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PubMed2026

Mapping Focal and Generalized Effects of Common Genetic Variants on Human Brain Structure.

Genome-wide association studies (GWAS) have advanced the quest to understand how specific genetic variants influence human brain structure and function. Recent work has identified hundreds of common variants associated with subcortical brain volumes, sparking interest in how these genetic markers overlap across brain networks. While this can be estimated by hierarchical clustering of the genetic correlation matrix to identify modular patterns of shared architecture, no brain-wide maps of these effects are available. To address this, we computed polygenic scores (PGS) from loci associated with ten brain volume regions of interest (ROIs): nine major subcortical structures and intracranial volume, with each locus weighted by its association with regional volume. In an independent sample from the discovery GWAS, we performed large-scale segmentation of 3D volumetric T1-weighted MRI scans using voxel-based morphometry (VBM) to map 3D profile of regions where gray matter volume (GMV) was associated with each PGS. We found statistically significant, localized effects for PGS defined for the amygdala, thalamus, and basal ganglia, but PGS for brainstem volume was associated with widespread differences throughout the brain. These brain-wide maps reveal patterns consistent with both localized and distributed genetic influences, offering a novel approach to interpret the genomic architecture of brain structure.

GWAS↗

PubMed2026

Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.

BACKGROUND: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease. METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods. RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error. CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.

Humans↗

PubMed2025

Genetic influence on choroidal vascularity index.

PURPOSE: To investigate the heritability of genetic influence on macular choroidal vascularity index (CVI). METHODS: Total choroidal area (TCA), luminal area (LA), and CVI was measured using horizontal scan of spectral-domain optical coherence tomography with enhanced depth imaging in the 373 healthy twin participants. Characteristics of the participants were investigated, including age, sex, axial length, hypertension, diabetes, drinking habits, and smoking status. Univariate and subsequent multivariate regression analyses were performed to evaluate the associations of these factors with TCA, LA, and CVI. RESULTS: Patients who were older and had a higher intraocular pressure, higher diastolic blood pressure, and lower pulse pressure showed associations with lower CVI (p<0.001, p = 0.014, p = 0.005, and p = 0.015, respectively). The covariate-adjusted heritability (±standard error) of the CVI was 0.716 ± 0.091, and the heritabilities of the TCA and LA were 0.691 ± 0.089 and 0.634 ± 0.100, respectively. CONCLUSION: The TCA, LA, and CVI are highly heritable.

Humans↗

PubMed2026

Spatial Proteomics of the Normal Breast Collagen Stroma: Links to Density and Body Mass Index.

Collagen breast stroma can become a breast cancer risk factor, yet proteomic regulation of normal breast stroma remains poorly defined. This study evaluates the spatial regulation of the collagen proteome from normal breast tissue. Normal breast tissue sections from the Susan G. Komen tissue bank were used (n = 40), with data including genetic ancestry (n = 20 African ancestry; n = 20 European ancestry), body-mass-index (BMI), age, and mammogram density by the Breast Imaging Reporting and Data System (BI-RADS). 10-plex cell marker staining showed CD44 and COL1A1 markers modulated with BMI. Collagen fiber widths by second harmonic generation microscopy contrasted in BMI categories by genetic ancestry. Targeted extracellular matrix proteomics mass spectrometry imaging showed the collagen alpha-1(I) chain proteome was spatially heterogeneous across the normal breast microenvironment with site-specific post-translational modification of proline hydroxylation. Signatures computationally extracted from stroma-rich regions reported that 47 collagen peptides distinguished BI-RADS categories (area under the receiver operating curve >0.7; p-value >0.05). Multivariate modeling of collagen peptides, fiber metrics, and clinical features supported a strong positive association with BMI as a determinant of collagen alterations in the normal breast. This study provides a foundation for larger studies investigating the clinical value of spatial collagen proteome alterations in human breast.

Humans↗

PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗

PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗

PubMed2026

Clinical Characteristics and Outcomes of Patients With Biventricular and Left-Dominant Arrhythmogenic Cardiomyopathy With Ring-Like Late Gadolinium Enhancement Pattern.

