HGG Advances最新文献

Differences in immune responses are observed between males and females, influenced by genetic, hormonal, and environmental factors. The sex-specific genetic effects on cytokine production however remain underexplored. This study aimed to identify sex-specific quantitative trait loci (QTLs) affecting cytokine production in response to diverse infectious antigens. We performed sex-stratified cytokine QTL (cQTLs) mapping in two population-based cohorts from Tanzania and the Netherlands. In the Tanzanian cohort, twelve genome-wide significant cytokine QTLs were identified, with seven observed in males and five in females. In the Dutch cohort, twelve genome-wide significant cQTLs were identified, with six cQTLs each in males and females. Colocalization analysis confirmed that all twelve genome-wide cQTLs from the Tanzanian cohort are sex-specific, while in the Dutch cohort ten genome-wide cQTL variants are modulated in a sex-specific manner. Furthermore, pathway and phenotype enrichment analyses linked the identified cQTL variants to relevant immune functions and sex-biased traits. Our study highlights the importance of sex-stratified genetic analyses when investigating the genetic basis of cytokine production in humans. We show that sex-specific cQTLs may underlie observed phenotypic differences between males and females and that accounting for such effects can inform the development of personalized medical treatments for sex-biased diseases.

Index-Trait bias (also called Index-Event Bias) can occur in genetic studies due to conditioning on incident trait, which can bias genetic associations with subsequent traits. We propose the use of two Bayesian Mendelian Randomization (MR) methods (Bayesian weighted MR [BWMR] and [MR-HORSE]) to correct index-trait bias in genome-wide association studies (GWAS) of subsequent traits. We compare these Bayesian MR methods to previously proposed methods for index-trait bias through a simulation study. We observe that BWMR has similar Type I error compared to using an inverse variance weighted MR (MR-IVW), weighted median MR (MR-WMED), and Dudbrige (MR-Egger), but has an inflated Type I error compared to SlopeHunter. MR-HORSE and Slopehunter have similar Type I errors for smaller correlations between incident and subsequent traits, however, MR-HORSE and Slopehunter have better controlled Type I error for a large negative correlation and large positive correlation, respectively. All methods have comparable power across correlations between incident and subsequent traits. We applied the methods to a GWAS of subsequent Acute Ischemic Stroke (AIS) or 3pt Major Adverse Cardiovascular Event (MACE) after an incident AIS event in the Million Veterans Program (MVP) and for Fasting Insulin (FI) adjusted for BMI, and we observed slight differences in the results between the methods. We observed that a single index trait bias correction method is not optimal across all scenarios, therefore applying multiple methods and checking for consistency between the estimates could provide an approach to determine the presence of and correction for index trait bias.

National guidelines from the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network recommend the use of family-health-history (FHH)-based risk assessment tools to guide genetic testing (GT) among women with an increased risk of inherited cancer and inform personalized cancer risk management. Prior research has focused on attitudes towards and decisions about initial uptake of GT in Black patients but little is known about the factors that impact the subsequent completion of GT after they have already provided consent. Using a community-based participatory research (CBPR) approach, we aimed to identify barriers and actionable strategies to improve GT completion offered through the Breast Health Assessment (BHA), an FHH screening tool administered at routine mammography visits. We conducted semi-structured interviews with 12 Black women who screened high-risk for inherited breast cancer and consented to GT through the BHA, but did not complete saliva sample collection. Thematic analysis revealed that lack of dedicated support throughout the BHA workflow emerged as a key obstacle to sample collection, whereas medical mistrust, shame, and limited knowledge were largely regarded as cultural barriers that had no impact on GT completion. Low utilization among participants reflected logistical challenges highlighting the need to evaluate multi-level implementation processes to better understand and address inequities in GT completion. Participants suggested implementing early educational outreach, culturally-relevant messaging, and interpersonal touchpoints to promote GT uptake. By applying a CBPR approach, we translated these findings into actionable, equity-focused strategies to improve GT completion within a population genetic screening program.

Keratinising desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear aetiology and treatment options. It is characterised by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinising epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole genome sequencing (WGS) was performed on three affected individuals and a truncating variant (RARG NM_000966.6:c.1237C>T; NP_000957.1:p.(Arg413*)) in the gene encoding Retinoic Acid Receptor gamma (RARγ) was identified to be segregating with the phenotype. The truncating variant does not destabilise the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RARγ, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinising squamous metaplasia of the urothelium. The implicated dominant negative mechanism reduces retinoic acid signalling via heterodimeric receptors that incorporate the variant γ subunit and indicates that this condition may be addressable with high dose retinoic acid receptor agonists.

Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study aims to report additional cases for the newly discovered IRD genes of the AP5-complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing and electroretinogram (ERG) testing. Whole genome and exome sequencing (WGS & WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. The identified variants were subsequently validated using Sanger sequencing. Five unrelated patients from Europe and Iran were identified with a distinctive macular degeneration associated with bi- allelic variants in AP5Z1 (HGNC: 22197) and AP5B1 (HGNC: 25104), subunits of the vesicular fifth adaptor protein (AP-5) complex. AP-5 complex is the part of the intracellular trafficking machinery thought to be involved in cellular homeostasis and lysosomal functioning in the retinal pigment epithelium (RPE). The identification of bi-allelic variants in two proteins of AP-5 complex expand the characterization of AP-5 genes in sustaining and preserving normal macular function.

Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain- and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject's cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.

Autonomy is a leading indicator of well-being and a cornerstone principal of research ethics. Yet adults with intellectual disability are routinely denied autonomy in research settings, affecting participation and generalizability. To inform health research policy and practice, we conducted a national survey of 150 adults with intellectual disability to explore their views on autonomy and decision-making in precision medicine research (PMR), a leading area of health research. Participants expressed strong interest in participating in PMR and controlling their participation decisions, sometimes with support. Findings highlight the need for policies and practices that honor these interests and facilitate autonomy. Over time, such efforts can improve health outcomes for this underserved population.

We report three individuals with biallelic variants in RNU6ATAC, which encodes the U6atac minor spliceosomal small nuclear RNA (snRNA), causing a multisystem minor spliceopathy. Through RNAseq analysis, we identified a distinctive excess of minor intron retention (MIR) in two unrelated individuals, which guided the identification of biallelic RNU6ATAC variants. The discovery cohort presented with variable multisystem manifestations. One individual presented with refractory epilepsy, microcephaly, developmental delay, ataxia, bilateral toe syndactyly, hypereosinophilia, and short stature, whereas the other exhibited failure to thrive, short stature, primary hypothyroidism, combined variable immunodeficiency, eosinophilic colitis, ichthyosis vulgaris, scoliosis, and chronic inflammatory demyelinating polyneuropathy without neurodevelopmental involvement. Despite organ-specific variation, both individuals displayed impaired growth and eosinophil-driven inflammation. Recently, we identified a third affected individual from an independent cohort whose phenotype bridges these features, combining microcephaly, growth failure with severe immunodeficiency, and skeletal abnormalities. The distinctive excess of MIR outliers in the discovery cohort supports minor spliceosome dysfunction, mirroring the molecular signature of RNU4ATAC-opathy. These findings nominate RNU6ATAC as a disease-associated gene, defining an expanded clinical spectrum of minor spliceopathies. Our study supports the power of integrating genomic and transcriptomic approaches for diagnosing splicing disorders and highlights the critical role of spliceosomal snRNAs in human disease.

Many datasets, including widely used biobanks, have more than one observation of numerous phenotypes for at least a portion of their sample. The majority of GWAS utilize only a single observation per individual, even when more than one observation may be available, and apply a standard model in which the additive allelic effect being estimated is assumed to be constant across the age or time range in the sample. Here, we test a set of simple approaches to utilize multiple observations per individual, under this same assumption, to characterize effects on GWAS power, SNP-heritability, gene set enrichment, and polygenic prediction. We find that utilizing the mean or median of the available observations rather than a single observation improves power to detect associated loci and enriched gene sets and yields higher out-of-sample polygenic score prediction accuracy. Despite growing biobanks, many deeply phenotyped samples are relatively small but have multiple observations. While explicitly modeling age- or time-dependent genetic effects can add nuance to genetic studies and estimates, most GWAS apply a standard, additive-only model; a simple approach of using the mean or median can improve power by reducing "noise" in the phenotype, utilize standard, optimized software, and be particularly impactful for smaller samples, including samples of diverse genetic ancestry currently existing in widely used biobanks such as the UK Biobank and HRS.

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified proteins such as GM2A and EPHB6, whose expression appears to be strongly associated with DNA methylation, suggesting potential as targets for epigenetic-based therapeutic interventions. These findings demonstrate the extensive impact of DNA methylation on the circulating proteome through cis- and trans-regulatory mechanisms and underscore the influence of population-level traits on epigenetic regulation. These findings highlight a broad impact of DNA methylation on circulating proteins through both cis- and trans-regulatory mechanisms and the roles of population-level phenotypes.