Pedigree Analysis Research Articles

The role of patient-specific variables in protein corona formation and therapeutic efficacy in nanomedicine.

Despite their potential, the adoption of nanotechnology in therapeutics remains limited, with only around eighty nanomedicines approved in the past 30years. This disparity is partly due to the "one-size-fits-all" approach in medical design, which often overlooks patient-specific variables such as biological sex, genetic ancestry, disease state, environment, and age that influence nanoparticle behavior. Nanoparticles (NPs) must be transported through systemic, microenvironmental, and cellular barriers that vary across heterogeneous patient populations. Key patient-dependent properties impacting NP delivery include blood flow rates, body fat distribution, reproductive organ vascularization, hormone and protein levels, immune responses, and chromosomal differences. Understanding these variables is crucial for developing effective, patient-specific nanotechnologies. The formation of a protein corona around NPs upon exposure to biological fluids significantly alters NP properties, affecting biodistribution, pharmacokinetics, cytotoxicity, and organ targeting. The dynamics of the protein corona, such as time-dependent composition and formation of soft and hard coronas, depend on NP characteristics and patient-specific serum components. This review highlights the importance of understanding protein corona formation across different patient backgrounds and its implications for NP design, including sex, ancestry, age, environment, and disease state. By exploring these variables, we aim to advance the development of personalized nanomedicine, improving therapeutic efficacy and patient outcomes.

Accounting for heterogeneity due to environmental sources in meta-analysis of genome-wide association studies.

Meta-analysis of genome-wide association studies (GWAS) across diverse populations offers power gains to identify loci associated with complex traits and diseases. Often heterogeneity in effect sizes across populations will be correlated with genetic ancestry and environmental exposures (e.g. lifestyle factors). We present an environment-adjusted meta-regression model (env-MR-MEGA) to detect genetic associations by adjusting for and quantifying environmental and ancestral heterogeneity between populations. In simulations, env-MR-MEGA has similar or greater association power than MR-MEGA, with notable gains when the environmental factor has a greater correlation with the trait than ancestry. In our analysis of low-density lipoprotein cholesterol in ~19,000 individuals across twelve sex-stratified GWAS from Africa, adjusting for sex, BMI, and urban status, we identify additional heterogeneity beyond ancestral effects for seven variants. Env-MR-MEGA provides an approach to account for environmental effects using summary-level data, making it a useful tool for meta-analyses without the need to share individual-level data.

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3.

The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM. To interrogate the clinical traits and diseases associated with BAG3 coding variation. This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study. Carrier status for BAG3 coding variants. Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358). BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Abstract 4120763: Predicting Disease Risk Among Variants in Cardiomyopathy-Associated Genes Across Diverse Genetic Ancestries

Background: Many cases of cardiomyopathy (CM) are genetically inherited, and the expansion of broad genomic sequencing has opened the door for predicting those at risk for developing disease. However, genetic tools that help determine variant pathogenicity employ genetic data from predominantly European genetic ancestries. Understanding the full diversity of genetic variants in cardiomyopathy genes is central to identifying which variants will cause disease. Hypothesis: Participants of non-European genetic ancestry will have a higher burden of cardiomyopathy gene variants with "VUS" designation in ClinVar but will have equivalent/less penetrance of clinical cardiomyopathy compared to a European ancestry group. Methods: Participants in the AllofUs database with exome sequencing (ES) were queried and a cohort of 230,013 participants were retained after sample quality control filters. Participant genetic ancestry was based on the designated ancestry group determined via AllofUs as previously described (1). Participants were queried for variants in genes with definitive or moderate evidence of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in ClinGen. Variants were filtered by ClinVar status (1* and above P/LP, 1* and above B/LB, and VUS). Participant CM disease status was determined via ICD-9/10 code. Results: For each ancestry group, prevalence of cardiomyopathy ranged from 0.34% in the Latino/admixed American ancestry group to 1.09% in the African group, with an average prevalence of 0.91% across all groups. The European group had a statistically significant lower percentage of ClinVar VUS variants at 26%, while all other non-European ancestry groups had a combined VUS prevalence rate of 35% (****p<0.0001). The penetrance of CM in participants with CM VUS variants was lower in combined non-European ancestry groups (0.84%) than European ancestry (1.02%) (*p=0.0156). Conclusion: Prevalence of ClinVar VUS variants varies across different genetic ancestry groups, with European ancestry having a lower burden of VUS variants compared to non-European groups. However, non-European ancestry groups with increased burden of VUS variants have lower disease penetrance. Citations: (1) The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature 627 , 340–346 (2024). https://doi.org/10.1038/s41586-023-06957-x

Abstract 4139115: Genomic, Phenomic, and Geographic Relationships with Leukocyte Telomere Length in the U.S. Yields New Insights for Neoplasms and Cardiometabolic Disease

Background: Leukocyte telomere length (LTL) is an age-related marker strongly associated with neoplasms and cardiometabolic disease. LTL is also intimately linked with clonal hematopoiesis of indeterminate potential (CHIP), a recently described risk factor for cardiovascular disease (CVD). However, population-scale investigations of LTL in diverse backgrounds are limited, and geolocational variance has not been studied. Method: LTL and CHIP were derived using blood-derived whole genome sequencing data from 244,819 diverse U.S. residents in the NIH All of Us Research Program (AoU). We performed association analyses of LTL with CHIP and other available health-related traits, Phecode, as well as geolocation data by ZIP code. Genome-wide association study (GWAS) of LTL in AoU and meta-analysis with UK Biobank were performed. All association tests were adjusted for age, sex, sequencing site, and the first 10 genetic principal components with multiple test corrections. Mediation analysis was adjusted for additional risk factors for CVD. Result: Among 244,819 AoU participants, 146,717 (59.9%) were female with mean (standard deviation) age 51.8 (±16) years. Estimated LTL correlated strongly with age, sex, and genetic ancestry in AoU. Socioeconomic status, lifestyle variables, anthropometry, blood biomarkers (e.g., lipids and glucose), and vital signs were associated with LTL in AoU. Phecode analysis showed LTL is associated with neoplasms and age-related conditions, including CVDs. LTL mediated some of the observed increased coronary artery disease risk among individuals with hematologic malignancies ( P < 2 × 10 -16 ). Significantly longer LTL clustered in the West Coast and Central Midwest ( P = 0.001 and 0.033, respectively), while significantly shorter LTL clustered in the Southeast ( P = 0.001) (Figure). GWAS meta-analyses identified 197 loci, of which 36 (18%) were novel, including ancestry-specific loci. Rare variant aggregation test found 9 novel associated genes. Conclusions: LTL is a marker of biological age that is associated and interacts with neoplasms, CVDs, and its various risk factors, with notable geographic variability within the U.S. Germline genetic analyses of LTL yield new insights into drivers of LTL.

Abstract 4133122: Integrative Metabolomic Analysis of Triglyceride-Independent Lipoprotein Lipase Pathway Mechanisms for Coronary Artery Disease

Background: Strong genetic evidence supports the associations between key genes in triglyceride (TG) metabolism via the lipoprotein lipase (LPL) pathway (i.e., LPL , APOC3 , and ANGPTL3 ) and coronary artery disease (CAD). Given sparse human genetic or clinical trial evidence for other TG-modulating pathways, it is unclear if CAD risk reduction is due to reductions in TG levels alone or a secondary mechanism of action. Aim: To determine if there are TG-independent mechanisms of CAD risk reduction specific to the LPL pathway using genomics and metabolomics. Methods: We assessed the genetic effects of LPL pathway genes (67, 46, and 17 SNPs for LPL , APOC3 , and ANGPTL3 , respectively) and non-LPL pathway genes (3462 SNPs) for TG levels and 168 metabolites. We identified metabolites with associated effects that were greater than the associated effects with TG levels for LPL pathway genes and showed heterogeneity compared to the effects for non-LPL pathway genes. Cox proportional-hazards models were used to evaluate the association of candidate metabolites measured at baseline with incident CAD in participants of the UK Biobank. Models were adjusted for age, sex, TG levels, BMI, prevalent type 2 diabetes, statin, and ten PCs of genetic ancestry. Results: Among 233,719 UK Biobank participants free of prevalent CAD and with metabolite measurements, the mean (SD) age was 57.1 (8.0) years, 105,111 (45.0%) were male, and all self-reported as white. Over a median (IQR) follow-up of 11.2 (10.5-11.9) years, there were 7992 (3.4%) incident CAD cases. There were 30, 6, and 93 metabolites with significantly greater genetic effects for LPL , APOC3 , and ANGPTL3 than what was observed with TG levels, respectively. Among 20 metabolites with heterogeneity for ≥2 LPL pathway genes compared to non-LPL pathway genes, multi-variable Cox regression revealed 19 significantly associated with CAD (P<3x10 -4 ). Conclusion: LPL pathway genes have convergent and distinct impacts across metabolites. While LPL and ANGPTL3 have large genetic effects on VLDL metrics, APOC3 may have genetic effects beyond lipoprotein metabolism that impact CAD risk. The extent to which these metabolites influence CAD risk beyond TG alterations requires further study.

