Explore the vast range of titles available.

Background Bullous pemphigoid (BP) and atopic dermatitis (AD) are currently thought to be tightly related, yet studies of the mechanisms of co‐morbidities are lacking. Methods We obtained GWAS data for BP (N = 376,274) and AD (N = 796,661) from the Finnish Genetic Research Program dataset and the UK Biobank, separately. Then, the following four analyses were performed: (1) cross‐trait linkage disequilibrium score regression (LDSC) to assess the genetic correlation between BP and AD, (2) cross‐phenotype association analysis (CPASSOC) to identify multiple effector loci shared by BP and AD, (3) transcriptome‐wide association study (TWAS) to determine whether their cross‐organizational expression patterns share genes with a common biological mechanism of relevance, and (4) bidirectional Mendelian randomization (MR) analysis to assess bidirectional causal effects of BP and AD. Results We found a positive genetic association between BP and AD (rg = 0.5476, p = 0.0495) as well as identified four pleiotropic loci and 59 common genes affecting BP and AD. Bidirectional MR analysis suggested that BP promotes the risk of AD. Conclusions We revealed a genetic link between BP and AD, which is associated with biological pleiotropy and causality. Awareness of the association between BP and AD helps dermatologists manage patients with these illnesses. We revealed a genetic link between atopic dermatitis and bullous pemphigoid, which is associated with biological pleiotropy and causality. Awareness of the association between BP and AD helps dermatologists manage patients with these illnesses.

Psoriasis and insomnia have co-morbidities, however, their common genetic basis is still unclear. We analyzed psoriasis and insomnia with summary statistics from genome-wide association studies. We first quantified overall genetic correlations, then ascertained multiple effector loci and expression-trait associations, and lastly, we analyzed the causal effects between psoriasis and insomnia. A prevalent genetic link between psoriasis and insomnia was found, four pleiotropic loci affecting psoriasis and insomnia were identified, and 154 genes were shared, indicating a genetic link between psoriasis and insomnia. Yet, there is no causal relationship between psoriasis and insomnia by two-sample Mendelian randomization. We discovered a genetic connection between insomnia and psoriasis driven by biological pleiotropy and unrelated to causation. Cross-trait analysis indicates a common genetic basis for psoriasis and insomnia. The results of this study highlight the importance of sleep management in the pathogenesis of psoriasis.

Background Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. Methods We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. Results We identified the East Asian–specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P  = 3.27 × 10 –8 ) and the ICOS / PARD3B locus on chromosome 2 with suggestive significance ( P  = 3.95 × 10 –7 ) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P  < 5.0 × 10 –8 ), a known risk locus for DLB and Alzheimer’s disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. Conclusions This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.

Background Approximately 40% of persons with inflammatory bowel disease (IBD) experience psychiatric comorbidities (PC). Previous studies demonstrated the polygenetic effect on both IBD and PC. In this study, we evaluated the contribution of genetic variants to PC among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of PC in persons with IBD. Materials and methods The polygenic risk score (PRS) was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated PRS and PC status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated PRS and PC status in IBD. Results The estimated PRS had a significantly positive association with PC status (for the highest effect: P-value threshold = 5 × 10 –3 , odds ratio = 2.0, P-value = 1.5 × 10 –5 ). Around 13% of the causal effect between the PRS and PC status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based PC prediction model is around 0.7 at the threshold of 5 × 10 –4 . Conclusion PC status in IBD depends on genetic influences among persons with European ancestry. The PRS could potentially be applied to PC risk screening to identify persons with IBD at a high risk of PC. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Background Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions. Methods In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies ( N  = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk. Results A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27 . Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk. Conclusions These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels.

Aim: Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about the genetic structure of BD subtypes. We aimed to investigate the genetic overlap and distinction of bipolar type I (BD I) & type II (BD II) by conducting integrative post-GWAS analyses. Methods: We utilized single nucleotide polymorphism (SNP)–level approaches to uncover correlated and distinct genetic loci. Transcriptome-wide association analyses (TWAS) were then approached to pinpoint functional genes expressed in specific brain tissues and blood. Next, we performed cross-phenotype analysis, including exploring the potential causal associations between two BD subtypes and lithium responses and comparing the difference in genetic structures among four different psychiatric traits. Results: SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184 , and RPL10AP3 , shared by BD I and II, and one locus ( MAD1L1 ) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes affecting BD I and II through expression in specific brain regions (nucleus accumbens for BD I). Cross-phenotype analyses indicated that BD I and II share continuous genetic structures with schizophrenia and major depressive disorder, which help fill the gaps left by the dichotomy of mental disorders. Conclusion: These combined evidences illustrate genetic convergence and divergence between BD I and II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.

