Bipolar disorder (BD) is among the most heritable psychiatric disorders, with a genetic architecture likely consisting of both common genetic variants with small effects and rare variants with strong effects in certain families or populations. Genome-wide association studies (GWAS) with increasingly large sample sizes have identified many susceptibility genes, but common variants in these genes do not have a clear pathophysiological pathway to BD. Genetic linkage studies have the potential to identify rare causal variants in certain families. We sought to determine the chromosomal regions linked with BD in a specific family that has many members affected by the lithium-responsive subtype of BD. We performed genome-wide genetic linkage analysis of a family identified through a lithium-responsive BD index patient with many relatives also affected with lithium-responsive BD-related mood disorders: three with BD I, four with BD II, and one with a major depressive episode. WGS (whole genome sequence) data were obtained for 12 members of the lithium-responsive BD pedigree including the eight affected subjects. Both parametric and nonparametric linkage analyses with the narrow BD phenotype and the broader phenotype including all eight with mood disorders provided evidence of linkage to the same region of chromosome 19. The maximum nonparametric linkage score was 3.89 for the broad phenotype, which exceeds typical thresholds for genome-wide significance. We identified a region of chromosome 19 that has not previously been linked to BD. Nor have significant GWAS variants been found in this region. It is possible that this family has different genetic origins for lithium-responsive BD than other patients studied previously. The family we analyzed is part of a larger cohort of BD patients and their family members, and genetic linkage analysis of additional families could be informative. These results provide a starting point for investigating genes in this chromosomal region that may be involved in the pathophysiology of the lithium-responsive subtype of BD.

Polygenic and spatial insights into the genetic uniqueness of essential tremor using common variants.

Genetic variation at the MECOM locus shaping human disease pathogenesis.

Development of a quantitative real-time PCR-based newborn screening system for citrin deficiency using dried blood spots.

Early enzyme replacement therapy in late-onset Pompe disease diagnosed by newborn screening.

Progressive gait and motor deficits in a rat model of Alexander disease.

Canine agility is a physically demanding sport that carries an inherent risk of injury. The weave pole obstacle is a mandatory component in agility courses under UK Kennel Club regulations, requiring a complex forward and lateral side-to-side gait that is not typically replicated outside the sport. This study aimed to evaluate key kinetic parameters-peak force (PF), peak vertical force (PVF), vertical impulse (VI) and stance time (ST)-experienced by forelimbs and hindlimbs during weave pole performance, and to assess differences across the three most common forelimb gait variations: front-feet single-stepping rear double (FFSS/RD), double-stepping (FFDS) and hopping (FFH). Seventeen experienced agility dogs completed a set of six competition-standard weave poles (FFSS/RD, n = 8; FFDS, n = 4; FFH, n = 5). Data were collected using two pressure-sensing walkways and statistically analysed. Outer limbs, in general, have shown significantly higher PVF, PV, VI and ST (p<0.001 for all variables on both forelimbs and hindlimbs). Peak vertical force was significantly greater in the outer forelimbs and outer hindlimbs of FFH dogs compared to FFDS and FFSS/RD (p<0.001 and 0.021, respectively, for forelimbs; p = 0.014 and 0.003, respectively, for hindlimbs). Stance time and VI were higher on the outer forelimb on FFSS/RD (the only forelimb used in this style) in comparison with FFH (ST: p = 0.003; VI: p = 0.024) and FFDS (ST: p = 0.041; VI: p = 0.032). Overall, there is a clear asymmetry in outer and inner limbs in all styles, which is consistent to the expected on turns. All gaits have shown a trend on redistribution of load towards the outer hindlimb, which was more extreme on FFSS/RD. Stance time was generally lower, and PVF and PF were higher in the FFH group. These factors raise questions regarding the long-term implications of weave pole performance in dogs exhibiting this gait.

Digenic and multigenic heterozygous FHL genotypes are common but clinically silent in the general population.

The Global Parkinson's Genetics Program (GP2) is an international initiative funded by Aligning Science Across Parkinson's (ASAP), in partnership with the Michael J Fox Foundation for Parkinson's Research (MJFF), to accelerate genetic discovery and improve ancestral representation in Parkinson's disease (PD) and related diseases through collaboration, open data sharing, and research capacity building. Since its launch in 2020, GP2 has assembled the largest and most ancestrally diverse PD dataset to date, integrating genotyping, sequencing, and harmonized clinical data from over 240 cohorts worldwide. Through its structured monogenic and complex disease networks, the program spans rare and common variant discovery to advance understanding of PD genetics. Recent GP2-supported studies have identified more than 50 novel genetic risk factors for PD, including a remarkably common GBA1 risk variant among people of African ancestry, and have confirmed new candidate causal genes such as RAB32. Ongoing efforts include whole-genome burden testing, multiple ancestrally-diverse genome-wide association studies (GWAS), polygenic risk modeling, and expansion into atypical Parkinsonism and prodromal cohorts. Beyond discovery, GP2 has invested extensively in research infrastructure and training, supporting more than 270 early-career investigators through workshops, hackathons, and a trainee-to-trainer mentorship framework. These initiatives build local capacity and empower researchers, particularly in underrepresented regions, to lead future genetic studies. GP2 provides an equitable, collaborative model for accelerating the field's understanding of the genetics of PD and related disorders. Continued expansion will enhance population diversity, refine mechanistic insights, better delineate disease onset and progression, and advance progress toward precision medicine across the Parkinsonian spectrum.