Invisible Treasures: Assessing Indonesia’s Unique Agrobiodiversity for Food and Nutrition Security

Indonesia is a biodiversity hotspot with high levels of endemism of globally important food crops and their crop wild relatives, as well as locally adapted cultivars. This rich diversity is essential to Indonesia’s food and nutrition security, while underpinning the livelihood strategies of small-scale farmers (both men and women) and traditional communities, who act as guardians of this genetic heritage. However, many of Indonesia’s plant genetic resources for food and agriculture are experiencing genetic erosion due to increased crop uniformity and the reduced use and demand for local varieties. Changes in food preferences and consumption patterns have driven the species into agricultural neglect with only some smallholder farmers cultivating the species for cultural reasons. These problems are exacerbated by land-use changes and climate variability. Recognizing the imperative to conserve agrobiodiversity in the region to ensure future food security and sustain livelihoods, the status of conservation and sustainable use of taro, yams, cloves and nutmeg in three target provinces in Indonesia was assessed. Mixed-method analyses were used to document existing conservation efforts and what is currently known of these target crops’ conservation status, both in ex situ collections and in the field, to identify unique biodiversity, as well as the barriers and knowledge gaps on how to better conserve and use this unique genetic diversity for future generations.

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.

Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10−8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

Genetic ancestry in Puerto Rican afro-descendants illustrates diverse histories of African diasporic populations.

Genetic studies of contemporary Puerto Ricans reflect a demographic history characterized by admixture between Indigenous American, African, and European peoples. While previous studies provide genetic perspectives on the general Puerto Rican population, less is known about the island's sub-populations, specifically Afro-Puerto Ricans. In this study, the genetic ancestry of Afro-Puerto Ricans is characterized and compared to other Caribbean populations. Thirty DNA samples collected among self-identified Puerto Ricans of African descent in Loíza (n = 2), Piñones (n = 13), San Juan (n = 2), Mayagüez (n = 9), and Ponce (n = 4), were genotyped at 750,000 loci on the National Geographic Genochip. We then applied unsupervised clustering and dimensionality-reduction methods to detect continental and subcontinental African and European genetic ancestry patterns. Admixture analyses reveal that on average, the largest genetic ancestry component for Afro-Puerto Ricans is African in origin, followed by European and Indigenous American genetic ancestry components. African biogeographic origins of Afro-Puerto Ricans align most closely with contemporary peoples of Lower Guinea and the Bight of Biafra, while the European genetic ancestry component is most similar to contemporary Iberian, Italian, and Basque populations. These findings contrast with the biogeographic origins of comparative Barbadian and Puerto Rican populations. Our results suggest that while there are similarities with regard to general patterns of genetic ancestry among African descendants in the Caribbean, there is previously unrecognized regional heterogeneity, including among Puerto Rican sub-populations. These results are also consistent with available historical sources, while providing depth absent from the documentary record, particularly with regard to African ancestry.

Spinocerebellar ataxia type 10 and Huntington disease-like 2 in Venezuela: Further evidence of two different ancestral founder effects.

The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub-Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease-like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub-Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela. In-phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded. The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus-specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case. Knowing the genetic ancestry and geographic origins of patients in Ibero-American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters.