High-density lipoprotein (HDL) cholesterol levels are closely associated with human health and diseases. To identify genes modulating plasma HDL levels, we integrated HDL measurements and multi-omics data collected from diverse mouse cohorts and combined a list of systems genetics methods, including quantitative trait loci (QTL) mapping analysis, mediation analysis, transcriptome-wide association analysis (TWAS), and correlation analysis. We confirmed a significant and conserved QTL for plasma HDL on chromosome 1 and identified that Tstd1 liver transcript correlates with plasma HDL in several independent mouse cohorts, suggesting Tstd1 may be a potential modulator of plasma HDL levels. Correlation analysis using over 70 transcriptomics datasets in humans and mice revealed consistent correlations between Tstd1 and genes known to be involved in cholesterol and HDL regulation. Consistent with strong enrichment in gene sets related to cholesterol and lipoproteins in the liver, mouse strains with high Tstd1 exhibited higher plasma levels of HDL, total cholesterol and other lipid markers. GeneBridge using large-scale expression datasets identified conserved and positive associations between TSTD1/Tstd1 and mitochondrial pathways, as well as cholesterol and lipid pathways in human, mouse and rat. In summary, we identified Tstd1 as a new modulator of plasma HDL and mitochondrial function through integrative systems analyses, and proposed a new mechanism of HDL modulation and a potential therapeutic target for relevant diseases. This study highlights the value of such integrative approaches in revealing molecular mechanisms of complex traits or diseases.

Summary Reliably generating rice varieties with low glycaemic index (GI) is an important nutritional intervention given the high rates of Type II diabetes incidences in Asia where rice is staple diet. We integrated a genome‐wide association study (GWAS) with a transcriptome‐wide association study (TWAS) to determine the genetic basis of the GI in rice. GWAS utilized 305 re‐sequenced diverse indica panel comprising ~2.4 million single nucleotide polymorphisms (SNPs) enriched in genic regions. A novel association signal was detected at a synonymous SNP in exon 2 of LOC_Os05g03600 for intermediate‐to‐high GI phenotypic variation. Another major hotspot region was predicted for contributing intermediate‐to‐high GI variation, involves 26 genes on chromosome 6 (GI6.1). These set of genes included GBSSI, two hydrolase genes, genes involved in signalling and chromatin modification. The TWAS and methylome sequencing data revealed cis‐acting functionally relevant genetic variants with differential methylation patterns in the hot spot GI6.1 region, narrowing the target to 13 genes. Conversely, the promoter region of GBSSI and its alternative splicing allele (G allele of Wxa) explained the intermediate‐to‐high GI variation. A SNP (C˃T) at exon‐10 was also highlighted in the preceding analyses to influence final viscosity (FV), which is independent of amylose content/GI. The low GI line with GC haplotype confirmed soft texture, while other two low GI lines with GT haplotype were characterized as hard and cohesive. The low GI lines were further confirmed through clinical in vivo studies. Gene regulatory network analysis highlighted the role of the non‐starch polysaccharide pathway in lowering GI.

Summary The regulation of gene expression plays an essential role in both the phenotype and adaptation of plants. Transcriptome sequencing enables simultaneous identification of exonic variants and quantification of gene expression. Here, we sequenced the leaf transcriptomes of 287 rice accessions from around the world and obtained a total of 177 853 high‐quality single nucleotide polymorphisms after filtering. Genome‐wide association study identified 44 354 expression quantitative trait loci (eQTLs), which regulate the expression of 13 201 genes, as well as 17 local eQTL hotspots and 96 distant eQTL hotspots. Furthermore, a transcriptome‐wide association study screened 21 candidate genes for starch content in the flag leaves at the heading stage. HS002 was identified as a significant distant eQTL hotspot with five downstream genes enriched for diterpene antitoxin synthesis. Co‐expression analysis, eQTL analysis, and linkage mapping together demonstrated that bHLH026 acts as a key regulator to activate the expression of downstream genes. The transgenic assay revealed that bHLH026 is an important regulator of diterpenoid antitoxin synthesis and enhances the disease resistance of rice. These findings improve our knowledge of the regulatory mechanisms of gene expression variation and complex regulatory networks of the rice genome and will facilitate genetic improvement of cultivated rice varieties.

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end‐products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole‐genome sequencing and correlated meta‐analyses on combined genome‐wide association study (GWAS) p‐values in 4182 individuals (age range: 24–110) from the Long Life Family Study (LLFS). We also conducted transcriptome‐wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10−8) and 17 TWAS genes (Bonferroni‐p < 2.73 × 10−6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA‐KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer‐promoter variants with kidney function‐related phenotypes at p < 5 × 10−8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA‐Europeans and TOPMed, suggesting better kidney function in healthy‐aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging‐related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney‐ and aging‐related signaling pathways. Our study, conducted through correlated meta‐analysis in the Long Life Family Study, which recruited participants in the upper generation with exceptional family longevity, identified 42 novel pleiotropic GWAS loci in 4182 individuals with whole‐genome sequencing, and 17 TWAS genes for eGFRcr, eGFRcys, and sRAGE. The identified loci and genes suggest their underlying shared genetic and functional regulatory effects and highlight their roles in kidney‐ and aging‐related signaling pathways.