Atopic dermatitis (AD) is a chronic itchy inflammatory disease of the skin. Genetic studies have identified multiple risk factors linked to the disease; however, most of studies have been derived from European and East Asian populations. The admixed genome of African American (AA) may provide an opportunity to discovery ancestry-specific loci involved in AD susceptibility. Herein, we present joint analysis of ancestry and genotype effects followed with validation using differential gene expression analysis on AD using 710 AD cases and 1015 non-AD controls from the AA population, genotyped using MEGA followed by imputation using the CAAPA reference panel. The joint analysis identified two novel AD-susceptibility loci, rs2195989 in gene ANGPT1 (8q23.1) and rs62538818 in the intergenic region LURAP1L-MPDZ (9p23). Admixture mapping (AM) results showed potential genomic inflation, and we implemented genomic control and identified five ancestry-of-origin loci with European ancestry effects. The multi-omics functional prioritization of variants in AM signals prioritized the loci SLAIN2, RNF39, and FOXA2. GWAS identified variants significantly associated with AD in the AA population, including SGK1 (rs113357522, OR = 2.81), EFR3A (rs16904552, OR = 1.725), and MMP14 (rs911912, OR = 1.791). GWAS variants were common in the AA but rare in the European population, which suggests an African ancestry-specific risk of AD. Four genes (ANGPT1, LURAP1L, EFR3A, and SGK1) were further validated using qPCR from AD and healthy skin. This study highlighted the importance of genetic studies on admixed populations, as well as local ancestry and genotype-ancestry joint effects to identify risk loci for AD.

BACKGROUND: Previous research has highlighted correlations between blood cell counts and chronic liver disease. Nonetheless, the causal relationships remain unknown.
OBJECTIVE: To evaluate the causal effect of blood cell traits on liver enzymes and nonalcoholic fatty liver disease (NAFLD) risk.
METHODS: Independent genetic variants strongly associated with blood cell traits were extracted from a genome-wide association study (GWAS) conducted by the Blood Cell Consortium. Summary-level data for liver enzymes were obtained from the United Kingdom Biobank. NAFLD data were obtained from a GWAS meta-analysis (8434 cases and 770180 controls, discovery dataset) and the Fingen GWAS (2275 cases and 372727 controls, replication dataset). This analysis was conducted using the inverse-variance weighted method, followed by various sensitivity analyses.
RESULTS: One SD increase in the genetically predicted haemoglobin concentration (HGB) was associated with a β of 0.0078 (95%CI: 0.0059-0.0096), 0.0108 (95%CI: 0.0080-0.0136), 0.0361 (95%CI: 0.0156-0.0567), and 0.0083 (95%CI: 00046-0.0121) for alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase, and gamma-glutamyl transferase, respectively. Genetically predicted haematocrit was associated with ALP (β = 0.0078, 95%CI: 0.0052-0.0104) and ALT (β = 0.0057, 95%CI: 0.0039-0.0075). Genetically determined HGB and the reticulocyte fraction of red blood cells increased the risk of NAFLD [odds ratio (OR) = 1.199, 95%CI: 1.087-1.322] and (OR = 1.157, 95%CI: 1.071-1.250). The results of the sensitivity analyses remained significant.
CONCLUSIONS: Novel causal blood cell traits related to liver enzymes and NAFLD development were revealed through Mendelian randomization analysis, which may facilitate the diagnosis and prevention of NAFLD.

To evaluate the genetics of chronic nonsuppurative otitis media (OM). We performed a genome-wide association study of 429,599 individuals included in the FinnGen study using three different case definitions: combined chronic nonsuppurative OM (7034 cases) (included serous and mucous chronic OM), mucous chronic OM (5953 cases), and secretory chronic OM (1689 cases). Individuals without otitis media were used as controls (417,745 controls). We used immunohistochemistry (IHC) of the murine middle ear to evaluate the expression of annexin A13. Four loci were significantly associated (p < 1.7 × 10-8) with nonsuppurative OM. Three out of the four association signals included missense variants in genes that may play a role in otitis media pathobiology. According to our subtype-specific analyses, one novel locus, located near ANXA13, was associated with secretory OM. Three loci (near TNFRSF13B, GAS2L2, and TBX1) were associated with mucous OM. Immunohistochemistry of murine middle ear samples revealed annexin A13 expression at the apical pole of the Eustachian tube epithelium as well as variable intensity of the secretory cells of the glandular structure in proximity to the Eustachian tube. We demonstrated that secretory and mucous OM have distinct and shared genetic associations. The association of GAS2L2 with ciliary epithelium function and the pathogenesis of dysfunctional mucosa in mucous OM is suggested. The abundant expression of annexin A13 in the Eustachian tube epithelium, along with its role in apical transport for the binding and transfer of phospholipids, indicates the role of annexin A13 and phospholipids in Eustachian tube dysfunction.