Interplay between lifestyle factors and polygenic risk for incident coronary heart disease in a large multiethnic cohort

IntroductionThe objective of this study was to examine the interplay of polygenic risk and individual lifestyle factors (and a composite score of lifestyle) as antecedents of CHD in a large multiethnic cohort. MethodsWe used Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort participants free of CHD at baseline (n = 60,568; 67 % female; 18 % non-European). The individual and joint associations of smoking, Mediterranean diet pattern, level of physical activity and polygenic risk with incident CHD were assessed using Cox regression adjusting for genetic ancestry and non-mediating risk factors. Hazard ratios (HRs) and number needed to treat (NNT) were estimated according to these lifestyle factors and polygenic risk categories. Strengths included large sample size, long-follow-up, ethnic diversity, a clinically-validated polygenic risk score (PRS), and rich phenotype information. ResultsAfter 14 years of follow-up, there were 3159 incident CHD events. We observed no statistically significant interactions between individual lifestyle factors and polygenic risk (all p > 0.23). For individuals with a high genetic risk, moving from the worse lifestyle combination (no favorable lifestyle factors) to the best lifestyle combination (all three) is associated with 52 % lower rate of CHD. The NNT was highest in the low polygenic risk group (34), lowest in the high polygenic risk group [19] and in-between (Jin et al., 2011) [24] in the intermediate polygenic risk group. ConclusionsLifestyle and polygenic risk together influence the risk of incident CHD. Our results support consideration of polygenic risk in lifestyle interventions because those with high polygenic risk are likely to derive the most benefit.

Phenotypic homogenization and potential fitness constraints following non-native introgression in an endemic sportfish.

Introgressive hybridization may lead to contrasting evolutionary outcomes that are difficult to predict, since they depend on the fitness effects of endogenous genomic interactions and environmental factors. Conservation of endemic biodiversity may be more effective with require direct measurement of introgressed ancestry and fitness in wild populations, especially for keystone taxa at risk of hybridization following species introductions. We assessed the relationship of non-native ancestry with growth and body condition in the basin-restricted Neosho Bass (Micropterus velox; NB), focusing on two streams in the NB native range that are admixed extensively with non-native Smallmouth Bass (M. dolomieu; SMB). We quantified genetic composition of 116 fish from Big Sugar Creek (N=46) and Elk River (N=70) at 14 microsatellite loci. Using back-calculated total length-at-age estimated from sagittal otoliths, we assessed whether genetic ancestry explained variation in von Bertalanffy growth model parameters, accounting for sex and stream effects. We then assessed the relationship of ancestry and body condition. We found no differences in growth parameters by sex, stream, or ancestry, suggesting phenotypic homogenization which could be mediated by selection on body size. We found a negative correlation between SMB ancestry and condition, including lower condition in Big Sugar Creek, possibly reflecting a trade-off between maximum length and condition with respect to overall fitness. We show that ongoing non-native introgression, which may be augmented by anthropogenic SMB introductions, may attenuate evolutionary differentiation between species and directly influence fitness, possibly having critical implications for long-term persistence and management of adaptive potential in a popular and ecologically important endemic sportfish.

Genetic, Linguistic and Molecular Anthropological Study of the Indian Ocean Littoral in Austronesian Dispersal Across the Pacific

The Indian Ocean region is a critical route/corridor/barrier for the migration and settlement of people whose social, linguistic and genetic ancestry is of interest to anthropologists worldwide. Varying from the ‘little tradition’ of small isolated populations to the ‘great tradition’ of global and admixed heritage, in the field of collating evidences from culture, language and anthropological genetics this paper will examine the ‘Austronesian dispersal’ within the boundaries of the Indian ocean sporadically sprinkled across Pacific islanders.

New Approaches for Regeneration of an Outstanding Baroque Living Heritage, the Széchenyi Linden Allée in Hungary