Epilepsy affects ~1% of the global population and often requires lifelong antiseizure medication (ASM) therapy. Valproic acid (VPA) is a commonly prescribed first-line ASM, yet only approximately half of patients achieve sustained seizure freedom. Treatment selection remains largely empirical. We aimed to develop and independently validate a multimodal predictive model to estimate response to VPA and support more individualized treatment strategies. This cross-sectional treatment response modeling study used data from a subset of the international Epi25 cohort (Belgium, Finland, Germany). Individuals with epilepsy were included if they had received VPA monotherapy and had available genetic or clinical data. Discovery data (1965-2021, 58% female) were split into a training set (n = 196) and test set (n = 133). Independent validation was performed in a Canadian cohort (2021-2022, n = 156, 40% female). The primary outcome was binary VPA response. Responders achieved ≥12 months of seizure freedom attributed to VPA; nonresponders had >50% seizure recurrence or discontinued VPA due to inefficacy, adverse effects, or unclear reasons. The predictive algorithm integrated features derived from common and rare variants in VPA pharmacokinetic and pharmacodynamic genes, invitro neuronal VPA response measures, and clinical features. Model performance was assessed using accuracy, predictive values (negative predictive value [NPV]/positive predictive value [PPV]), and area under the curve (AUC). In the independent validation cohort, the multimodal classifier achieved a balanced accuracy of 63% (95% confidence interval [CI] = 52%-73%), NPV of 70% (95% CI = 51%-85%), PPV of 60% (95% CI = 46%-72%), and AUC of .73 (95% CI = .63-.83). Models restricted to single or dual data modalities showed consistently lower predictive performance. This proof-of-concept study demonstrates that integrating genetic, cellular, and clinical data enables prediction of VPA treatment response with clinically meaningful accuracy. Although not yet ready for clinical application, this approach supports the feasibility of biomarker-informed ASM selection and may ultimately reduce time to effective seizure control.

Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV-trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.

Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering LMNA variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and LMNA variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in LMNA exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic SCN10A enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic LMNA variant, supporting a broader mechanism in which rare LMNA variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.

Recent studies have demonstrated that vitamin D (VD) influences gut microbiota (GM) by regulating epithelial barrier function and immune responses, thereby affecting microbial composition and diversity. Additionally, host genetic factors, particularly single-nucleotide variants (SNVs) in genes related to VD metabolism, may influence GM composition. Postmenopausal women are a particularly relevant population to assess the impact of these SNVs, as this group experiences reduced hormonal variability and a higher burden of vitamin D deficiency (VDD), enabling clearer evaluation of the association between vitamin D-related genetic variants and gut microbiota composition. To explore the relationship between SNVs in genes involved in VD metabolism and their impact on GM. We genotyped nine variants: rs10741657 (CYP2R1), rs6013897 (CYP24A1), rs10877012 (CYP27B1), rs10783219 and rs4516035 (VDR), rs4588 and rs7041 (GC), rs4944957 and rs3794060 (NADSYN1). GM was characterized by sequencing the V4 hypervariable region of the 16S rRNA gene. We compared taxon abundance at the genus level across host genotypes using the dominant model. Quantile regression was used to analyze non-mean diversity responses, and PICRUSt2 identified functional pathways. We also calculated the genetic risk score (GRS) using rs4516035, rs3794060, and rs4944957, which were associated with lower alpha diversity. Alpha microbial diversity differed significantly for the VDR (rs4516035) and NADSYN1 (rs3794060, rs4944957) variants, both for risk alleles and genotypes. Differential abundance analysis identified taxonomic disparities, notably in the genera DTU014, Fusobacterium, Negativibacillus, Pseudomonas, Peptococcus, and [Clostridium]_innocuum_group. PICRUSt2-predicted functional pathways for the rs4516035- C allele revealed significant glutamine-glutamate, folate, galactose, and fatty acid metabolism. A GRS was associated with lower alpha diversity indices and differences in the insulin signaling pathway and oxidative phosphorylation. These findings highlight the role of SNVs in GM modulation and suggest potential implications for VD metabolism and host health.

