Recent Genome-wide Association Studies Research Articles

Enhanced osteogenic potential of iPSC-derived mesenchymal progenitor cells following genome editing of GWAS variants in the RUNX1 gene

Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD), including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1 expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiated into osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lacking these loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containing these loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes and Alizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMD-associated loci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple gene promoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence. Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on the shorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removal removed a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model in mice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMD-associated variants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuable insights into genetic regulation of bone density and potential therapeutic targets.

Endometriosis-Related Genetic Factors and Their Role in Preterm Birth: A Two-Sample Mendelian Randomisation Study.

Endometriosis affects 10% of women worldwide and is linked to adverse pregnancy outcomes, including preterm birth. Recent epidemiological and genetic studies indicate that endometriosis may influence gestational duration and the likelihood of preterm birth. This study aimed to estimate the direct genetic causal effects of endometriosis on gestational duration and preterm birth using Mendelian randomisation (MR) analysis, leveraging genetic data from recent genome-wide association studies (GWASs). A two-sample MR study. Summary statistics from published GWASs on European ancestry populations for endometriosis and gestational duration. Instrumental variables for endometriosis were derived from a meta-analysis comprising 60 674 endometriosis cases and 701 926 controls. Genetic correlations and heritability estimates were calculated using linkage disequilibrium score regression. Two-sample MR with multiplicative random-effects inverse variance weighting assessed the primary objectives, supplemented by sensitivity analyses to validate MR assumptions. Primary outcomes were gestational duration and preterm birth, sourced from the latest GWAS data. LD score regression revealed no genetic correlation between endometriosis and either gestational duration or preterm birth. MR analysis showed no causal association between endometriosis and maternal effects on offspring gestational duration (β = 0.40, 95% CI: -0.39 to 1.19, p = 0.32) or preterm birth (OR = 0.94, 95% CI: 0.82-1.06, p = 0.36). Sensitivity analyses indicated pleiotropy but no violations of MR assumptions. Of the four loci overlapping between the gestational duration and endometriosis GWASs, three (EBF1, WNT4, and GDAP1) were identified as outliers using MR-Presso. Contrary to observational studies, MR analyses found no direct causal link between endometriosis and gestational duration or preterm birth. Overlaps in genomic regions suggest that the relationship may be mediated through different biological pathways.

CRISPR-based genetic screens in human pluripotent stem cells derived neurons and brain organoids.

Recent large-scale genome-wide association and single-cell RNA sequencing (scRNA-seq) studies have uncovered disease-associated genetic risk factors and cell type-specific genetic alterations. However, our understanding of how these genetic variants cause diseases and the underlying mechanisms remains largely unknown. Functional genomics screens using CRISPR-based technologies offer an effective tool for studying genes relevant to disease phenotypes. Here, we summarize recent CRISPR-based functional genomics screen approaches applied to human pluripotent stem cell (hPSC)-derived neurons and brainorganoids. These screens have identified genes crucial for neurogenesis, neuronal survival, morphological development, and migration. Combining CRISPR-based genetic screens with scRNA-seq, researchers have revealed downstream genes and cellular pathways impacted by these genetic variants in human neural cells, providing new insights into the pathogenesis of neurodevelopmental disorders, such as microcephaly and autism spectrum disorders. Finally, we discuss current challenges and future directions for using CRISPR-based screens in furthering our understanding of neurological diseases and developing potential therapeutic strategies. Despite challenges, CRISPR-based screens have enormous potential for advancing the therapeutic development of many diseases.

The Association of Interleukin 6 Receptor Gene Variant (Rs4129267) with Susceptibility to Ankylosing Spondylitis and Soluble IL-6 Receptor Level in Iranian Patients

