Human Genomics

Psoriasis has been associated with increased adiposity measures driving systemic inflammation, which may lead to metabolic dysfunction and comorbidities. In this population-based, cross-sectional study, we used data from 56 042 individuals in the fourth wave of the Trondelag Health Study (HUNT4), to investigate the associations between psoriasis and body composition measures assessed using bioelectrical impedance analysis, cardiometabolic risk factors, and comorbidities. Further, we investigated the associations between HLA-C*06:02 status, a potential clinical biomarker for a distinct psoriasis endotype, and these outcomes. Psoriasis was associated with increased adiposity measures, including increased body and visceral fat, and lower levels of skeletal muscle and soft lean mass, as well as higher prevalence of cardiovascular, respiratory and endocrine disorders. HLA-C*06:02-positive individuals with psoriasis had lower levels of hsCRP, increased prevalence of atrial fibrillation and decreased prevalence of migraine. Our results point to altered body composition in psoriasis with increased levels of fat, and particularly metabolically active visceral fat, and provide support for a broad clinical approach to psoriatic patients in a general population.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1 and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, and NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk of NOTCH1- associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.

Dermatophytosis is an infection caused by fungi that utilize keratinized tissues, such as skin, nails, and hair, as their energy source. This infection commonly presents as red, itchy and ring-like patches on the skin, nail thickening, or hair loss. With ever-increasing case numbers, it has become a significant public health concern estimated to affect 20 % of the worlds population. Despite the high prevalence, the genetic risk factors for dermatophytosis are poorly understood. Our goal was to elucidate the biological mechanisms underlying individual susceptibility to dermatophytosis and to explore its genetic associations with other diseases and traits. We performed a large-scale genome-wide association meta-analysis of dermatophytosis infections with over 250,000 cases and 1,370,000 controls using data from FinnGen, Estonian Biobank, UK Biobank and Million Veterans Program. We identified 30 genome-wide significant loci including seven missense variants and two variants in high linkage disequilibrium with missense variants. The strongest associations were with variants within or closest to ZNF646 (p = 6.60x10-79, beta = 0.07), HLA-DQB1 (p = 1.42x10-36, beta = 0.05), FLG (p = 1.96x10-27, beta = -0.22), FTO (p = 5.75x10-26, beta = -0.04), SLURP2 (p = 3.33x10-24, beta = 0.04) and KRT77 (p = 1.28x10-15, beta = 0.03) genes. Overall, our findings implicate keratin lifecycle and skin integrity, immune defense, and obesity as risk factors for dermatophytosis. Our findings highlight the clinical comorbidities with other skin diseases and with high BMI and identify novel genetic variants some of which are novel candidates for managing dermatophytosis infection.

AbstractAtopic Dermatitis (AD) and psoriasis (PsO) are two frequent dermatologic conditions that may co-occur in a cluster of patients, yet current understanding of how these two conditions relate to one-another remains poorly understood. One way to better understand their relationship is through a process called phenotypic switching, where AD and PsO can turn into one another. We utilized a pharmacovigilance-based epidemiological approach to better understand this phenomenon. By generating adverse event-related disproportionality signals for various therapies and therapeutic classes used in AD and PsO, several potential mechanisms for the AD-PsO phenotypic switch were uncovered. This includes mechanisms involving TH2 and TH22 repolarization, TH17 and TH22 repolarization, and immune shifting between TH1, TH17, and TH2 cells. Clinically and immunologically related conditions were also analyzed to gain a clearer understanding of the specificity of the switch from PsO to an eczematous phenotype. Together, these findings provide mechanistic insight into the underpinnings behind the AD-PsO phenotypic switch through a novel approach, adding evidence to the fluid nature of immune phenotypes in common medical conditions. One Sentence SummaryThe atopic dermatitis-psoriasis phenotypic switch creates an overlap phenotype that is likely TH22-driven.