BACKGROUND: The ring-like pattern of late gadolinium enhancement (RL-LGE) on cardiac magnetic resonance (CMR) has been proposed as a distinctive imaging marker of arrhythmogenic cardiomyopathy (ACM) with left ventricular (LV) involvement. However, the clinical characteristics and prognostic significance remain to be further clarified. OBJECTIVES: This study sought to assess the clinical profile, genetic background, and prognostic significance of RL-LGE in ACM with LV involvement. METHODS: In this observational cohort study, we included consecutive patients with a diagnosis of biventricular or left-dominant ACM (BIV-ACM or LD-ACM). RL-LGE was defined as subepicardial or midmyocardial LGE involving ≥3 contiguous LV segments on the same short-axis slice. The primary endpoint was a composite of sudden cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter-defibrillator (ICD) interventions. RESULTS: Among 149 patients (mean age 36 ± 12 years, 66% male), RL-LGE was identified in 73 (49%), most frequently in association with DSP variants, with a higher prevalence in BIV-ACM (70%) than in LD-ACM (30%). Over a median follow-up of 31 months, 24 patients experienced the primary endpoint, 67% of whom had RL-LGE. In multivariable Cox regression, RL-LGE emerged as an independent predictor of the primary endpoint (HR: 2.47; 95% CI: 1.10-6.02; P = 0.042), along with nonsustained ventricular tachycardia (HR: 2.62; 95% CI: 1.17-6.41; P = 0.033), whereas genetic status did not provide additional prognostic information. Incorporating RL-LGE into the arrhythmogenic right ventricular cardiomyopathy risk model significantly improved its predictive performance (likelihood ratio test: P = 0.006). CONCLUSIONS: RL-LGE independently predicts arrhythmic events in ACM, regardless of genotype status, and refines the prognostic performance of traditional risk models. Its detection may aid in early recognition of high-risk patients and inform primary-prevention ICD therapy.

Adult↗

PubMed2020

Chemical Imaging of Retinal Pigment Epithelium in Frozen Sections of Zebrafish Larvae Using ToF-SIMS.

Variants of the SLC24A5 gene, which encodes a putative potassium-dependent sodium-calcium exchanger (NCKX5) that most likely resides in the melanosome or its precursor, affect pigmentation in both humans and zebrafish (Danio rerio). This finding suggests that genetic variations influencing human skin pigmentation alter melanosome biogenesis via ionic changes. Gaining an understanding of how changes in the ionic environment of organelles impact melanosome morphogenesis and pigmentation will require a spatially resolved way to characterize the chemical environment of melanosomes in pigmented tissue such as retinal pigment epithelium (RPE). The imaging mass spectrometry technique most suited for this type of cell and tissue analysis is time-of-flight secondary ion mass spectrometry (ToF-SIMS) because it is able to detect many biochemical species with high sensitivity and with submicron spatial resolution. Here, we describe chemical imaging of the RPE in frozen-hydrated sections of larval zebrafish using cryo-ToF-SIMS. To facilitate the data interpretation, positive and negative polarity ToF-SIMS image data were transformed into a single hyperspectral data set and analyzed using principal component analysis. The combination of a novel protocol and the use of multivariate data analysis allowed us to discover new marker ions that are attributable to leucodopachrome, a metabolite specific to the biosynthesis of eumelanin. The described methodology may be adapted for the investigation of other classes of molecules in frozen tissues from zebrafish and other organisms.

Animals↗

PubMed2026

Toward precision prognosis: Predicting recurrence-free survival in high-grade serous ovarian cancer patients using multi-time point clinical and computed tomography radiomics data.

OBJECTIVE: To evaluate the predictive value of clinical, genomic, and radiomics features in estimating recurrence-free survival (RFS) in patients with high-grade serous ovarian carcinoma (HGSOC) treated with neoadjuvant chemotherapy (NACT). METHODS: This single-center, retrospective study included 91 patients with HGSOC who underwent treatment with NACT followed by surgery, and who had portal venous phase contrast enhanced CT imaging at baseline and after NACT. First-order texture features based on 2D segmentation were extracted from baseline and post-NACT CT images for selected disease sites using commercially available texture software. Multivariate Cox models assessed the prognostic significance of features at baseline, after NACT, and post-surgery time points, and model performance in predicting RFS was evaluated using C-statistics. RESULTS: A model including only baseline clinical data had C-statistic 0.53, while a model including both clinical and radiomics features at baseline had C-statistic 0.63. After NACT, a model including all baseline data plus the change in radiomics features between baseline and post-NACT had C-statistic 0.63. Post-surgery, a model including all baseline data plus surgical outcome had C-statistic 0.69. Incorporating changes in radiomic features between time points did not measurably enhance model performance in the post-surgery data set (C-statistic 0.7). Age, residual disease at surgery, and kurtosis were individually associated with shorter RFS. CONCLUSIONS: Radiomic features extracted from CT imaging may offer additive prognostic value for predicting RFS in HGSOC when integrated with clinical and genetic data. Our results support the potential integration of radiomic analysis with clinical data to improve outcome prediction in HGSOC.

