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De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.

Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder ca

HDL cholesterol esters mediate the genetic link between sedentary behavior and urological cancers: Insights from mediation and validation analyses.

This study explores the causal relationship between sedentary behavior and urological cancers, focusing on bladder cancer (BC), prostate cancer, and kidney cancer, using Bayesian Mendelian randomization and mediation analysis. A two-sample Mendelian randomization (MR) framework was employed, using genetic variants as instrumental variables. Bayesian and multivariate MR assessed causal effects of sedentary behaviors (TV watching, computer use, driving) on urological cancers. Sensitivity analyses (MR-Egger, MR-PRESSO, and Cochran Q) ensured robustness. Mediation analysis identified high-density

Causal associations between gut microbiota and rheumatoid arthritis: A two-sample Mendelian randomization study.

The gut microbiota has been implicated in the development of rheumatoid arthritis (RA), but whether these associations reflect causal relationships remains unclear. We conducted a two-sample Mendelian randomization analysis to investigate the potential causal effects of gut microbial taxa on RA risk. Summary-level data from the MiBioGen consortium (n = 13,266) and a large RA genome-wide association study (n = 97,173) were used. Multiple Mendelian randomization methods and sensitivity analyses were applied to ensure robustness. Four microbial taxa showed nominal associations with RA. Increased

Causal relationships between gut microbrome and digestive system diseases: A two-sample Mendelian randomization study.

Growing evidences of recent studies have shown that gut microbrome are causally related to digestive system diseases (DSDs). However, causal relationships between the gut microbiota and the risk of DSDs still remain unclear. We utilized identified gut microbiota based on class, family, genus, order and phylum information and digestive system diseases genome-wide association study (GWAS) dataset for two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used to evaluate causal relationships between gut microbiota and 7 DSDs, including chronic gastritis,

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379

Causal relationship between citrate and gestational diabetes mellitus: a two-sample Mendelian randomization analysis.

BACKGROUND: Diabetes Mellitus (GDM) is a common metabolic disease during pregnancy, mainly manifested as impaired glucose tolerance in the middle and late stages of pregnancy. As a key intermediate product in the tricarboxylic acid cycle, citrate has been widely recognized for its role in regulating blood glucose levels. However, the potential association between citrate and impaired glucose tolerance during pregnancy needs further research, The aim of this study is to investigate the relationship between citrate levels in the human body and the incidence of gestational diabetes mellitus. MET

The use of statins can reduce the risk of osteoarthritis and osteoporosis.

BACKGROUND: Observational studies suggest that statins may be protective against osteoporosis and osteoarthritis. However, the association between statins and the risk of osteoporosis and osteoarthritis has not been fully clarified. OBJECTIVE: The association between statins and the risk of osteoporosis and osteoarthritis was explored by Mendelian randomization analyses using pooled data from a large population-based genome-wide association study (GWAS). METHODS: Data on statin-associated single-nucleotide polymorphisms were obtained from version 10 of the FinnGen database, while information

Mendelian randomization analysis does not reveal a causal influence between keratoconus and three major mental disorders.

BACKGROUND: Observational studies have suggested at a possible link between keratoconus (KC) and various mental disorders, but the exact direction of causation in these associations remains unclear. This study aims to investigate the potential causal link between KC and three prominent mental conditions: Anxiety, Depression, and Schizophrenia. METHODS: Using instrumental variables identified from Genome-wide association study (GWAS) data of European individuals, we conducted bidirectional two-sample Mendelian Randomization (MR) analyses to explore potential causal relationships between KC and

Dissecting the shared genetic architecture between migraine subtypes and cardiovascular diseases: a multi-layered genomic analysis.

BACKGROUND: Epidemiological studies have linked migraine to an increased risk of cardiovascular disease (CVD); however, the shared genetic basis and putative causal relationships between migraine subtypes and cardiovascular traits remain poorly understood. METHODS: Leveraging large-scale GWAS summary statistics for migraine phenotypes (overall migraine, migraine with aura [MA], and migraine without aura [MO]) from FinnGen R12, along with seven cardiovascular diseases from publicly available consortia, we conducted a multi-layered genetic analysis. This integrative framework encompassed geneti

East Asian Mendelian-Randomization Evidence Linking PCOS to Gestational Diabetes Mellitus.

BACKGROUND: Previous Mendelian randomization (MR) studies explored causal links between polycystic ovary syndrome (PCOS) and pregnancy complications and adverse outcomes mainly in European populations, with limited generalizability. This two-sample MR study addresses this limitation. METHODS: Independent genetic instruments for PCOS were selected at genome-wide significance (P<5×10-8) and statistical pruned using LDTrait. East Asian (EAS)-based genome-wide association study data were analyzed for gestational diabetes mellitus (GDM), preeclampsia, intrahepatic cholestasis of pregnancy, miscarr

Causal effects of diabetes and alcohol intake on Dupuytren's disease: a two-sample Mendelian randomization study in UK Biobank and FinnGen.

BACKGROUND: Dupuytren's disease (DD) is associated with metabolic and lifestyle traits. However, these associations remain uncertain because exposures frequently cluster, and conventional studies are vulnerable to residual confounding and reverse causation. METHODS: A two-sample Mendelian randomization (MR) analysis using genetic instruments for diabetes, obesity-related, smoking, and alcohol-related traits from genome-wide association studies of large European ancestry was conducted. Summary statistics of DD were obtained from UK Biobank and FinnGen and combined using meta-analysis. Multipli

Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci.

