the associations between rs6567160 and the risk of stroke events nor in an interaction between rs17817449 and rs6567160 in the two-stage analyses. Conclusion: The G allele of rs17817449 at the FTO, not rs6567160 at the MC4R, was associated with a decreased risk of fatal stroke occurrence; its functional role in stroke should be explored in relatively healthy middle-aged to older Chinese people.

Genetic Loci in Phospholipase C-Like 1 (PLCL1) are Protective Factors for Allergic Rhinitis in Han Population of Northern Shaanxi, China.

Background: Allergic rhinitis (AR) is a common allergic disease in otolaryngology. Its pathogenesis is still unclear. PLC1 plays a key role in calcium homeostasis and immune response, which is potentially related to AR. We aimed to explore the association between PLCL1 genetic loci and susceptibility to AR. Methods: We recruited 1975 volunteers to perform an association analysis through SNPStats online software. False-positive report probability (FPRP) analysis was used to detect whether the positive findings were worth noting. Linkage disequilibrium and haplotype analysis were completed through Haploview and SNPStats. The influence of SNP-SNP interaction on AR susceptibility was evaluated through multifactor dimensionality reduction (MDR). Results: The results showed that four genetic loci in PLCL1 (rs2139049, rs212164068, rs2228135, and rs6738825) are associated with AR susceptibility under multiple genetic models. Allele "A" of PLCL1-rs2139049 (OR = 0.85, p = 0.031) or of -rs212164068 (OR = 0.85, p = 0.030), and allele "G" of PLCL1-rs6738825 (OR = 0.84, p = 0.022) are significantly associated with reduced AR risk. PLCL1-rs2228135 is associated with an increased risk of AR in males or participants older than 43 years of age. FPRP analysis showed that most of positive results are noteworthy findings. Three loci model composed of rs2139049, rs2164068, and rs2228135 is the best model for predicting AR risk (p = 0.0022). In addition, the haplotype "Grs2139049Ars6738825Ars2164068Ars2228135" (OR = 0.50, p = 0.033) can reduce the AR risk. Conclusion: Allele "A" of PLCL1-rs2139049, allele "A" of -rs212164068, and allele "G" of PLCL1-rs6738825 are protective factors of AR in Han population from northern Shaanxi, China.

Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche.

STUDY QUESTION: Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER: Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY: Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION: In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE: In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. LIMITATIONS, REASONS FOR CAUTION: A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Whole Genome Re-sequencing and Bulk Segregant Analysis Reveals Chromosomal Location for Papaya Ringspot Virus W Resistance in Squash.

Squash (Cucurbita moschata) is among the most important cucurbit crops grown worldwide. Plant pathogen, Papaya ringspot virus W (PRSV-W) causes significant yield loss in commercial squash production globally. The development of virus-resistant cultivars can complement integrated disease management and mitigate losses due to viral infections. However, the genetic loci and molecular markers linked to PRSV-W resistance that could facilitate marker-assisted selection (MAS) for accelerated cultivar development are unknown. In this study, quantitative trait loci (QTL), molecular markers, and candidate genes associated with PRSV-W resistance in squash were identified in an F2 population (n = 118) derived from a cross between Nigerian Local accession (resistant) and Butterbush cultivar (susceptible). Whole genome re-sequencing-based bulked segregant analysis (QTLseq method; n = 10 for each bulk) and non-parametric interval mapping were used to identify a major QTL associated with PRSV-W resistance on chromosome 9 (QtlPRSV-C09) (p < 0.05) of C. moschata. QtlPRSV-C09 extended from 785,532 to 5,093,314 bp and harbored 12,245 SNPs among which 94 were high-effect variants. To validate QtlPRSV-C09, 13 SNP markers were assayed as Kompetitive allele-specific PCR (KASP) markers in the F2 population and tested for the association with PRSV-W resistance. Among these, two KASP markers (Ch09_2080834 and Ch09_5023865-1) showed significant association with PRSV-W resistance (p < 0.05). The two SNPs were located within exons of putative disease-resistant genes encoding the clathrin assembly family and actin cytoskeleton-regulatory complex proteins, which are implicated in disease resistance across plant species. The findings of this study will facilitate MAS for PRSV-W resistance in squash and allow further understanding of the functional mechanisms underlying potyvirus resistance in Cucurbita species.