Genome-wide association studies (GWAS) are employed to identify genomic regions and candidate genes associated with several traits. The aim of this study was to perform a GWAS to identify causative variants and genes associated with milk yield, frame, and udder conformation traits in Gir dairy cattle. Body conformation traits were classified as \"frame,\" and \"udder\" traits for this study. After genotyping imputation and quality control 42,105 polymorphisms were available for analyses and 24,489 cows with pedigree information had phenotypes. First, P-value was calculated based on the variance of the prediction error of the SNP-effects on the first iteration. After that, 2 more iterations were performed to carry out the weighted single-step genome-wide association methodology, performed using genomic moving windows defined based on linkage disequilibrium. The significant SNPs and top 10 windows explaining the highest percentage of additive genetic variance were selected and used for QTL and gene annotation. The variants identified in our work overlapped with QTLs from the animal QTL database on chromosomes 1 to 23, except for chromosome 4. The Gir breed is less studied than the Holstein breed and as such the animal QTL database is biased to Holstein results. Hence it is noteworthy that our GWAS had similarities with previously described QTLs. These previously known QTLs were related to milk yield, body height, rump angle, udder width, and udder depth. In total, 5 genes were annotated. Of these genes, FAM13A and CMSS1 had been previously related to bone and carcass weight in cattle.

Over the last two decades, numerous genome-wide association studies (GWAS) have been performed to unveil the genetic architecture of human complex traits. Despite multiple efforts aimed at the trans-biobank integration of GWAS results, no systematic analysis of the variant-level properties affecting the replication of known associations (or identifying novel ones) in genome-wide meta-analysis has yet been performed using biobank-scale data. To address this issue, we performed a systematic comparison of GWAS summary statistics for 679 complex traits in the UK Biobank (UKB) and FinnGen (FG) cohorts. We identified 37,148 index variants with genome-wide associations with at least one trait in either cohort or in the meta-analysis, only 3528 (9.5%) of which were shared between UKB and FG. Nearly twice as many variants (6577) were replicated in another dataset at the significance level adjusted for the number of variants selected for replication. However, as many as 9230 loci failed to be replicated. Moreover, as many as 5813 loci were observed as significant associations only in meta-analysis results, highlighting the importance of trans-biobank meta-analysis efforts. We showed that variants that failed to replicate in UKB or FG tend to correspond to rare, less pleiotropic variants with lower effect sizes and lower LD score values. Genome-wide associations specific to meta-analysis were also enriched in low-effect variants; however, such variants tended to be more common and have more consistent frequencies between populations. Taken together, our results show a relatively high rate of non-replication of genome-wide associations in the studied cohorts and highlight both widely appreciated and less acknowledged properties of the associations affecting their identification and replication.

The aim of the current study was to investigate interindividual differences in muscle thickness of the rectus femoris (MTRF) following 12 wk of resistance training (RT) or high-intensity interval training (HIIT) to explore the genetic architecture underlying skeletal muscle hypertrophy and to construct predictive models. We conducted musculoskeletal ultrasound assessments of the MTRF response in 440 physically inactive adults after the 12-wk exercise period. A genome-wide association study was used to identify variants associated with the MTRF response, separately for RT and HIIT. Using the polygenic predictor score (PPS), we estimated the genetic contribution to exercise-induced hypertrophy. Predictive models for the MTRF response were constructed using random forest (RF), support vector mac (SVM), and generalized linear model (GLM) in 10 cross-validated approaches. MTRF increased significantly after both RT (8.8%, P < 0.05) and HIIT (5.3%, P < 0.05), but with considerable interindividual differences (RT: -13.5 to 38.4%, HIIT: -14.2 to 30.7%). Eleven lead single-nucleotide polymorphisms in RT and eight lead single-nucleotide polymorphisms in HIIT were identified at a significance level of P < 1 × 10-5. The PPS was associated with the MTRF response, explaining 47.2% of the variation in response to RT and 38.3% of the variation in response to HIIT. Notably, the GLM and SVM predictive models exhibited superior performance compared with RF models (P < 0.05), and the GLM demonstrated optimal performance with an area under curve of 0.809 (95% confidence interval: 0.669-0.949). Factors such as PPS, baseline MTRF, and exercise protocol exerted influence on the MTRF response to exercise, with PPS being the primary contributor. The GLM and SVM predictive model, incorporating both genetic and phenotypic factors, emerged as promising tools for predicting exercise-induced skeletal muscle hypertrophy.NEW & NOTEWORTHY The interindividual variability induced muscle hypertrophy by resistance training (RT) or high-intensity interval training (HIIT) and the associated genetic architecture remain uncertain. We identified genetic variants that underlie RT- or HIIT-induced muscle hypertrophy and established them as pivotal factors influencing the response regardless of the training type. The genetic-phenotype predictive model developed has the potential to identify nonresponders or individuals with low responsiveness before engaging in exercise training.

Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) and persist even in their absence. Consequently, dysregulation of circadian rhythms adversely affects the well-being of the organism. This timekeeping system is generated and sustained by a genetically encoded endogenous mechanism composed of interlocking transcriptional/translational feedback loops that generate rhythmic expression of core clock genes. Genome-wide association studies (GWAS) and forward genetic studies show that SNPs in clock genes influence gene regulation and correlate with the risk of developing various conditions. We discuss genetic variations in core clock genes that are associated with various phenotypes, their implications for human health, and stress the need for thorough studies in this domain of circadian regulation.

Speech-in-noise (SIN) perception is a primary complaint of individuals with audiometric hearing loss. SIN performance varies drastically, even among individuals with normal hearing. The present genome-wide association study (GWAS) investigated the genetic basis of SIN deficits in individuals with self-reported normal hearing in quiet situations. GWAS was performed on 279,911 individuals from the UB Biobank cohort, with 58,847 reporting SIN deficits despite reporting normal hearing in quiet. GWAS identified 996 single nucleotide polymorphisms (SNPs), achieving significance (p < 5*10-8) across four genomic loci. 720 SNPs across 21 loci achieved suggestive significance (p < 10-6). GWAS signals were enriched in brain tissues, such as the anterior cingulate cortex, dorsolateral prefrontal cortex, entorhinal cortex, frontal cortex, hippocampus, and inferior temporal cortex. Cochlear cell types revealed no significant association with SIN deficits. SIN deficits were associated with various health traits, including neuropsychiatric, sensory, cognitive, metabolic, cardiovascular, and inflammatory conditions. A replication analysis was conducted on 242 healthy young adults. Self-reported speech perception, hearing thresholds (0.25-16 kHz), and distortion product otoacoustic emissions (1-16 kHz) were utilized for the replication analysis. 73 SNPs were replicated with a self-reported speech perception measure. 211 SNPs were replicated with at least one and 66 with at least two audiological measures. 12 SNPs near or within MAPT, GRM3, and HLA-DQA1 were replicated for all audiological measures. The present study highlighted a polygenic architecture underlying SIN deficits in individuals with self-reported normal hearing.

UNASSIGNED: Sorghum bicolor is a promising cellulosic feedstock crop for bioenergy due to its high biomass yields. However, early growth phases of sorghum are sensitive to cold stress, limiting its planting in temperate environments. Cold adaptability is crucial for cultivating bioenergy and grain sorghum at higher latitudes and elevations, or for extending the growing season. Identifying genes and alleles that enhance biomass accumulation under early cold stress can lead to improved sorghum varieties through breeding or genetic engineering.
UNASSIGNED: We conducted image-based phenotyping on 369 accessions from the sorghum Bioenergy Association Panel (BAP) in a controlled environment with early cold treatment. The BAP includes diverse accessions with dense genotyping and varied racial, geographical, and phenotypic backgrounds. Daily, non-destructive imaging allowed temporal analysis of growth-related traits and water use efficiency (WUE). A genome-wide association study (GWAS) was performed to identify genomic intervals and genes associated with cold stress response.
UNASSIGNED: The GWAS identified transient quantitative trait loci (QTL) strongly associated with growth-related traits, enabling an exploration of the genetic basis of cold stress response at different developmental stages. This analysis of daily growth traits, rather than endpoint traits, revealed early transient QTL predictive of final phenotypes. The study identified both known and novel candidate genes associated with growth-related traits and temporal responses to cold stress.
UNASSIGNED: The identified QTL and candidate genes contribute to understanding the genetic mechanisms underlying sorghum\'s response to cold stress. These findings can inform breeding and genetic engineering strategies to develop sorghum varieties with improved biomass yields and resilience to cold, facilitating earlier planting, extended growing seasons, and cultivation at higher latitudes and elevations.

UNASSIGNED: Research has showcased a correlation between disruptions in gut microbiota and primary membranous nephropathy (pMN), giving rise to the concept of the \'gut-kidney axis\'. However, the precise relationship between gut microbiota and pMN remains elusive. Hence, this study endeavors to investigate whether a causal relationship exists between gut microbiota and pMN utilizing Mendelian randomization (MR) analysis.
UNASSIGNED: The primary method employed for MR analysis is the inverse variance weighting method, supplemented by MR-Egger and the weighted median method, to infer causality. This approach was validated within the pMN cohort across two distinct populations.
UNASSIGNED: At the species level, the abundance of Bifidobacterium bifidum and Alistipes indistinctus was negatively correlated with the risk of pMN. Conversely, pMN was positively associated with Bacilli abundance at the class level, Lachnospiraceae abundance at the family level, and Dialister abundance at the genus level. Specifically, at the species level, pMN was positively correlated with the abundance of Ruminococcus lactaris, Dialister invisus, and Coprococcus_sp_ART55_1.
UNASSIGNED: These findings lay the groundwork for future research exploring the interplay between pMN and the gut microbiota, with substantial implications for the prevention and treatment of pMN and its associated complications.