Objectives: Ankylosing spondylitis (AS) is an axial skeleton-related auto-inflammatory arthritis. Interleukin 6 (IL-6) and its receptor (IL-6R) play a role in the etiopathology of AS. The recent genome-wide association studies (GWASs) revealed that rs4129267; an intrinsic variant of IL6-R is associated with the risk of AS. We aimed to study the rs4129267 IL6R variant in Iranian AS patients and the correlation of this variant with the soluble interleukin-6 receptor (sIL-6R) serum level. Materials and Methods: In this case-control study, we genotyped rs4129267 IL6-R variant in extracted DNA from 498 AS patients and 495 matched healthy controls by Amplification-Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR). The serum level of sIL-6R and IL-6 was also analysed in 39 controls and 42 AS patients by the ELISA method. The correlation between rs4129267 IL-6R variants and patients’ clinical manifestations and sIL-6R level was also investigated. Results: In comparison to the AS individuals, C allele were significantly less prevalent in the healthy control group (OR = 1.23 [1.01 –1.48], P value = .034). Patients had significantly elevated levels of IL-6 serum levels. There was a significant correlation between the presence of the rs4129267 T allele and increased sIL-6R level. Conclusions: Our study confirmed the significant association between the rs4129267 T variant and the protection against AS disease susceptibility. Increased IL-6 level and reduced frequency of sIL-6R rs4129267 T allele in patients which contributes to reduced sIL-6R serum level, highlights the significant role of IL-6 signalling pathway in AS pathogenesis.

Investigation on regulation of N-acetyltransferase 2 expression by nuclear receptors in human hepatocytes.

Arylamine N-acetyltransferase 2 (NAT2) expresses a well-defined genetic polymorphism in humans that modifies drug and xenobiotic metabolism. Recent studies and genome wide association studies have reported that genetic variants of NAT2 are associated with differential risks of developing dyslipidemia and cardiometabolic disorders, suggesting a previously unrecognized role of NAT2 in pathophysiology of metabolic disorders. In support of this notion, we recently showed that human NAT2 expression is differentially regulated by glucose and insulin. Moreover, our in silico analysis showed that NAT2 is co-expressed with nuclear receptors enriched in the liver, e.g., NR1H4 (FXR) and NR1I2 (PXR), that have been previously implicated in regulation of hepatic glucose and lipid homeostasis. Identification of transcriptional regulator(s) of human NAT2 would aid in understanding novel functions that it may play in the liver. Thus, the present study was designed to investigate if NAT2 is transcriptionally regulated by hepatic nuclear receptors. To test this, we treated cryopreserved human hepatocytes with agonists towards four different hepatic transcription factors/nuclear hormone receptors, namely FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA), and measured their effects on the level of NAT2 mRNA. While the treatment with a FXR, PXR, or LXR agonist (i.e., GW-4064, SR-12813, or GW-3965) significantly induced their respective target genes, treatment with these agonists did not significantly alter the transcript level of NAT2 in human hepatocytes. PPARα agonist, GW-7647, treatment resulted in a statistically significant decrease in the NAT2 transcript level. However, its magnitude was marginal. In summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter NAT2 expression in cryopreserved human hepatocytes. Additional studies are needed to identify transcriptional regulators of hepatic NAT2 expression.

MIGRAINE

Background Migraine is a prevalent neurological disorder characterized by chronic headaches, significantly impacting the global population. This comprehensive review aims to advance the understanding of migraine pathogenesis and treatment, focusing on molecular markers and novel therapeutic strategies. Material Molecular markers such as calcitonin gene-related peptide (CGRP) and their role in migraine development. Traditional medical treatments and emerging therapeutic strategies, including neuromodulation, are analyzed for their effectiveness and limitations. Clinical studies and imaging techniques are leveraged to identify key mechanisms and triggers in migraine pathology. Approximately 95% of people experience a headache at some point, with migraines being a significant contributor. Migraine is recognized by the World Health Organization as one of the top ten causes of disability globally, particularly affecting women. CGRP is identified as a crucial factor in migraine development. Inhibitors targeting CGRP have shown significant effectiveness in managing migraines. Other molecular markers, including proinflammatory cytokines and neurotransmitters, are discussed for their roles in pain transmission and migraine pathophysiology. Traditional treatments, such as triptans and NSAIDs, are evaluated alongside new therapies, including CGRP inhibitors and neuromodulation techniques. Neuromodulation, involving devices like external trigeminal nerve stimulators, shows promise in migraine management. Genetic markers associated with familial hemiplegic migraine (FHM) and common migraine forms are reviewed. Recent genome-wide association studies (GWAS) have identified several genetic variants linked to migraine susceptibility. Conclusion This presentation enhances the understanding of migraine pathogenesis and introduces novel therapeutic possibilities. By focusing on molecular markers like CGRP and exploring advanced treatment options, the study aims to improve migraine management and patient care. The findings underscore the need for continued research and innovation in migraine treatments to reduce the global burden of this debilitating condition.