Ultraviolet (UV) radiation induces cyclobutane pyrimidine dimers (CPDs) in DNA, initiating mutagenic cascades that underlie photocarcinogenesis. Even hours after irradiation, dark-CPDs photoproducts generated via melanin-mediated chemiexcitation continue to form in melanocytes (4-6). While melanin confers photoprotection, its oxidative by-products can paradoxically extend DNA damage. Here we empirically validate an ancestry-aware computational framework coupling population pigmentation genetics with transcriptional regulation of DNA-repair pathways using Genotype-Tissue Expression (GTEx v9) skin RNA-seq data. We analyzed 604 GTEx donors from sun-exposed and non-exposed skin (lower leg, suprapubic) across inferred ancestry axes. Expression modules for melanin synthesis (TYR, TYRP1, SLC24A5, MC1R) and nucleotide-excision/oxidative-repair (XPC, DDB2, POLH, OGG1) were examined through differential expression, random-forest modeling, and 1,000-fold bootstrap uncertainty quantification. POLH and DDB2 were significantly upregulated in sun-exposed tissue (log2FC = 0.88 +/- 0.12 and 0.64 +/- 0.18; FDR < 0.05), whereas SLC24A5 and TYR displayed ancestry-linked gradients consistent with prior GWAS (8-10, 15, 16). Predictive modeling of a composite dark-CPD index achieved mean R^2 = 0.62 +/- 0.04 and RMSE = 0.21 +/- 0.03 (95 % CI), highlighting SLC24A5 (27 %) and XPC (19 %) as major contributors. These results empirically demonstrate co-regulation between pigmentation and repair pathways within realistic transcriptomic uncertainty bounds. Our integrative approach provides a reproducible, ancestry-aware platform for equitable dermatogenomic risk assessment and mechanistic insight into delayed UV mutagenesis.

Currently, the genetic architecture of Middle Eastern populations is underrepresented in global genomic databases. This gap increases the rate of Variants of Uncertain Significance (VUSs) and clinical misinterpretations of genomic data especially in Middle Eastern populations. Whole exome sequencing was conducted on 90 healthy individuals from Jordan and the data were analysed using Principal Component Analysis (PCA) and multi-computational filtering. PCA revealed a double ancestry (EUR-AFR) admixture rather than a triple admixture (EUR-AFR-AMR). More than 3,500 populations-specific variants (PSVs) were identified, of which 72% were singletons. Additionally, 19 variants were significantly enriched compared to the maximum allele frequencies in public global databases (Fisher's exact test with Benjamini-Hochberg false discovery rate correction, p-value < 0.05). Consequently, the results suggest the reclassification of variants of Uncertain Significance (VUS) which reside in the ECE2 gene to likely benign and the variants of Conflicting Classification of Pathogenicity in the genes IL1RN and THPO to benign based on the significant allele frequency (AF=0.0389, p-value < 0.05). Furthermore, a pathogenic ClinVar variant was identified in a healthy individual, warranting careful interpretation. The findings underscore the importance of identifying PSVs in order to minimize or even prevent clinical misdiagnosis and highlight the unique genetic signature in Jordan. The study serves as a foundational resource for precision medicine in the region.

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a debilitating genodermatosis caused by pathogenic mutations in the COL7A1 gene, which induce absence or reduction in the number of anchoring fibrils. The severity of RDEB depends on the mutation type and localization, but many aspects of this dependence remain to be elucidated. Here, we report a novel variant of RDEB Intermediate in two unrelated patients. Their disease manifestation includes early skin and oral mucosa blistering and is associated with localized atrophic scarring. According to the exome and Sanger sequencing results, both investigated Probands are the carriers of complex heterozygosity in the COL7A1 gene with the same deletion in intron 19 of the COL7A1 gene. RT-PCR followed by sequence analysis revealed skipping of the part of exon19, as well as the rescue of the open reading frame (ORF) of COL7A1 in both Probands. We hypothesize that the mutation in the acceptor splice site leads to the activation of the cryptic donor splice site, resulting in the truncated but partially functional protein and the milder phenotype of intermediate RDEB. This rare type of mutation expands our understanding of RDEB etiology and invites further investigation.

Autoimmune diseases (ADs) are a group of more than 80 heterogeneous disorders that occur when there is a failure in the self-tolerance mechanisms triggering self-attacking autoantibodies. Most autoimmune disorders are polygenic and associated with genes in the human leukocyte antigen (HLA) region. However, additional non-HLA genes are also found to be associated with different ADs, and often these are also implicated in more than one disorder. Previous studies have observed associations between various health-related and lifestyle phenotypes and ADs. Polygenic risk scores (PRS) allow the calculation of an individuals genetic liability to a phenotype and are estimated as the sum of the risk alleles weighted by their effect sizes in a genome-wide association study (GWAS). Here, for the first time, we conducted a comparative PRS-PheWAS analysis for 11 different ADs (Celiac Disease, Juvenile Idiopathic Arthritis, Multiple Sclerosis, Myasthenia Gravis, Primary Sclerosing Cholangitis, Psoriasis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Type 1 Diabetes, Vitiligo Early Onset, Vitiligo Late Onset) and 3,281 outcomes available in the UK Biobank that cover a wide range of lifestyle, socio-demographic and health-related phenotypes. We also explored the genetic relationships of the studied ADs, estimating their genetic correlation and performing cross-disorder GWAS meta-analyses for the identified AD clusters. In total, we observed 554 outcomes significantly associated with at least one disorder PRS, and 300 outcomes were significant after variants in the HLA region were excluded from the PRS calculations. Based on the genetic correlation and genetic factor analysis, we observed five genetic factors among studied ADs. Cross-disorder meta-analyses in each factor revealed genome-wide significant loci that are pleiotropic across multiple ADs. Overall, our analyses confirm the association of different factors with genetic risk for ADs and reveal novel observations that warrant further exploration.

Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. Here, we report results from a genome-wide meta-analysis of AD in 37,541 cases and 1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci of which 10 were novel. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD, and of early and late-onset AD, with data from the FinnGen project. 55 of the 79 tested variants in the associated loci showed larger effect estimates for severe than mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlay the development of new therapeutic strategies.

Polygenic risk score (PRS) methods are evolving, and the benefit of adding functional annotations to the variant weights has been especially promising. However, less attention has been given to how the linkage disequilibrium (LD) reference panel used affects the score performance. In the current study, we compared two Bayesian approaches, one that incorporates functional annotations (LDpred-funct) and one that does not (PRS-CS), extending these applications to the hypertension (HTN) trait across two ancestry groups (European Americans EA, and African Americans, AA). In PRS-CS we used the standard HapMap 3 LD (HM3) reference panel, as well as a modified multi-ancestry reference panel (TagIt) with better coverage of variants from multiple ancestries. Individual-level data in 1,533 EA (58% with HTN) and 8,603 AA (71% with HTN) participants from the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) was used to optimize scores across the two approaches. PRS performance metrics including R2 and odds ratios (OR) per standard deviation (SD) were then used to assess PRS performance in 1,270 EA (55% with HTN) and 1,896 AA (69% with HTN) participants from the Hypertension Genetic Epidemiology Network Study (HyperGEN). Among EAs in HyperGEN we observed an R2 of 6.0% for LD-Pred-funct and R2 of 7.3% for PRS-CS-TagIt versus R2 of 1.4% for PRS-CS-HM3. The magnitude of the OR per SD for HTN was also higher for PRS-CS-TagIt OR=2.17 (95% CI 1.65-2.85, p=3.0*10-8) and LD-Pred-funct OR=2.14 (95% CI 1.61-2.85, p=1.46*10-7) versus PRS-CS-HM3 (OR=1.40; 95% CI 10.8-1.82). Among AAs in HyperGEN, the improvements were more modest, where we observed R2 of 1.9% for LD-Pred-funct and R2 of 2.9% for PRS-CS-TagIt versus 0.7% for PRS-CS-HM3. We found that both annotations and the updated LD panel improved the scores in both ancestry groups, but did not make the scores more equitable across the groups. Author SummaryGenomics can aid in risk prediction and prevention. Polygenic risk score (PRS) development and application is becoming more popular because theres a lot of genetic data available for training PRS, and they have the potential to be useful in healthcare. However, PRS are not yet widely used in clinics, and the methods are still developing. Early PRS methods only used certain genetic markers, but newer ones use more data and better models to try to predict disease risk more accurately. Still, these tools often dont work as well for people from underrepresented populations, which could increase health inequalities. Researchers are trying to fix this by using more up-to-date data and adding extra information about how genes function. In our study of HTN, we investigated newer approaches which made PRS more accurate for both for African American individuals and European American individuals--but they didnt fully close the performance gap between the groups.

Psoriasis is a common chronic inflammatory skin disease characterized by disturbed interactions between infiltrating immune cells and keratinocytes. To enhance our understanding of the underlying molecular and cellular mechanisms driving psoriasis pathobiology, and to identify potential biomarkers for disease severity, we conducted RNA sequencing of skin biopsies from 75 patients with psoriasis vulgaris and 46 non-psoriatic controls. To increase the robustness of the results, we meta-analysed our data with four publicly available datasets, bringing the total number of samples to 534. By comparing lesional psoriatic (PP) to healthy control (NN) skin, we identified 2269 differentially expressed genes (DEGs) (|log2FC|>1.0, FDR <0.1), and 58 DEGs when comparing non-lesional psoriatic (PN) to NN skin. We also identified 54 DEGs associated with disease severity (PASI [&ge;]10 vs. PASI <10). Cellular deconvolution analysis showed that differentiated keratinocytes emerged as the most prominent cell type among the DEGs in PP/NN. Functional enrichment analysis in PN/NN revealed several IL-17 related pathways and confirmed a previously reported pre-inflammatory signature across all psoriatic skin. This study provides insights into the psoriasis transcriptome and identifies a severity-specific signature, which may serve as candidate for future studies aimed at identifying psoriasis biomarkers and predicting disease progression.