Allées used to be the essential artistic tools and indispensable parts of the strictly architectural, formal Baroque gardens. Beyond the practical purposes of edging paths and garden ways for walking, hunting, or horse and carriage riding, allées played a vital role in marking visual and landscape connections and thus the spatial projection of the noble estate, its wealth, and social rank. In Historical Hungary, Baroque architecture and garden art appeared in German-Austrian and French examples in the 18th century. The Széchenyi Linden Allée is an outstanding linear garden space of Baroque Garden art at Nagycenk, West Hungary. The generous composition, created by the prominent Count Széchenyi family in the mid-18th century, has remained a magnificent entity in the landscape ever since. Despite barely two hundred years of detected or unknown environmental or habitat changes, as early as 1942, the allée received a nature conservation nomination. More than a half-century later, in 2002, the allée became a historical and landscape aesthetical heritage within the Fertő-Hanság Cultural Landscape World Heritage site. Unfortunately, the once magnificent tree lines have severely eroded in recent decades due to mature trees’ subsequent death, inadequate replacement, lack of regular maintenance and tree care, and effects of climate change. In recent years (2011, 2018), landscape and horticultural analyses and visual and instrumental tree assessments were performed to help the conservation and rebirth of the allée, maintain the mature trees, and restore the landscape within a long-term renewal plan. Along with the 2018 survey and plan, the short-term maintenance works were completed in 2019–2020. This study, based on site surveys in 2022 and 2024, aims to identify the results of the primary management, analyses the vitality of mature trees after crown reductions, and then proposes a resilient and sustainable regeneration method with the habitat, cultural, natural, and genetic heritage, and the feasible maintenance contexts in focus. As proposed in the 2018 plan, the reproduction of mature trees started in 2020 and resulted in well-developing grafts for a later allée restoration. Due to the challenges of climate change, the regeneration project requires a special, long-term restoration management plan with a special focus on the still vital and possible remaining mature trees, the well-growing individuals from previous replanting, and the nursery school seedlings conserving the genetic heritage of the Széchenyi lime trees with long-viability capacity.

Fahr's Syndrome with Pseudohypoparathyroidism: Oral Features and Genetic Insights.

Fahr's syndrome is a rare neurodegenerative disorder with limited research on its oral manifestations. This study investigates the dental features and genetic background of Fahr's syndrome through a pedigree analysis and a retrospective literature study. A clinical examination and whole-exome sequencing (WES) were conducted on a female patient with Fahr's syndrome and pseudohypoparathyroidism, along with her family members. The patient presented with super-numerary teeth, tooth agenesis, enamel hypoplasia, and abnormal tooth eruption. The WES did not reveal any known pathogenic mutations related to pseudohypoparathyroidism or Fahr's disease. However, genetic variations in KIF1A, FZD8, and PDGFA may underlie these dental abnormalities. Additionally, a retrospective analysis of 22 reported cases from PubMed and the Human Gene Mutation Database (1 January 1965-30 June 2024) was conducted with keywords such as "Fahr's disease", "Fahr's syndrome", "dental", and "hypoparathyroidism". The analysis showed that patients with Fahr's syndrome, pseudohypoparathyroidism, and idiopathic hypoparathyroidism exhibited similar oral abnormalities, including tooth agenesis, root dysplasia, dental malformations, and abnormal tooth eruption. Variations in the incidence of tooth agenesis and dental malformation among these groups may be linked to differences in parathyroid hormone metabolism. These findings suggest oral abnormalities are the key local features of Fahr's syndrome and related parathyroid disorders.

Characterization of Y chromosome diversity in newfoundland and labrador: evidence for a structured founding population.

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700s-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL-based cohort were analyzed using 5,761 Y-specific SNPs. We identified 160 distinct terminal haplogroups, the majority of which (71.4%) belong to the R1b haplogroup. When compared with global reference populations, the NL population haplogroup composition and frequencies primarily resemble those observed in English and Irish ancestral source populations. There is also evidence of genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers who frequented NL. Interestingly, the observed population structure shows geographical and religious clustering that can be associated with the settlement of the ancestral source populations from predominantly Protestant, England, and Catholic, Ireland respectively. For example, the R1b-M222 haplogroup, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplogroups in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation, and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.

Coronary artery disease polygenic risk score in patients undergoing coronary angiography and risk of future revascularization