Abstract 4145884: Left ventricular 3D-sphericity is associated with 92 genetic loci

Introduction: Left ventricular (LV) sphericity is a measure of the degree to which the LV blood pool resembles a sphere. Analyses of cardiovascular magnetic resonance imaging (MRI) in the MESA cohort have shown that LV sphericity is an important mode of variation in cardiac structure that is associated with ischemia, heart failure, and atrial fibrillation. A recent genome-wide association study (GWAS) of a two-dimensional estimate of sphericity in 38,000 UK Biobank participants identified 4 genetic loci (near PDZRN3, HLA, PLN, and ANGPT1). Genetic contributions to three-dimensional (3D) sphericity remain unknown. Aims: To measure 3D sphericity from cardiovascular MRI at scale and characterize the genetic contributions to 3D sphericity. Methods: Deep learning models were constructed to perform semantic segmentation in the short- and long-axis view from cardiovascular MRI in UK Biobank. These models were applied to all participants with MRI. Poisson surface reconstruction was used to build 3D meshes of the left ventricle. Sphericity was estimated at end-systole and end-diastole as the area of a perfect sphere with the same volume as the left ventricle, divided by the estimated surface area from the mesh. Heritability was estimated with ldsc; GWAS was conducted with REGENIE. Results: Sphericity was estimated in 68,978 individuals, of whom 3,096 were excluded due to atrial fibrillation or atrial dysfunction, and 2,686 were excluded during genetic quality control; 63,196 participants were included in the GWAS. Ldsc heritability was 29.7% for sphericity in diastole and 26.0% for sphericity in systole. 49 genetic loci were associated with 3D sphericity in diastole as were 64 in systole (92 distinct loci). 46 of these loci were unique to sphericity and not found for other LV traits, including loci near the genes encoding calsequestrin 2, troponin T2, palladin, supervillin, and angiopoietins 1 and 2. Shared loci included those near RXFP4, encoding a relaxin-family peptide receptor, and MICU2 (previously implicated in cardiac relaxation). Conclusion: Left ventricular sphericity is heritable, with genetic underpinnings distinct from standard LV measurements.

Shared genetic architecture of psychiatric disorders and hemorrhoidal disease: a large-scale genome-wide cross-trait analysis.

The genetic association between psychiatric disorders and hemorrhoidal disease (HEM) is still not well known. The work aims to investigate their comorbidity at a genetic level. Utilizing recent large-scale genome-wide association studies (GWAS), we investigated the genetic overlap at the single nucleotide polymorphism (SNP), gene, and molecular level between depression and HEM, bipolar disorder (BD) and HEM, neuroticism and HEM, as well as schizophrenia (SCZ) and HEM. The cross-trait genes were validated through the utilization of transcriptome and proteome methodologies. The causal link was assessed using bidirectional two-sample Mendelian randomization analysis (MR) analysis. MRlap corrects for the potential bias in estimation caused by sample overlap. We discovered significant positive genetic associations between these four types of psychiatric disorders and HEM. Cross-phenotypic association analyses identified shared SNPs along with 17 specific loci between psychiatric disorders and HEM. MAGMA identified a total of 2304 pleiotropic genes, several of which showed significant expression in the results of transcriptome and proteome analyses. We observed that these genes are mostly associated with the regulation of transcription factors and particular DNA binding activities. Lastly, MR analysis provided evidence supporting a correlation between these conditions. This study revealed a genetic correlation between four psychiatric disorders and HEM, identified pleiotropic loci, found multiple candidate genes, and confirmed causal relationships. This has enhanced our comprehension of the common genetic mechanisms of psychiatric disorders and HEM.

Cooling lactating sows exposed to early summer heat wave alters circadian patterns of behavior and rhythms of respiration, rectal temperature, and saliva melatonin.

