LRRK2 in Focus: A Global Browser Linking Genetic Diversity to Functional Effects

From genes to pathways: genetic convergence in early-onset Parkinsons disease in India

mV2G: a multiomic atlas for tissue-specific variant-to-gene prioritization

The multiomic Variant-to-Gene (mV2G, https://mv2g.hbliulab.org) is a comprehensive atlas that integrates diverse functional genomic evidence to prioritize tissue-specific variant-to-gene (V2G) associations. While genome-wide association studies (GWAS) have identified millions of associations between genetic variants and diseases, translating these findings into biological mechanisms remains challenging because >90% of variants reside in noncoding regions. Existing V2G resources provide complementary regulatory evidence but are fragmented and often lack tissue-specific interpretation. To address this challenge, we constructed the mV2G atlas by integrating 24 types of functional genomic evidence across 50 human tissues, including molecular quantitative trait loci, enhancer–gene predictions, three-dimensional chromatin interactions, and experimental validation. The atlas contains 188,634,118 evidence-supported V2G pairs involving 13,618,039 variants and 69,521 genes. We further developed a unified tissue-specific V2G prioritization framework and prioritized 1,530,420 high-confidence functional V2G pairs involving 1,131,316 unique variants, with 87% exhibiting tissue-specificity. The mV2G atlas provides searchable variant- and gene-centered interfaces, an interactive browser for visualizing variants, target genes, cis-regulatory elements, and chromatin states, as well as downloadable datasets. By integrating complementary regulatory evidence into a unified framework, mV2G provides an accessible resource for interpreting the functional and phenotypic impact of genomic variation in relevant tissues for human diseases. GRAPHICAL ABSTRACT

GCH1 genetic variation as a prognostic factor in Parkinson disease across populations

Insights from GWAS, TWAS, and DEG analysis: CDKN2B-AS1, MAP3K4, and P2RX2-encoded P2X2 receptor identified as potential therapeutic targets for ischemic heart disease in Russian adults and long-living individuals

Background The purpose of this study was to investigate genetic risk factors associated with ischemic heart disease (IHD) in Russian adults, to develop prognostic PRS models for IHD risk stratification, and to gain a better understanding of molecular mechanisms underlying IHD through a transcriptome analysis. Materials and methods The study analyzed data from three independent cohorts: a population sample of 69,500 individuals, a cardiac sample of 5,875 IHD patients, and a sample of 2,870 long-living adults. To identify genomic loci associated with IHD, a GWAS was performed, and its findings were used to develop a PRS model for the IHD phenotype. Additionally, a transcriptome analysis was conducted. Results The GWAS for IHD adjusted for sex, age, and the first ten principal component accounting for population structure identified 75 variants, with 67 located at 9p21.3. Based on the GWAS findings, PRS models were developed and validated for IHD. The risk of IHD adjusted for sex, age, and BMI was the lowest in the sample of long-living adults. The TWAS revealed a significant association between IHD and increased CDKN2B expression in the aorta. According to the DEG results, the CDKN1A gene, a member of the same gene family as CDKN2B, was significantly hypoexpressed in the lower limb veins of patients with IHD. Conclusion PRS models offer great benefits for IHD risk prediction, particularly in individuals at the e tremes of the heritable risk distribution. lncRNAs, such as CDKN2BAS1 and lncRNA-MAP3K4, as well as P2X2 receptors, could be potential therapeutic targets for IHD.

The LRRK2 R1441G+M1646T haplotype is associated with slower motor symptom progression in Parkinson's disease

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy

This work provides a platform for extending genome engineering in induced pluripotent stem cells to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing the understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies.