Genetically Research Articles

Exploring the genetic implications of demographic dynamics in Jammu and Kashmir using autosomal STRs.

The Union Territory of Jammu and Kashmir has always been a point of contention among India, Pakistan, and China for various reasons. This region has great significance historically due to its geography and ethnic diversity. However, a comprehensive genetic study providing the genetic landscape of Jammu and Kashmir was lacking until now. In this study, we analysed 21 hyper-variable autosomal STR loci of 694 individuals from Jammu and Kashmir and compared them with neighbouring populations to explore the genetic implications of demographic dynamics that have taken place in this region. Our findings suggest that the population of Jammu and Kashmir is a genetic mixture of two major clines, northern and southern, that correspond with the variation in geography, linguistics, and demography of the region. Broadly, the gene flow into the southern cline appears to be in historical times perhaps as a result of the spread of Gurjars, Dogri language and invasions of Mongols. However, the arrival of ancient nomadic tribes into this region may belong to the time depth of the arrival of pastoralist communities in this region. As a future perspective, a comprehensive study including samples from individual tribes will provide fine-scale structure of the gene pool of Jammu and Kashmir.

Author Correction: A genetic study to identify pathogenic mechanisms and drug targets for benign prostatic hyperplasia: a multi-omics Mendelian randomization study

Author Correction: A genetic study to identify pathogenic mechanisms and drug targets for benign prostatic hyperplasia: a multi-omics Mendelian randomization study

Large-scale exome sequencing identified 18 novel genes for neuroticism in 394,005 UK-based individuals.

Existing genetic studies of neuroticism have been largely limited to common variants. Here we performed a large-scale exome analysis of white British individuals from UK Biobank, revealing the role of coding variants in neuroticism. For rare variants, collapsing analysis uncovered 14 neuroticism-associated genes. Among these, 12 (PTPRE, BCL10, TRIM32, ANKRD12, ADGRB2, MON2, HIF1A, ITGB2, STK39, CAPNS2, OGFOD1 and KDM4B) were novel, and the remaining (MADD and TRPC4AP) showed convergent evidence with common variants. Heritability of rare coding variants was estimated to be up to 7.3% for neuroticism. For common variants, we identified 78 significant associations, implicating 6 unreported genes. We subsequently replicated these variants using meta-analysis across other four ancestries from UK Biobank and summary data from 23andMe sample. Furthermore, these variants had widespread impacts on neuropsychiatric disorders, cognitive abilities and brain structure. Our findings deepen the understanding of neuroticism's genetic architecture and provide potential targets for future mechanistic research.

Genetic Insights and Epidemiological Models in Understanding Primary Open Angle Glaucoma

Primary open-angle glaucoma (POAG) is a multifactorial chronic optic neuropathy with significant genetic heterogeneity. The pathogenesis of POAG involves an imbalance between the production and drainage of aqueous humor (AH). Genetic theories suggest that transgenic mice demonstrating the GLU50LYS mutation in optineurin (OPTN) experience retinal ganglion cell apoptosis, while mutant myocilin (MYOC) proteins induce endoplasmic reticulum (ER) stress, leading to an unfolded protein response (UPR) and subsequent apoptosis of trabecular meshwork cells (TMC). Furthermore, the interaction between MYOC and mitochondria in the trabecular meshwork (TM) and astrocytes may lead to mitochondrial membrane depolarization and calcium channel dysregulation, contributing to POAG. Overexpression of MYOC variants (P370L, Q368X) is also implicated, as are epigenetic modifications and signaling pathways such as histone and DNA modification. POAG has been associated with autosomal dominant inheritance, with mutations in MYOC and OPTN being prominent causative factors, although many cases involve multiple genetic loci. Currently, over 20 genetic loci have been linked to POAG, with 14 chromosomal loci (GLC1A to GLC1N) identified, 5 of which contribute to juvenile-onset open-angle glaucoma (JOAG). Of these loci, MYOC, OPTN, WD repeat domain 36 (WDR36), and neurotrophin-4 (NTF4) are the most studied causative genes. The ongoing study of molecular genetics offers potential pathways for future therapeutic advances in the treatment of POAG.

Polygenic Risk of Epilepsy and Poststroke Epilepsy.

Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE. We conducted a case-control genetic association study nested within the UK Biobank, a large UK-based prospective cohort. Our exposures of interest were 2 distinct polygenic risk scores-generalized and focal epilepsy-modeled as deciles and constructed using genetic variants identified in the latest International League Against Epilepsy genome-wide association study meta-analysis. We aimed to evaluate the association between these polygenic risk scores and their corresponding subtype of PSE-generalized and focal. In sensitivity analyses, we evaluated participants of European ancestry separately and considered focal and generalized epilepsy outcomes in participants without a history of stroke. In secondary analyses, we evaluated the polygenic risk of PSE by stroke subtype (ischemic, hemorrhagic, or any stroke). Multivariable logistic regression models were fitted, adjusting for age, sex, genetic ancestry, and the first 5 principal genetic components. Among 17 549 UK Biobank stroke survivors with available genetic information (mean age, 61; 43% female), 185 (1%) developed generalized PSE, while 124 (0.7%) developed focal PSE. Multivariable logistic regression results showed that, when compared against the lowest decile, participants within the highest PRS decile for generalized PSE had 5-fold higher odds of developing generalized PSE (OR, 5.05 [95% CI, 2.37-12.5]; P trend<0.001). Similarly, when compared against the lowest decile, participants within the highest polygenic risk score decile for focal PSE had 3-fold higher odds of developing focal PSE (OR, 3.20; [5% CI, 1.25-9.82]; P trend=0.024). Sensitivity analyses among participants of European ancestry yielded similar results. Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.

Genetic Variation Study of Several Romanian Pepper (Capsicum annuum L.) Varieties Revealed by Molecular Markers and Whole Genome Resequencing

Numerous varieties of Capsicum annuum L. with multiple valuable traits, such as adaptation to biotic and abiotic stress factors, can be found in south-east Romania, well known for vegetable cultivation and an important area of biodiversity conservation. To obtain useful information about sustainable agriculture, management, and conservation of local pepper varieties, we analyzed the genetic diversity and conducted deep molecular characterization using whole genome resequencing (WGS) for variant/mutation detection. The pepper varieties used in the present study were registered by VRDS in the ISTIS catalog between 1974 and 2019 and maintained in conservative selection; however, no studies have been published yet using WGS analysis in order to characterize this specific germplasm. The genome sequences, annotation, and alignments provided in this study offer essential resources for genomic research as well as for future breeding efforts using the C. annuum local varieties.

A large cohort from an immunology reference center and an algorithm for the follow-up of chronic neutropenia.

Chronic neutropenia causes involve nutritional deficiencies and inborn errors of immunity(IEI), such as severe congenital neutropenia. To classify common chronic neutropenia causes in a pediatric immunology unit. We enrolled 109 chronic neutropenia patients admitted to a pediatric immunology department between 2002-2022. We recorded clinical/laboratory features and genetic characteristics. The male/female ratio was 63/46. Fifty-eight patients had parental consanguinity(57.4%). 26.6% (n = 29) patients had at least one individual in their family with neutropenia. Common symtpoms at presentation were upper respiratory tract infections(URTI)(31.1%), oral aphthae(23.6%), skin infections(23.6%), pneumonia(20.8%), and recurrent abscesses(12.3%). Common infections during follow-up were URTI(56.8%), pneumonia(33%), skin infections(25.6%), gastroenteritis(18.3%), and recurrent abscesses(14,6%). Common long-term complications were dental problems(n = 51), osteoporosis(n = 22), growth retardation(n = 14), malignancy(n = 16)[myelodysplastic syndrome(n = 10), large granulocytic leukemia(n = 1), acute lymphoblastic leukemia(n = 1), Hodgkin lymphoma(n = 1), EBV-related lymphoma(n = 1), leiomyosarcoma(n = 1), and thyroid neoplasm(n = 1)]. We performed a genetic study in 86 patients, and 69(71%) got a genetic diagnosis. Common gene defects were HAX-1(n = 26), ELA-2 (ELANE)(n = 10), AP3B1(n = 4), and ADA-2(n = 4) gene defects. The IEI ratio(70.6%) was high. GCSF treatment(93.4%), immunoglobulin replacement therapy(18.7%), and HSCT(15.9%) were the treatment options. The mortality rate was 12.9%(n = 14). The most common long term complications were dental problems that is three times more common in patients with known genetic mutations. We prepared an algorithm for chronic neutropenia depending on the present cohort. An important rate of inborn errors of immunity, especially combined immunodeficiency(11.9%) was presented in addition to congenital phagocytic cell defects. Early diagnosis will allow us tailor the disease-specific treatment options sooner, preventing irreversible consequences.

Fine-scale genetic structure and rare variant frequencies.

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect such as the Ashkenazi Jews and the population of the Quebec' province. We leverage the fine-scale population structure to explore its impact on the frequency of rare variants. Notably, we observed an 8-fold increase in frequency for a variant associated with the Usher syndrome in one Quebec subpopulation. Our study underscores that smaller cohorts with greater genetic similarity demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants' discovery.

Two new species of Thomasomys (Cricetidae: Sigmodontinae) from the western Andes of Ecuador and an updated phylogenetic hypothesis for the genus

Abstract The Andean cloud forests of Ecuador are home to numerous unique mammals. Rodents of the tribe Thomasomyini are particularly abundant in many Andean localities, with Thomasomys – the largest genus in the subfamily Sigmodontinae (51 species) – especially species-rich and diverse. Despite recent advances on the systematics of the genus, where seven species have been described in the last five years, there is tantalizing evidence that its true diversity remains completely understood. Over the course of approximately ten years of fieldwork in Ecuador, a significant number of Thomasomys specimens were collected from various localities in both, the eastern and western Andean ranges. Through an extensive genetic study of these specimens, augmented with what is available in public databases, we argue that there exist at least 20 undescribed species in the genus, with no less that twelve potential new species in Ecuador alone. In this paper, we describe two of these species belonging to the group cinereus, one recently collected and the other previously referred to as Thomasomys sp. 1; further, we present an updated cyt b gene tree of the genus. The gene tree includes at least 56 valid and putative species and supports the monophyly of the genus, while at the same time suggest a paraphyletic “aureus” group. Our findings suggest that the genus likely exhibits additional hidden diversity in significant portions of Colombia, Peru, and Bolivia which calls for the need for a comprehensive reassessment of the entire genus. The recognition of these two new species brings the total number of known Thomasomys to 53 species, 19 of which occur in Ecuador, including 17 that are endemic to this country.

Characterization of genetic landscape and novel inflammatory biomarkers in patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD cohort to investigate the underlying pathology and identify novel targets for potential treatment. We investigated AOSD cases (n=60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n=106), alongside measurements of NLRP3 inflammasome activation using a custom assay, and Type I Interferon (IFN) score using a novel method. We observed higher-than-expected frequencies of rare germline variants associated with monogenic autoinflammatory disorders in AOSD cases (AOSD 38.4% vs healthy controls 20.4%), and earlier onset of putative somatic variants associated with clonal haematopoiesis of indeterminate potential. Transcriptome profiling revealed positive correlation between Still's activity score (SAS) and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and Type I IFN scores were significantly elevated in AOSD cases compared to healthy controls (p=0.0001 and 0.0015 respectively), in addition to several cytokines: IL-6 (p<0.0001), IL-10 (p<0.0075), IL-12p70 (p=0.0005), IL-18 (p<0.0001), IL-23 (p<0.0001), IFN-α2 (p=0.0009), and IFNγ (p=0.0002). Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not, by themselves, be sufficient to cause disease but may contribute to a polygenic model for AOSD.

Tissue specific innate immune responses impact viral infection in Drosophila.

All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.

Unlocking Spanish pear genetic diversity: strategies for construction of a national core collection

Spanish pear germplasm collections are crucial for preservation, research, and breeding efforts. However, genetic diversity and structure is unknown at national level. A coordinated national project analyzed 1251 accessions from 7 Spanish pear collections using an internationally recognized set of 14 SSRs to enhance the utilization of these collections. Key findings included the identification of 760 unique genotypes (490 diploids and 270 triploids). Notably, genotypes represented by a single accession accounted for 49% of the total, indicating high vulnerability of this material. Using a Bayesian clustering method revealed two main genetic groups, G1 containing most foreign cultivars and G2 retaining local Spanish cultivars, which were further divided into two other subgroups using a nested approach, revealing moderate but significant differentiation among them. The populations were renamed according to the origin of the reference samples assigned to each group as ‘South’ (G1.1), ‘Western Europe-1’ (G1.2), ‘Western Europe-2’ (G2.1) and ‘No-Pyrus communis’ (G2.2). The results led to the creation of a ‘generalist’ collection, aiming to maximize genetic diversity representativeness, starting with 68 genotypes but expanding to 111 to achieve better allele recovery. This core collection is a valuable resource for genetic studies and conservation, enhancing efforts to preserve pear biodiversity.

Genetic Diversity and Evolutionary Biology of Indian Wildlife- A Review

The genetic diversity and evolutionary biology of Indian wildlife, emphasizing the critical role of genetic variability in ensuring species adaptability and long-term survival. India is one of the world’s megadiverse countries, home to a wide range of unique flora and fauna spread across its biodiversity hotspots, including the Western Ghats and the Eastern Himalayas. However, rapid habitat fragmentation, deforestation, and poaching have severely impacted the genetic health of many wildlife species, leading to reduced gene flow, population bottlenecks, and increased inbreeding. This has heightened the risk of extinction for small, isolated populations such as the Asiatic lion and the Great Indian bustard. Genetic studies using advanced genomic tools have provided key insights into the population structure, phylogenetic relationships, and adaptive potential of species like the Bengal tiger, Asian elephant, and snow leopard. Conservation strategies, including genetic rescue, habitat corridors, and the use of captive breeding programs, are recommended to preserve genetic diversity and prevent further genetic erosion. Technological advances, such as non-invasive sampling and bioinformatics, are transforming wildlife research, enabling more precise and less intrusive genetic monitoring. The integration of genetic data into conservation policies and practices is essential for developing targeted management plans that maintain the evolutionary potential of Indian wildlife.

Genetic Evaluation of Monthly Test-Day Milk Yields of Jersey Crossbred Cattle Under Farmers' Production System in Tamil Nadu, India.

Tamil Nadu, a state in southern India, is bereft of any native dairy or dual-purpose cattle breeds, and the state depends chiefly on crossbred cattle for milk production. Jersey crossbred cattle account for 90% of the state's milk production. This genetic evaluation study aimed to assess milk production traits, including test-day milk yields (TDMYs), total lactation milk yield (TMY), and 305-day milk yield (305MY), in these cattle reared under farmers' conditions. Data on monthly TDMYs (TDMY1 to TDMY10) of Jersey crossbred cows (n = 75,627) reared by the farmers over 11 years (2012-2022) were collected for evaluation. The influence of non-genetic factors viz., location (agroclimatic zones), period and season of calving, and parity on TDMYs, TMY and 305MY were assessed, and the variance and covariance components for genetic parameters (heritability and genetic correlation) of the traits were estimated by the method of restricted maximum likelihood (REML) under a multivariate animal model and by a random regression model (RRM). The overall means of various TDMYs ranged from 4.98 (TDMY10) to 9.95 kg (TDMY2), and for TMY and 305MY, the means were 2480.33 and 2393.71 kg, respectively. The heritabilities estimated by the multivariate animal model for TDMYs were moderate and ranged from 0.26 ± 0.02 to 0.37 ± 0.02 and the estimates were less variable throughout lactation, while the estimates obtained by RRM were medium to high and ranged between 0.29 ± 0.01 and 0.67 ± 0.02 for milk yield on day 5 to 305 (DIM 5-DIM 305). The heritabilities estimated for TMY and 305MY were 0.43 ± 0.02 and 0.43 ± 0.02, respectively. The estimates of heritability for mid-lactation yields were comparatively less than those at the beginning and the end of lactation. The moderate to high estimates of heritabilities for TDMYs, TMY, and 305MY obtained in the present study offer ample scope for improving milk production through selective breeding. Genetic correlations between TDMYs estimated by the multivariate animal model were positive and high, with a range between 0.75 ± 0.03 and 0.99 ± 0.00. Considerably higher estimates (0.98-0.99) were observed between adjacent TDMYs showing strong genetic associations. By RRM, genetic correlations estimated between DIMs were positive (except for DIM 5 with DIM 125 to DIM 185 and DIM 125 with DIM 305), and the magnitude of genetic correlation decreased with an increase in the interval between the DIMs. The high genetic correlation observed between the TDMYs (in the early stage of lactation) and total lactation milk yield suggested that these test-day yields could be used favorably for the early selection of cows for milk production, which facilitates reduction in the generation interval and consequently increases the annual genetic gain for the milk production traits.

Hidradenitis Suppurativa from a Multi-Omic Scope.

Hidradenitis suppurativa (HS) is recognized as a systemic immune-mediated disease (IMID), sharing genetic and environmental risk factors with other IMIDs such as inflammatory bowel disease and psoriasis. Over time, correlating clinical findings with genetic, proteomic, and metabolomic results has been challenging due to diverse sampling methods, analysis techniques, and the use of variable clinical phenotype descriptions across studies. This review aims to summarize the results from various omics fields to explore the etiopathology of HS. Genetic studies highlight defects in Notch and γ-secretase signaling and inflammasome function. Syndromic HS involves specific mutations in autoinflammatory syndromes such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) and pyoderma gangrenosum, acne, and HS (PASH). Proteomic analyses reveal key inflammatory pathways indicating activation of both innate and adaptive immunity. Additionally, microbiome studies show an increased presence of anaerobes like Prevotella in HS lesions and a decreased presence of commensals such as Staphylococcus epidermidis. Gut microbiota dysbiosis, particularly involving Ruminococcus gnavus and Clostridium ramosum, is associated with HS. Moreover, metabolomic profiling indicates dysregulated tryptophan catabolism and lipid metabolism, with increased 5-lipoxygenase-derived metabolites and odd-chain fatty acids suggesting bacterial involvement. In summary, despite advances, robust associations between genetics, proteomics, microbiome, and metabolomics in HS are still lacking. Integrating these datasets could identify new clinical phenotypes, genetic predispositions, microbial signatures, and therapeutic targets, enhancing personalized treatment strategies and biomarker discovery for HS classification, prognosis, and treatment response.