Thalassemia, a genetically inherited hemoglobinopathy, represents a significant global health challenge with profound socioeconomic implications, particularly in endemic regions. The emergence of third-generation sequencing (TGS) technologies has revolutionized thalassemia research and diagnostic paradigms, offering unprecedented capabilities for comprehensive genetic characterization. Between 2021 and 2024, we conducted a comprehensive analysis of 536 clinically suspected thalassemia cases from southern China, conventional diagnostic methods and Nanopore TGS were performed simultaneously. Among the 536 subjects analyzed, TGS identified 332 cases harboring either common or rare variants, which included 160 cases with rare thalassemia variants, 50 cases with abnormal hemoglobin variants, and 122 cases carrying common α- or β-thalassemia mutations. --THAI and HKαα emerging as the most prevalent variants among rare thalassemia, followed by Chinese (Aγδβ)0 and α-Fusion gene. The predominant abnormal hemoglobin was Hb New York (HBB:c.341 T > A). We used TGS and discovered three rare variants that have not been identified by conventional diagnostic methods for thalassemia, the variants included two cases of α-globin chain 32.8 kb deletions and one case of β-globin chain 3.5 kb deletion. Hb G-Ferrara (HBB:c.174 C > A) and Hb Ethiopia (HBA2:c.421 T > C) were firstly identified in the Chinese population. Moreover, two novel α-globin variants: NC_000016.10:g.176260-176930del and HBA1:c.386 T > C were discovered in this study. This study expands the genetic landscape of hemoglobinopathies in Southern China by characterizing a comprehensive spectrum of rare variants. Our findings demonstrate the superior diagnostic capability of TGS in identifying rare thalassemia genotypes, suggesting its potential as a first-line molecular diagnostic tool for comprehensive hemoglobinopathy screening.

ABSTRACTStudies have shown that substance use liability is associated with novelty seeking, anxiety‐like behavior, and pain sensitivity. We examined whether common genetic variation in outbred Sprague–Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single‐nucleotide polymorphism heritability and performed genome‐wide association analyses using permutation‐derived significance thresholds (N = 534–654 rats across traits). Heritability estimates ranged from 0.14 to 0.38 across 11 traits. Three independent loci were identified: chromosome 1 for elevated plus maze open‐arm behavior (α = 0.05), chromosome 14 for elevated plus maze immobility (α = 0.10), and chromosome 17 for tail flick latency (α = 0.05). Candidate genes included Slc18a2, Gfra1, and Pdzd8 (chromosome 1); Rel and Bcl11a (chromosome 14); and Eci2 and Eci3 (chromosome 17). We compared these loci with our genome‐wide association study of a F2 intercross of selectively bred high‐ and low‐responder rats, originally derived from Sprague–Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high‐ and low‐responder F2s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction‐relevant behaviors.

ABSTRACT DAOA gene has been implicated in both schizophrenia (SZ) and bipolar disorder (BD), where genetic variants were associated with each disorder individually. However, the common variants shared between SZ and BD within this gene remain underexplored. The current study investigates locus‐specific genetic variants with a focus on DAOA . A total of 120 BD and 200 SZ patients, along with equal numbers of age‐ and sex‐matched controls from the Pakistani population, were included for genotyping, risk association analysis, haplotype, genotype‐phenotype analysis, and clinical correlations. The DAOA SNP rs2391191 (G/A) showed a nominal association with both SZ and BD. In contrast, rs1935062 showed no association with either disorder, but genotype‐phenotype analysis indicated nominal associations with disorder‐specific clinical features, such as insomnia and disorganized thoughts in BD, and restricted mood and feelings of threat in SZ patients. Our findings suggest locus‐specific associations for SZ and BD at the DAOA locus; however, due to the limited sample size, these findings should be considered exploratory and require further validation in larger cohorts. Further, patterns of allele frequencies and effect sizes diverge from several European studies and global reports, highlighting the population‐specific genetic architecture and allelic heterogeneity.

Mycophenolate mofetil (MMF) is widely used in lupus nephritis (LN), but interindividual variability in pharmacokinetics and pharmacogenetics may affect treatment response. This study investigated the relationship between MMF pharmacokinetics, key genetic polymorphisms, and therapeutic response in Egyptian female LN patients. In this prospective study, 53 female patients with active LN (ISN/RPS class III-IV) maintained on 2g/day MMF were enrolled at the Urology and Nephrology Center, Mansoura University, Egypt. Baseline clinical, laboratory, and histopathological data were collected. Serial blood samples were obtained over 8h for mycophenolic acid (MPA) quantification by LC/MS. Genomic DNA was extracted for UGT2B7 (rs7438135) and SLCO1B1 (rs183624077) genotyping using TaqMan real-time PCR assays. Treatment response was classified as complete or partial remission versus non-response at 6 months. Population pharmacokinetics were analyzed using Monolix 2020R1. Considerable variability in MPA exposure was observed (mean AUC₀-₈: 22.4 ± 12.9µg·h/mL; mean Cmax: 12.9 ± 5.5µg/mL). Responders exhibited higher median AUC₀-₈ than non-responders (23.1 vs. 16.2µg·h/mL; p = 0.039). SLCO1B1 and UGT2B7 genotypes did not differ significantly between responders and non-responders, though TT carriers showed lower MPA AUC₀-₈. Multivariate analysis identified biopsy class (III vs. IV), induction therapy with MMF, and higher MPA AUC₀-₈ as independent predictors of response. MMF exposure, biopsy class, and induction regimen significantly influence therapeutic response in LN. Pharmacokinetic monitoring of MPA may help optimize MMF therapy, while common UGT2B7 and SLCO1B1 variants showed limited predictive value in this cohort.