Abstract Background Coronary artery disease (CAD) polygenic risk score (PRS) is a strong predictor of incident CAD. The role of CAD PRS in patients with known or suspected CAD already presenting for invasive coronary angiography remains poorly understood. Purpose We aimed to (i) study the association between CAD PRS and coronary angiography traits, and (ii) determine whether CAD PRS can predict risk of future revascularization after an initial coronary angiogram. Methods Patients who underwent coronary angiography at a single hospital and were part of its biobank were included in the study. Participants were classified into 3 risk groups based on CAD PRS distribution–low (0-20%), intermediate (21-80%), and high (81-100%)–computed from a recently reported PRS comprised of 1,296,172 variants (GPSMult, PGS003725). Revascularization was defined as a composite of coronary artery bypass graft and percutaneous coronary intervention with a 3-month blocking window after the initial angiogram. Associations between coronary stenosis severity and burden, and CAD PRS were assessed using multinomial logistic regression adjusted for age, sex, and genetic ancestry. The cumulative incidence of revascularization was tested using Fine-Gray regression accounting for competing risk of all-cause mortality and compared across CAD PRS strata by log-rank test. Results Among 3,518 participants (29.90% female, mean age 63.29±12.14 years), 2,568 (73%) had angiographic evidence of CAD – 340 (13.24%) mild, 346 (13.47%) moderate, and 1,882 (73.29%) severe. Out of those with CAD, 844 (32.87%) presented with acute coronary syndromes (ACS) and 1,724 (67.13%) with stable CAD. CAD PRS was strongly associated with angiographic presence of CAD (OR 2.62, 95%CI 2.08-3.29) and this did not differ among patients presenting with ACS vs. stable CAD (Fig1A). The association was weakest for mild CAD (OR 1.14, 95%CI 0.77-1.68) and strongest for severe CAD (OR 3.04, 95%CI 2.40-3.84). Besides severity, CAD PRS was also strongly associated with angiographic burden of CAD with the strongest association observed for presence of left main coronary stenosis (OR 2.63, 95%CI 1.86-3.73). Each standard deviation increase in CAD PRS was associated with a 10-point increase in the Gensini score, a continuous measure of angiographic burden of CAD (p&amp;lt;2e-16) (Fig1B). Over a mean follow-up period of 9.26±5.81 years, 659 (18.73%) patients required revascularization at a mean period of 5.31±4.69 years. Risk of revascularization varied dramatically by CAD PRS; HR was 1.64 (95%CI 1.28-2.10, p=8.7e-5) for high vs. low CAD PRS (Fig2). CAD PRS remained predictive of future revascularization even after adjusting for the angiographic burden of CAD at baseline (HR 1.41, 95%CI 1.09-1.82, p=7.9e-3). Conclusion CAD PRS is strongly associated with severity and burden of CAD assessed on coronary angiography and is predictive of future risk of revascularization even after accounting for baseline disease burden.Figure 1.CAD PRS and angiographic traitsFigure 2.CAD PRS and revascularization

Obesity-dependent selection of driver mutations in cancer

Obesity is a risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. We examined the relationship between obesity and tumor genotype in two clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma and cancers of unknown primaries, independent of clinical covariates, demographic factors and genetic ancestry. Obesity is therefore a driver of etiological heterogeneity in some cancers.

Genetic Diversity and Forensic Utility of X-STR Loci in Punjabi and Kashmiri Populations: Insights into Population Structure and Ancestry

Background: X-chromosomal short tandem repeats (X-STRs) are crucial in forensic applications, particularly in complex kinship cases, and play an important role in population genetics. However, there is limited data on X-STR variation in Pakistani populations, especially among ethnic groups like Kashmiri and Punjabi. Methodology: This study investigates the forensic and genetic properties of 12 X-STRs from the Investigator Argus X-12 Kit (QIAGEN, Hilden, Germany) in 125 families (75 Kashmiri, 50 Punjabi) from Azad Jammu and Kashmir and Punjab, Pakistan. Results: In both populations, a total of 222 alleles were identified across the 12 X-STR loci (Punjabi 171 alleles, Kashmiri 161 alleles), with allele frequencies ranging from 0.0056 to 0.3033. DXS10148 was the most polymorphic locus with 28 alleles, while DXS7132 was the least polymorphic with 9 alleles. Most loci were in linkage equilibrium, except for the DXS10135/DXS10148 pair in males, with no loci exhibiting significant linkage disequilibrium in females. The combined power of discrimination was 0.999 999 9977 for Kashmiri males, 0.999 999 999 999 9746 for Kashmiri females, and 0.999 999 999 999 9781 for Punjabi females. In Kashmiri males, 34, 31, 28, and 32 haplotypes were observed across the four linkage groups (LG1, LG2, LG3, and LG4), though these groups did not form stable haplotypes, as indicated by Linkage Equilibrium within and significant Linkage Disequilibrium between groups. Conclusions: Genetic structure analysis using Principal Component Analysis and STRUCTURE revealed distinct clustering patterns for the Kashmiri and Punjabi populations, indicating unique genetic backgrounds and ancestry influences, particularly distinguishing them from East Asian populations. This study provides a comprehensive analysis of X-STR variation in Punjabi and Kashmiri populations, offering valuable insights for forensic and population genetic studies.