Background Orofacial clefts (OFCs) and other palate abnormalities (PAs) are among the most common birth defects worldwide and are characterized by the abnormal formation of the lip and/or palate. Genetic studies have traditionally classified OFC cases as either syndromic, involving OFCs alongside other congenital anomalies, or nonsyndromic, which represent the majority of cases and occur in isolation. Emerging genomic evidence indicates that genes traditionally associated with syndromic forms of OFC can also harbor variants contributing to isolated cases, challenging the notion of a strict dichotomy between these categories and supporting their integration for gene discovery. Methods In this study, we applied multiple analytic approaches to characterize the genetic architecture of OFC and PAs by integrating genomic data from 2,497 trios with an OFC (n=2080) and PA (n=417) affected proband. We compared these findings across OFC subtypes and syndromic status with those from 5,515 control trios to identify enriched biological pathways and mechanisms and to prioritize candidate genes using variant burden testing. Results We observed a significant enrichment of de novo protein-truncating and damaging missense variants in cases compared to controls (OR = 2.17, p = 1.21x10-32), with particularly strong signals in biologically relevant gene sets involving OFC-associated, constrained, Mendelian disorder, and mouse candidate genes. Variant burden testing identified 39 OFC risk genes at FDR [&le;] 0.05, which we then integrated with 593 established OFC genes to interrogate the functional underpinnings of OFC via network analysis. This analysis revealed 309 high-order interactor genes not previously associated with OFC. Notably, this OFC network clustered into ten distinct biological pathways, with nucleosome-associated genes showing significant enrichment among cases in our cohort (OR = 14.8, p = 8.1x10-4). In a final integrative step, we combined evidence across all analyses to nominate 231 candidate genes, 32 of which contained at least two deleterious de novo variants in our cohort. Conclusions These findings underscore the value of integrating diverse OFC and PA subtypes, syndromic status, and variant classes to refine the genetic architecture of these disorders, highlighting both phenotypic expansion of known disease genes and the emergence of novel gene-phenotype associations.

Helicobacter pylori (H. pylori) infection, a prevalent bacterial ailment affecting the stomach, has been linked to diverse gastrointestinal disorders. Nevertheless, the correlation between H. pylori infection and skin disorders has not been definitively established. We use Mendelian randomization analysis to explore causal relationships with seven pylori antibody levels and five skin diseases, such as rosacea, psoriasis, alopecia areata, pruritus and urticaria. The primary analytical method employed was inverse variance weighted (IVW), and a sensitivity analysis was executed to evaluate the robustness of the primary findings. The results revealed a positive causal relationship between H. pylori catalase antibody levels and AA (IVW: OR = 1.32, 95% CI = 1.07 to 1.61, P = 0.008), as well as a positive causal relationship between H. pylori UreA antibody levels and pruritus (IVW: OR = 1.17, 95% CI = 1.05 to 1.31, P = 0.006). These effects were robust to sensitivity analyses. Our results suggested that H. pylori infection was a risk factor for AA and pruritus. This finding may have implications for the prevention and treatment of these skin disorders.