Heat stress (HS) exerts detrimental effects on animal production, with lactating sows being particularly vulnerable. Understanding the mechanisms involved in HS response could aid in developing effective strategies against the negative impacts on livestock. Recent genome wide association studies identified two core circadian clock genes as potential candidates in mediating HS response. The study aimed to investigate how cooling lactating sows under natural heat stress conditions impacted circadian patterns of respiration rate (RR), rectal temperature (RT), behavior, salivary melatonin and cortisol levels, and diurnal patterns of cytokines in saliva. Mixed parity lactating sows were assigned to one of two treatment groups: electronic cooling pad (C; n = 9) and heat-stressed (H; n = 9). The experiment spanned two 48 h periods of elevated ambient temperatures due to summer heat wave. In the first 48 h period, RR was recorded every 30 min, RT every 60 min, and behaviors (eating, standing, sitting, laying, sleeping, drinking, and nursing) every 5 min. In the second 48 h period, saliva samples were collected every 4 h. Cooling reduced RR and RT and altered circadian patterns (P < 0.05). Cooling did not affect amount of time engaged in any behavior over the 48 h period (P > 0.05), however, daily patterns of eating, standing and laying differed between the treatments (P < 0.05), with altered eating behavior related to RT increment in H sows (P < 0.05). Cooling increased and altered the circadian pattern of salivary melatonin (P < 0.05). Cooling also influenced the diurnal pattern of saliva cytokines. Cooling had no impact on saliva cortisol levels. In conclusion, cooling HS sows impacted circadian rhythms of physiology and behavior, supporting the need for further research to understand if circadian disruption underlies decreased production efficiency of HS animals.

Accelerometer-Derived Sleep Metrics in Adolescents Reveal Shared Genetic Influences with Obesity and Stress in a Brazilian Birth Cohort Study.

We aimed to test the association between sleep-related polygenic scores (PGSs) and accelerometer-based sleep metrics among Brazilian adolescents, and to evaluate potential mechanisms underlying the association through the enrichment of obesity, and cortisol pathway-specific polygenic scores (PRSet). Utilizing data from The 2004 Pelotas (Brazil) Birth Cohort, sleep time window and sleep efficiency were measured at the 11-year-old follow-up using ActiGraph accelerometers. Three sleep-PGSs were developed based on the most recent genome-wide association study (GWAS) of accelerometer-based sleep measures. PRSet, calculated using variants linked to body mass index (BMI) and plasmatic cortisol concentration, aimed to assess pleiotropic effects. Linear regression models, adjusted for sex and the first 10 principal components of ancestry, were employed to explore the impact of sleep-PGS and specific-PRSet on sleep phenotypes. The number of nocturnal sleep episodes-PGS was positively associated with sleep time window (β =2.306, SE: 0.92, p=0.011). Nocturnal sleep episodes were also associated with sleep time window when restricted to BMI-PRSet (β=2.682, SE: 0.912, competitive-p=0.003). Both number of sleep episodes and sleep time window cortisol-PRSets were associated (β=0.002, SE: 0.001, p=0.013; β=0.003, SE: 0.001, p=0.003, respectively) and exhibited enrichment in molecular pathways (competitive-p=0.011; competitive-p=0.003, respectively) with sleep efficiency. Sleep polygenetic components observed in European adults may partially explain accelerometer-based sleep time window in Brazilian adolescents. Specific BMI molecular pathway strengthened the association between sleep-PGS and sleep time window, while cortisol concentration pathway had a significant impact on the genetic liability for sleep efficiency. Our results suggest genetic overlap as a potential etiological pathway for sleep-related comorbidities, emphasizing common genetic mechanisms.

Utility of polygenic risk score for prediction of dilated cardiomyopathy and modulation of severity of LV dysfunction among cases