Several lines of evidence suggest that normal-range facial features and nonsyndromic orofacial clefts (OFCs) exhibit a shared genetic basis. Approaches designed to leverage this relationship hold the possibility of revealing new OFC risk loci by boosting discovery power. To test this idea, we applied a pleiotropy-informed genome-wide association study (GWAS) method (conditional false discovery rate [cFDR]-GWAS) with summary statistics from large, independent European GWASs of normal facial shape (n = 4,680; n = 3,566) and nonsyndromic cleft lip with or without cleft palate (nsCL/P; n = 3,969).

Circadian disruption and circulating TGF-β1 in workers: evidence from Mendelian randomization and observational data.

BACKGROUND: Circadian disruption is increasingly recognized as an important biological stressor underlying chronic disease, yet its direct immunological effects remain unclear. Observational studies are limited by residual confounding and reverse causation. METHODS: We integrated two-sample Mendelian randomization (MR) with an exploratory observational biomarker study. Genetic instruments for genetically proxied shift-work propensity were derived from the UK Biobank GWAS, and outcome data for 46 circulating proteins were obtained from the AGES-Reykjavik Study in Iceland. Inverse-variance weig

Genomic Evidence on Antihypertensive Drug Targets and Oral Disease Outcomes.

AIM: Antihypertensive medications are widely prescribed for hypertension, yet evidence regarding their oral health safety remains limited. We aimed to investigate whether genetically proxied pharmacological actions of antihypertensive drug classes influence the risk of periodontitis and dental caries using a two-sample drug-target Mendelian randomization framework. METHODS: Genetic instruments were obtained for 12 antihypertensive drug classes using variants within or near target genes associated with systolic blood pressure (SBP) in two genome-wide association study (GWAS) meta-analyses: one

Association between interleukin-12 p40 subunit and risk of primary Sjögren's disease: a Mendelian randomization study.

OBJECTIVES: IL-12 signalling was proposed in the immunopathogenesis of primary Sjögren's disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren's disease using Mendelian randomization. METHODS: We selected single nucleotide polymorphisms from protein quantitative trait loci of IL12A, IL12B, IL12Rβ1, IL12Rβ2 and IL23R to examine the association between alterations in their levels and risk of primary Sjögren's disease. Genetic asso

The causal relationship between immune cells and rheumatoid arthritis: A dual sample Mendelian randomization study.

The etiology of rheumatoid arthritis (RA) is still unclear, but it has been shown to be genetically related. While previous studies have shown a causal relationship between immune cells and RA, there has been no systematic evaluation of the causal relationship between immune cell characteristics and RA in terms of genetic variation. For this study, a comprehensive Mendelian randomization analysis was performed to determine the causal relationship between immune cell characteristics and RA. On the basis of publicly available genetic data, we examined the causal relationship between 731 immune c

Взаимодействие полов и генотипов в ассоциациях по борьбе с заболеваниями: комплексный сетевой анализ в Биобанке Соединенного Королевства.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: Сопоставимость заболеваний и более долгосрочные осложнения, обусловленные биологическими связями между фенотипами, могут привести к повышению риска серьезных последствий для здоровья. С учетом того, что многие болезни отличаются по признаку пола в их генетике, наша цель состояла в том, чтобы определить, влияют ли связи генотипа в разбивке по полу (GxS) аналогичным образом на межфенотипные ассоциации. Путем сопоставления сетей по борьбе с болезнями, которые были зарегистрированы на сексуальной почве, где узлы представляют собой болезни и края, представляют собой их взаимо

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… We must consider the genetics underlying the entire landscape of the human phenome and genome, known as the human “diseasome [ 14 ],” with a particular focus on the effects of polygenicity and genetic pleiotropy. … Overall, our sex-stratified network comparison confirms the presence of GxS interactions in cross-phenotype associations and helps to navigate the study of complex diseases through the lens of genetic pleiotropy and polygenicity. …

Bidirectional two-sample mendelian randomization analysis identifies causal associations of MRI-based cortical thickness and surface area relation to NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients have exhibited extra-hepatic neurological changes, but the causes and mechanisms remain unclear. This study investigates the causal effect of NAFLD on cortical structure through bidirectional two-sample Mendelian randomization analysis. METHODS: Genetic data from 778,614 European individuals across four NAFLD studies were used to determine genetically predicted NAFLD. Abdominal MRI scans from 32,860 UK Biobank participants were utilized to evaluate genetically predicted liver fat and volume. Data from the ENIGMA Consortium, compri

Inflammatory proteins and hidradenitis suppurativa: Insights from genetic correlation and Mendelian randomization.

Previous research has highlighted a significant association between inflammatory proteins and the development and progression of hidradenitis suppurativa (HS). Nevertheless, the potential causative link between these factors remains to be definitively established. To investigate the genetic correlation between inflammatory proteins and HS, linkage disequilibrium score regression (LDSC) was employed. Mendelian randomization (MR) analysis, incorporating inverse variance weighted, MR-Egger, and weighted median methodologies, was utilized to evaluate the possible causal relationship between circul

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study.

BACKGROUND: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. METHODS: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we p