BackgroundCholecystitis is an inflammatory disease involving the gallbladder, often associated with digestive disorders and systemic immune response. This systemic immune response could potentially influence the immune status of the skin, particularly in conditions like dermatitis. Despite extensive research on dermatitis, the causal relationship between cholecystitis and dermatitis subtypes (DSs) remains unclear. ObjectiveThe aim of this study was to investigate the causal relationship between cholecystitis and DSs. MethodsTwo-sample Mendelian randomization (MR) was used to analyze the causal relationship between cholecystitis and DSs. We then utilized the Bayesian Weighted Mendelian Randomization (BWMR) method to validate our findings and applied bidirectional MR analysis to confirm the causal direction. After establishing the associations between traits, we delved into the underlying mechanisms of this interesting finding. Subsequently, we used 91 inflammatory proteins as mediators and performed summary data-based mendelian randomization (SMR) analysis to further investigate the pathogenesis of DSs. ResultsMR results evidently showed that cholecystitis can significantly reduce the risk of allergic contact dermatitis (ACD) (IVW, OR=0.8834, p=0.0368) and exfoliative dermatitis (ED) (IVW, OR=0.5738, p=0.0126). BWMR also provided secondary validation of the casual associations. In the subsequent reverse direction MR analyses, reverse causality was not present, so cholecystitis had a unidirectional effect and existed as a protective factor for ACD and ED. Interestingly, cholecystitis appears to lower the risk of ACD and ED by downregulating IL-6, IL-7, and IFN-{gamma}. Additionally, the genes HCG27 and HLA-DRB5 may play a significant role in the pathogenesis of ACD. ConclusionThis study used a two-step MR analysis of genetic summary data to investigate to what extent inflammatory proteins impact the protective role of cholecystitis on dermatitis. We also identified several proteins and genes that could serve as potential drug targets. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/24313850v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@13c8bb1org.highwire.dtl.DTLVardef@1f734faorg.highwire.dtl.DTLVardef@b70e32org.highwire.dtl.DTLVardef@517dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundHow skin microbiota in psoriasis patients responded to systematic therapeutics remained unknown. ObjectivesTo profile temporal shifts in transcriptionally active skin microbiota in psoriasis patients receiving systemic therapies. MethodsWe prospectively enrolled 61 psoriasis patients and 29 skin-healthy controls in 2015-2019. Using RNA-based 16S rRNA gene sequencing, we analyzed 969 samples from skin lesions and compared microbial abundance and diversity by therapeutic classes and disease severity. ResultsLesional microbiota in patients on conventional systemics and TNF- inhibitor was different in relative abundances in Firmicutes (7.83% higher, adjusted P < 0.001) and Proteobacteria (6.98% lower, adjusted P < 0.01) from that in patients on anti-interleukin monoclonal antibodies (anti-ILAb) at baseline. The only difference during treatment was a 1.47% lower abundance in Bacteroides associated with nonbiologics use (adjusted P < 0.01). We identified no indicator taxa by disease severity at baseline yet noticed that a minor relative reduction in Corynebacterium sp. was associated with clinical responses to treatment. Compared to anti-ILAb, TNF- inhibitor and nonbiologics were associated with -0.21 lower Shannon Diversity (adjusted P < 0.01) and 0.03 higher Shannon Evenness (adjusted P < 0.01). Results of ordinated principal coordinates analysis revealed that, lesional microbiota from patients of these 3 therapeutic groups was compositionally distinct. Our work also demonstrated concurrent changes in clonal shifts in systemic T cell receptor clonotypes that were associated with systemic use of biologics. ConclusionsCommunity abundances and diversities of skin microbiota may be useful in distinguishing skin microbiota from patients receiving different systemic therapeutics. Specifically, use of anti-ILAb and TNF- inhibitor was associated with sample-wise microbial abundances and diversities, but not richness, over time. These findings highlighted the potential utility of skin microbiota as biomarkers for personalized treatment plans in patients with moderate-to-severe psoriasis.

Nonsyndromic orofacial clefts (OFCs) are common, heritable birth defects caused by both genetic and environmental risk factors. Despite the identification of many genetic loci harboring OFC-risk variants, there are many unknown genetic determinants of OFC. Furthermore, while the process of embryonic facial development is well characterized, the molecular mechanisms that underly it are not. This represents a major hurdle in understanding how disruptions in these biological processes result in OFC. Thus, we sought to identify novel OFC-risk loci through a genome-wide multi-ancestry study of five nested OFC phenotypes (isolated cleft lip [CLO], isolated cleft palate [CPO], cleft lip and palate [CLP], cleft lip with/without cleft palate [CL/P], and any cleft [ANY]) representing distinct cleft subtypes to identify subtype-specific signals and grouped types to maximize power to detect shared genetic effects. We performed genome-wide meta-analyses of these five OFC phenotypes from three cohorts totaling >14,000 individuals using METAL. In addition to replicating 13 known OFC-risk loci, we observed novel association in three regions: the 1p36.32 locus (lead variant rs584402, an intergenic variant, pCLO = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1, pCLP = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1, pCL/P = 1.53e-9, pANY = 1.93e-9). We also observed a novel association within the known risk locus 8q22.1 that was independent of the previously reported signal (lead variant rs4735314, an intronic variant in ESRP1, pCLP = 1.07e-9, pCL/P = 3.88e-8). Next, we performed multi-tissue TWAS with s-MulTiXcan and identified four overlapping genes with significant genetically predicted transcription associated with OFC risk. These genes also overlapped the genome-wide significant association signals from the meta-analysis, including CALD1 and ESRP1 and known OFC-risk genes TANC2 and NTN1. Each of the newly reported loci has potential regulatory effects, including evidence of craniofacial enhancer activity, that offer new clues as to the molecule mechanisms underlying embryonic facial development. Author SummaryOrofacial clefts, including cleft lip and cleft palate, are common birth defects that can be caused by both genetic and environmental factors. While many of these factors are known, there are still significant gaps in our understanding of how and why clefts arise. To help address this deficiency, we measured association between variants across the genome and clefting in cases and controls from diverse genetic ancestries. We identified three new candidate genes (CALD1, ESRP1, and RBFOX1) that may be involved in cleft risk and reaffirmed the role of 12 previously reported risk genes. We also found evidence that clefting was associated with predicted gene expression at CALD1 and ESRP1 and that the associated variants in these genes were located near regions known to be involved in the regulation of gene expression in craniofacial tissues during development.