Abstract Background Dilated cardiomyopathy (DCM) is a predominant cause of heart failure and a leading indication for cardiac transplantation. While rare genetic variants are established as causative factors in familial forms of the disease, recent genome-wide association studies (GWAS) have also underscored the significant contribution of common genetic variation to DCM. Polygenic scores (PGS) constructed from GWAS have demonstrated promise in risk stratification for a range of common diseases and may similarly have value for risk prediction in DCM. However, data regarding the clinical utility of PGS in DCM remains sparse. Purpose We aimed to evaluate the utility of PGS for prediction of DCM and its association with left ventricular ejection fraction (LVEF) and family history. We further aimed to assess the contribution of PGS in DCM patients with established causative rare variants (genotype-positive) and those without (genotype-negative). Methods We used a previously-constructed PGS, which was developed from a GWAS meta-analysis (8387 DCM cases and 939161 controls) and multi-trait analysis (MTAG) with cardiac MRI traits. In the present analysis, we calculated PGS for a newly assembled cohort of 978 DCM cases from a major university medical centre and 7207 controls from a national register. To evaluate the clinical utility of PGS, we built logistic regression models and assessed the association between PGS and DCM status. Subsequently, we performed subgroup analyses, including: i) individuals of European ancestry, ii) non-European ancestry, iii) males, iv) females, v) genotype-positive participants(n=193), and vi) genotype-negative participants (n=294). We then used linear and logistic regression models, respectively, to assess the associations of PGS with LVEF and documented family history of DCM. Results PGS demonstrated a significant enrichment among DCM cases compared to controls (OR per SD 1.93, P = 9.47E-68). This association persisted with consistent effect estimates - ranging from OR 1.5 to 2.2 - across all examined subgroups and demonstrated sufficient statistical significance (all P&amp;lt;1.58E-06) (Figure 1). Genotype-negative cases had a significantly higher PGS compared to genotype-positive individuals (P = 0.0015), although PGS was significantly enriched in both groups as compared to controls. Furthermore, among DCM cases, higher PGS was significantly associated with lower LVEF at first presentation (P=0.03, beta=-0.5% per SD) (Figure 2). There was no significant association found between PGS and family history. Conclusions PGS is strongly associated with risk of DCM, and may modulate the severity of LV dysfunction among DCM cases. Polygenic burden contributes to DCM risk in both genotype-positive and negative cases, although the contribution is stronger in patients without known causative rare variants. Overall, our results suggest a potential clinical applicability for PGS in DCM risk stratification.Figure 1.Association of PGS with DCMFigure 2.Association of PGS with LVEF

Investigating the role of WT1 in Brugada syndrome pathophysiology

Abstract Background Brugada syndrome (BrS) is a heritable arrhythmic disorder presumably caused by conduction slowing in the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study found an association between common variants on chromosome 11 near WT1, tagged by the SNP rs72905083, and BrS susceptibility. Purpose To study whether WT1 affects cardiac conduction and could therefore represents the underlying association of the chr11 locus with BrS susceptibility. Methods We conducted in silico analyses of omics datasets to identify the likely causal gene at the chr11 BrS locus. Next, we conducted electrophysiological studies in heterozygous young adult (4 months old) Wt1-deficient (Wt1+/-) mice and wild-type littermates to explore the effect of Wt1 on cardiac conduction. To study the potential role of Wt1 in the setting of reduced conduction reserve, we compared aged Scn5a haploinsufficient mice (Scn5a+/-;Wt1+/+, 17 months) with littermates haploinsufficient for both Wt1 and Scn5a (Scn5a+/-;Wt1+/-). Optical mapping was performed in Langendorff-perfused hearts, where conduction was further challenged by acute ajmaline administration or by pacing at the effective refractory period (ERP). Transcriptomic analyses were conducted in Wt1+/- and wild-type mice by RNAseq of PCM1-sorted cardiomyocytes. Results Analysis of omics datasets uncovered WT1 as the likely causal gene since WT1 was the closest gene to, and in fact overlapped, the BrS-associated region; promoter capture Hi-C data in human tissue showed chromatin contact between the promoter of WT1 and the associated region; and H3K27ac ChIP-seq signals (i.e. enhancer activity) of putative cardiac enhancers located within the associated region were correlated with WT1 transcript abundance across multiple tissues (Z-score = 4.32, p=1.57e-05). No differences were observed in ECG parameters or optically mapped epicardial conduction between Wt1+/- mice and wild-type littermates. However, comparison of aged Scn5a+/-;Wt1+/- and Scn5a+/-; Wt1+/+ hearts, in the setting of acute ajmaline challenge or pacing at the ERP, showed faster conduction in RV/RVOT in the presence of Wt1 haploinsufficiency (genotype effect: p=0.057 and p=0.041 for RV and RVOT epicardial conduction, respectively, during ajmaline challenge; p=0.034 for RV epicardial conduction during pacing at ERP). RNAseq of RV/RVOT cardiomyocytes revealed higher Scn5a expression in Wt1+/- vs wild-type (p=0.006). Conclusion We identified WT1 as the gene that most likely underlies the effect of the chr11 BrS susceptibility locus. Functional data revealed protective effects of reduced Wt1 expression in the setting of reduced conduction reserve. Transcriptomic data suggest that this occurs through a transcriptional effect on Scn5a expression.