Desert landscape features influencing the microgeographic genetic structure of Nelson's pocket mouse Chaetodipus nelsoni.

Elucidating the factors that drive the genetic patterns of natural populations is key in evolutionary biology, ecology and conservation. Hence, it is crucial to understand the role that environmental features play in species genetic diversity and structure. Landscape genetics measures functional connectivity and evaluates the effects of landscape composition, configuration, and heterogeneity on microevolutionary processes. Deserts constitute one of the world's most widespread biomes and exhibit a striking heterogeneity of microhabitats, yet few landscape genetics studies have been performed with rodents in deserts. We evaluated the relationship between landscape and functional connectivity, at a microgeographic scale, of the Nelson's pocket mouse Chaetodipus nelsoni in the Mapimí Biosphere Reserve (Chihuahuan desert). We used single-nucleotide polymorphisms and characterized the landscape based on on-site environmental data and from Landsat satellite images. We identified two distinct genetic clusters shaped by elevation, vegetation and soil. High elevation group showed higher connectivity in the elevated zones (1250-1350 m), with scarce vegetation and predominantly rocky soils; whereas that of Low elevation group was at <1200 m, with denser vegetation and sandy soils. These genetic patterns are likely associated with the species' locomotion type, feeding strategy and building of burrows. Interestingly, we also identified morphological differences, where hind foot size was significantly smaller in individuals from High elevation compared to Low elevation, suggesting the possibility of ecomorphs associated with habitat differences and potential local adaptation processes, which should be explored further. These findings improve our understanding of the genetics and ecology of C. nelsoni and other desert rodents.

A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins.

Prevalence of chondrocalcinosis and calcium pyrophosphate deposition disease in a cohort of adult patients with low alkaline phosphatase levels and a positive versus negative genetic ALPL study.

To estimate the prevalence of chondrocalcinosis and calcium pyrophosphate dihydrate deposition disease (CPPD) in patients with low alkaline phosphatase (ALP) levels and a positive ALPL genetic study (+GT) for hypophosphatasia (HPP) compared to those with the same biochemical abnormality and a negative genetic test (-GT). As a secondary objective, to analyze the biochemical factors associated with its presence in subjects with ALPL variants. Seventy-eight subjects with persistently low ALP levels and ALPL genetic test were included. Baseline and 24-mo knee ultrasounds were performed in 42 + GT and 36 -GT subjects, in whom the fibrocartilage, hyaline cartilage of menisci, tendons, and synovial fluid were scanned to detect calcium pyrophosphate deposits. A MyLabTwice ultrasound machine (Esaote) with a multifrequency linear array transducer (4-13MHz) was used. A higher percentage of chondrocalcinosis was observed in the +GT group [9/42 (21.4%)] compared to the -GT group [2/36 (5.6%), p=.045)]. Two patients (4.76%), both in the +GT group, had arthritis secondary to CPPD. No new cases were identified at the 24-mo control. When comparing +GT patients with and without chondrocalcinosis, ALP levels were lower, and pyridoxal-5'-phosphate (PLP) and phosphate levels were higher in the former group (p<.05). Logistic regression analysis revealed that higher PLP levels are associated with the presence of chondrocalcinosis (OR: 1.1; 95% confidence interval, CI, 1.001-1.012). Chondrocalcinosis was a frequent ultrasonographic finding in HPP. Arthritis secondary to calcium pyrophosphate deposits, however, proved less prevalent. Genetic causes, such as HPP, should be considered when evaluating patients with chondrocalcinosis in clinical practice.

Genetic associations of metabolic factors and therapeutic drug targets with polycystic ovary syndrome

IntroductionPolycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. ObjectivesTo comprehensively identify the metabolic causal factors and potential drug targets for PCOS. MethodsThis genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. ResultsThe PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65–4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17–2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07–1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09–1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47–0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. ConclusionThis study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA generates transcript isoforms by utilizing various polyadenylation sites (PASs) from the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.