RUNX1 is a commonly mutated transcriptional regulator of hematopoiesis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mutated RUNX1 (mRUNX1) may associate with cross-lineage immunophenotypic aberrancy, presenting potential complications for blast lineage assignment at diagnosis. Clinical and laboratory data were reviewed for patients with RUNX1 mutations (N = 125) at Vancouver General Hospital from 2016 to 2022. Diagnostic flow cytometry data were reanalyzed, and RUNX1 mutation characteristics and associations with pathologic, comutation, and flow cytometric features were assessed. Missense RUNX1 mutations (overall 42.9% missense, 57.1% truncating) were enriched in the runt homology domain (RHD; 81.7%, Adj. p = 0.011). Several recurrent hotspot mutations were seen, including common hotspot variants. The most commonly comutated genes with RUNX1 in both acute leukemia with mRUNX1 and MDS-mRUNX1 were ASXL1 (44.4%; 59.3%), SRSF2 (40.7%; 37.3%), and TET2 (35.8%; 55.9%). The mRUNX1 group demonstrated frequent positivity for B-lymphoid markers, with 14.4% having increased expression in at least three B-lineage markers. Differences in antigen expression were associated with RUNX1 mutation type and location, with increased CD10 expression associated with RUNX1 mutations in the RHD (Adj. p = 0.02764), and increased CD79a expression associated with RUNX1 missense mutations (Adj. p = 0.004452). In our cohort, we observed missense variants clustering in the RHD and recurrence of common pathogenic variants. Higher-risk comutations were found in a substantial fraction of mRUNX1 cases which may contribute to its adverse risk associations. Comparable degrees of aberrancy in B-lineage markers were seen in mRUNX1 patients versus the comparator cohorts of MPAL-wtRUNX1 and AML with rearranged RUNX1.

Burden of heterozygote carriers for autosomal recessive conditions in the Middle East: A study of 14,392 genomes.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common X-linked enzymopathy, is highly prevalent in North Africa and impairs antioxidant defense by reducing NADPH production. Its relationship with diabetes mellitus (DM) remains unclear. To assess G6PD enzymatic activity, determine the prevalence of G6PD deficiency, and identify common G6PD gene variants in Tunisian patients with type 1 (T1D) and type 2 diabetes mellitus (T2D). This case-control study included 45 T1D and 46 T2D patients, each matched by age and sex to healthy non-diabetic controls (n = 45 and n = 46, respectively). Complete blood count, reticulocyte count, HbA1c, and G6PD activity were measured. Deficiency was defined as <4U/g Hb in males and <5.84U/g Hb in females. ARMS-PCR screened deficient patients for the African Gd A⁻(202A) and Mediterranean B⁻(563T) variants. G6PD activity (mean ± SD) did not differ significantly between T1D patients and controls (9.29 ± 2.18 vs. 9.07 ± 1.77 U/g Hb; p = 0.8523). T2D patients had significantly lower activity (5.90 ± 1.40 vs. 7.23 ± 2.16 U/g Hb; p = 0.0024), with a deficiency prevalence of 18.33 % (95 % CI: 9.52-30.44) versus 9.43 % (95 % CI: 3.13-20.66) in controls (p = 0.032, McNemar's test). G6PD activity showed a significant inverse correlation with fasting blood glucose (beta = -0.0058, SE = 0.0016, p = 0.001) and HbA1c (beta = -0.289, SE = 0.062, p < 0.001) in the T2D group. This suggests that poorer glycemic control is associated with reduced enzymatic antioxidant capacity, particularly when HbA1c exceeds a threshold of 8.4 %. Of 11 deficient patients, four heterozygous T2D females (30.36 %) carried the African GdA⁻ variant; no Mediterranean B⁻ variants were found. T2D is associated with reduced G6PD activity and higher deficiency prevalence in Tunisia, especially in poorly controlled patients. The predominance of the African Gd A⁻ variant highlights the need for population-specific screening to prevent oxidative stress-related complications and guide personalized diabetes care.