DINGO: increasing the power of locus discovery in maternal and fetal genome-wide association studies of perinatal traits

Perinatal traits are influenced by fetal and maternal genomes. We investigate the performance of three strategies to detect loci in maternal and fetal genome-wide association studies (GWASs) of the same quantitative trait: (i) the traditional strategy of analysing maternal and fetal GWASs separately; (ii) a two-degree-of-freedom test which combines information from maternal and fetal GWASs; and (iii) a one-degree-of-freedom test where signals from maternal and fetal GWASs are meta-analysed together conditional on estimated sample overlap. We demonstrate that the optimal strategy depends on the extent of sample overlap, correlation between phenotypes, whether loci exhibit fetal and/or maternal effects, and whether these effects are directionally concordant. We apply our methods to summary statistics from a recent GWAS meta-analysis of birth weight. Both the two-degree-of-freedom and meta-analytic approaches increase the number of genetic loci for birth weight relative to separately analysing the scans. Our best strategy identifies an additional 62 loci compared to the most recently published meta-analysis of birth weight. We conclude that whilst the two-degree-of-freedom test may be useful for the analysis of certain perinatal phenotypes, for most phenotypes, a simple meta-analytic strategy is likely to perform best, particularly in situations where maternal and fetal GWASs only partially overlap.

Hypertensive disorders of pregnancy and stroke: a univariate and multivariate Mendelian randomization study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of stroke later in life in multiparous women. However, causality of these associations remains unclear. This study employed 2-sample univariate and multivariate Mendelian randomization (MR) to assess the causal connection between HDP and stroke. Genetic variants for HDP and two subtypes were identified from recent large-scale genome-wide association studies and the FinnGen consortium. Stroke summary data were obtained from the MEGASTROKE consortium. The primary analytical approach for univariate MR was the inverse variance weighting method. Sensitivity analyses incorporated methods such as MR-Egger regression, weighted median, and maximum likelihood to ascertain the robustness of the results. Additionally, multivariable MR analyses were conducted to account for potential associative effects of hypertension and type 2 diabetes. Genetically predicted HDP was associated with a high risk of large artery atherosclerosis (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.17-1.91, P=1.13×10-3) and small vessel stroke (OR=1.29, 95% CI: 1.20-1.50, P=1.52×10-3). HDP may also correlate with ischemic stroke (OR=1.13, 95% CI: 1.04-1.23, P=4.99×10-3) and stroke (OR=1.11, 95% CI: 1.03-1.20, P=8.85×10-3). An elevated risk of small vessel stroke (OR=1.20, 95% CI: 1.01-1.43, P=3.74×10-2) and large artery atherosclerosis (OR=1.22, 95% CI: 1.01-1.47, P=4.07×10-2) may be related with genetically predicted susceptibility to gestational hypertension. Genetically predicted susceptibility to preeclampsia or eclampsia may be associated with an increased risk of stroke (OR = 1.10, 95% CI: 1.02-1.19, P = 1.16×10-2) and ischemic stroke (OR = 1.10, 95% CI: 1.02-1.20, P = 1.84×10-2). Type 2 diabetes mellitus and hypertension were identified as significant factors contributing to the association between HDP and stroke. This study provides genetic evidence supporting an association between HDP and increased stroke risk bolstering HDP as a cerebrovascular risk factor.

NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.

Association of plasma arachidonic acid levels with a bipolar disorder and the effects of a FADS gene variant

Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.36, p = 0.023) and arachidonic acid (AA) (β = −0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.

Modulating OCA2 Expression as a Promising Approach to Enhance Skin Brightness and Reduce Dark Spots.

The oculocutaneous albinism II (OCA2) gene encodes a melanosomal transmembrane protein involved in melanogenesis. Recent genome-wide association studies have identified several single nucleotide polymorphisms within OCA2 genes that are involved in skin pigmentation. Nevertheless, there have been no attempts to modulate this gene to improve skin discoloration. Accordingly, our aim was to identify compounds that can reduce OCA2 expression and to develop a formula that can improve skin brightness and reduce hyperpigmented spots. In this study, we investigated the effects of OCA2 expression reduction on melanin levels, melanosome pH, and autophagy induction through siRNA knockdown. Additionally, we identified several bioactives that effectively reduce OCA2 expression. Ultimately, in a clinical trial, we demonstrated that topical application of those compounds significantly improved skin tone and dark spots compared to vitamin C, a typical brightening agent. These findings demonstrate that OCA2 is a promising target for the development of efficacious cosmetics and therapeutics designed to treat hyperpigmentation.