ObjectivesTo understand the crosstalk between the host and microbiota in psoriatic skin, using a systems biology approach based on transcriptomics and microbiome profiling. MethodsWe collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions, and the associations between the host defense and microbiota dynamic. ResultsWe found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using coexpression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a "core" set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the "core network" of genes. ConclusionsWe identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition.

Meniere disease (MD) is a polygenic condition defined by episodes of vertigo associated with sensorineural hearing loss and tinnitus. Genetic studies in familial MD in East Asian population are limited and the potential MD genes remain to be established in non-Finnish European populations. By exome sequencing and rare variant analysis, we search for existing and novel genes associated with MD in a South Korean cohort of 16 MD individuals with bilateral sensorineural hearing loss. We have found one individual with two rare missense variants in the OTOP2 gene, a new candidate gene for MD and three heterozygous variants in the MYO7A gene, supporting the hypothesis of biallelic inheritance. Protein modelling was conducted on three rare missense variants in OTOP2 to further elucidate functional consequences. The structural and functional implications inferred from these models suggest a likely pathogenic role, providing additional insights into the molecular mechanisms underlying MD.

DNA sequencing of patients with rare disorders has been highly successful in identifying "causal variants" for numerous conditions. However, there are many reports of healthy individuals who harbor these deleterious variants, leading to the concept of incomplete penetrance and doubt about the utility of genetic testing in clinical practice and population screening. As the deleterious variants are rare, the penetrance of these variants in the population is largely unknown. We analyzed the genetic and clinical data from 486,956 participants of the Taiwan Precision Medicine Initiative (TPMI) to determine the risk difference between those with and without deleterious variants. In all, we analyzed 292 disease-relevant variants and their clinical outcomes to assess their association. We found that only 15 variants show a risk difference exceeding 5% between those with or without the variants. In essence, 87.3% of deleterious variants exhibit minimal risk differences, suggesting a limited impact on the individual and population levels. Our analysis revealed increasing trends with age in six cardiovascular and degenerative diseases and bell-shaped trends in two cancers. Additionally, we identified three clinical outcomes exhibiting a dose-response relationship with the number of deleterious variants. Our findings show that large-scale testing of deleterious variants found in the literature is not warranted, except for those exhibiting large disease risk differences.

The escalating adoption of Next Generation Sequencing (NGS) in clinical diagnostics reveals genetic variations, termed secondary findings (SFs), with health implications beyond primary diagnoses. The Collaborative Spanish Variant Server (CSVS), a crowdsourced database, contains genomic data from more than 2100 unrelated Spanish individuals. Following the American College of Medical genetics (ACMG) guidelines, CSVS was analyzed, identifying pathogenic or likely pathogenic variants in 78 actionable genes (ACMG list v3.1) to ascertain SF prevalence in the Spanish population. Among 1129 samples, 60 reportable SFs were found in 5% of individuals, impacting 32 ACMG-listed genes, notably associated with cardiovascular disease (59.4%), cancer (25%), inborn errors of metabolism (6.3%), and other miscellaneous phenotypes (9.4%). The study emphasizes utilizing dynamic population databases for periodic SF assessment, aligning with evolving ACMG recommendations. These findings illuminate the prevalence of significant genetic variants, enriching understanding of secondary findings in the Spanish population.