Primary Aldosteronism Influences Cardiac Structure, Function, and Disease Risk: Evidence From Mendelian Randomization Analysis.

Although observational studies have linked primary aldosteronism (PA) with cardiovascular diseases (CVDs), the causality remains uncertain. In this study, we aimed to investigate whether PA is causally associated with CVD risk and cardiac magnetic resonance (CMR) parameters using the Mendelian randomization (MR) method. Independent and genome-wide significant single nucleotide polymorphisms for PA were extracted from genome-wide association study (GWAS) summary statistics. Genetic associations with the CVDs and CMR parameters were obtained from recent large-scale GWASs or genetic consortia. Inverse-variance weighted (IVW) method was utilized for the preliminary estimates, and multiple sensitivity analyses (including weighted median, Cochran's Q test, MR-Egger, MR-PRESSO, and leave-one-out analysis) were conducted to verify the robustness of the results. The MR analyses using the IVW method showed that genetically predicated PA was significantly associated with atrial fibrillation (OR = 1.046, 95% CI: 1.029-1.062, padj<0.001), myocardial infarction (OR = 1.029, 95% CI: 1.005-1.053, padj = 0.027), heart failure (OR = 1.023, 95% CI: 1.004-1.042, padj = 0.027), any stroke (OR = 1.062, 95% CI: 1.031-1.095, padj<0.001), any ischemic stroke (OR = 1.058, 95% CI: 1.022-1.095, padj = 0.004), and small vessel stroke (OR = 1.116, 95% CI: 1.041-1.196, padj = 0.004). Notably, PA also had a causal effect on adverse cardiac remodeling, including larger ventricular and atrial volumes, higher ventricular stroke volume, and reduced left atrial emptying fraction. Our findings support a causal role of PA in higher cardiovascular disease risk and adverse cardiac remodeling. Given the diagnostic delay and disease burden in PA, more attention should be paid to the screening and treatment of PA to reduce the incidence of cardiovascular outcomes.

Impact of systemic lupus erythematosus on cardiovascular morphologic and functional phenotypes: a Mendelian randomization analysis.

Previous studies have established a correlation between systemic lupus erythematosus (SLE) and cardiovascular health, but the potential causal effects of SLE on heart function and structure remain poorly understood. Cardiovascular magnetic resonance imaging (CMR), a novel non-invasive technique, provides a unique assessment of cardiovascular structure and function, making it an essential tool for evaluating the risk of heart disease. In this study, we performed a Mendelian randomization analysis to determine the causal relationship between SLE and CMR traits. Genetic variants independently linked to SLE were selected from a genome-wide association study (GWAS) containing 5,201 cases and 9,066 controls as instrumental variables. A set of 82 CMR traits was obtained from a recent GWAS, serving as preclinical indicators and providing preliminary insights into the morphology and function of the four cardiac chambers and two aortic segments. Primary analysis employed a two-sample Mendelian randomization study using the inverse-variance weighted method. Heterogeneity testing, sensitivity analyses, and instrumental variable strength assessments confirmed the robustness of the findings. SLE exhibited a correlation with increased stroke volume (βLVSV = 0.007, P = 0.045), regional peak circumferential strain (βEcc_AHA_9 = 0.013, P = 0.002; βEcc_AHA_12 = 0.009, P = 0.043; βEcc_AHA_14 = 0.013, P = 0.006), and global peak circumferential strain of the LV (βEcc_global = 0.010, P = 0.022), as well as decreased regional radial strain (βErr_AHA_11 = -0.010, P = 0.017). This research presents evidence of a potential causal association between traits of SLE and alterations in cardiac function, guiding cardiac examinations and disease prevention in lupus patients.

Plasma Ghrelin and Risks of Sex-Specific, Site-Specific, and Early-Onset Colorectal Cancer: A Mendelian Randomization Analysis.

Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis. Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied. We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81-1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer. Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite-stratified colorectal cancer risk. This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.