Humans↗

PubMed2026

Shared genetic basis and structure of syndromic and normal facial variation.

The question of how gene mutations of large effect and common variants of small effect relate to phenotypic variation dates from the origins of genetics. Mendelian diseases result from rare germline variants with major effects, while complex traits are associated with multiple, mostly common variants of small effect. High-dimensional phenotypes, such as facial shape, can shed new light on this age-old dichotomy, as their variation can be characterized in terms of directions in multivariate morphospace. Within such spaces, do Mendelian disease mutations move phenotypes along the same directions as common variants, or do they forge new directions that diverge from the common structure of background variation? Here, we analyze facial shape variation for 66 syndromes, quantify multivariate axes of facial shape variation for each syndrome, and test whether common genetic variants in cohorts of non-syndromic subjects are associated with phenotypic position along these same axes. We find that syndromic facial shape generally follows the background variance-covariance structure of facial shape in the general population. Furthermore, syndromic probands' unaffected relatives have subtle facial morphology resembling the syndromes of their affected relatives. These results suggest that Mendelian disease variants act on facial shape in ways similar to common variants. Syndromic probands with higher "severity" likely occur on genetic backgrounds with higher cumulative severity of common variants for each syndromic axis. These findings position Mendelian diseases at extremes along phenotypic continua that exist in the background population rather than as qualitatively different phenotypes distinct from the overall structure of normal human phenotypic variation.

Humans↗

PubMed2026

Physical Activity and Cardiovascular Outcomes in Phenotype-Negative Cardiomyopathy Variant Carriers.

IMPORTANCE: Exercise may lead to disease progression and higher risk of sudden death in individuals with genetic cardiomyopathies, but the effects of exercise among individuals carrying a cardiomyopathy-associated variant without clinical manifestations (G+P-) are unclear. OBJECTIVE: To examine whether the effects of moderate to vigorous physical activity (MVPA) on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and malignant ventricular arrhythmias (VAs) vary by G+P- status. DESIGN, SETTING, AND PARTICIPANTS: UK Biobank participants with whole-genome sequencing providing 1 week of accelerometer-based physical activity data and without prevalent heart failure (HF), atrial fibrillation (AF), cardiomyopathy, VAs, or implantable cardioverter-defibrillators were included in this cohort study. The study was conducted at 22 assessment centers throughout the UK from February 2013 to December 2015 with a median follow-up of 8 years. Data were analyzed from March 2024 to June 2025. EXPOSURE: Accelerometer-measured MVPA (minutes/week). MAIN OUTCOMES AND MEASURES: Associations were analyzed between MVPA volume and future incidence of adverse CV outcomes (AF, HF, myocardial infarction [MI], and stroke), cardiac magnetic resonance (CMR)-based measures of cardiac remodeling, and surrogates for clinical cardiomyopathy onset (cardiomyopathy and VA). Associations were compared between G+P- carriers and noncarriers. RESULTS: Among 84 699 individuals (mean [SD] age, 62 [8] years; 48 353 [57%] women; 3979 G+P- carriers), greater MVPA was associated with a lower risk of adverse CV outcomes over a median (IQR) 8.0 (7.5-8.5) years, irrespective of genotype. In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in G+P- carriers (hazard ratio [HR] at optimal MVPA level vs zero [95% CI], AF: 0.68 [0.58-0.79]; HF: 0.58 [0.47-0.71]; MI: 0.49, [0.24-1.00]; stroke: 0.35 [0.12-0.99]). For G+P- carriers, MVPA in the range of 100 to 400 minutes per week was generally associated with lowest risk. Among individuals with CMR imaging, MVPA was associated with a similar pattern and extent of cardiac remodeling (eg, left ventricular dilation and left ventricular hypertrophy) in G+P- carriers vs noncarriers. Among G+P- carriers, higher MVPA was associated with lower risk of incident cardiomyopathy (HR at optimal MVPA vs 0, 0.03; 95% CI, 0.00-0.98) with no increase in risk of VA (eg, HR at 400 minutes of MVPA vs 0, 0.98; 95% CI, 0.83-1.14). Findings were generally consistent across variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy, although precision of estimates for arrhythmogenic right ventricular cardiomyopathy were limited. CONCLUSIONS AND RELEVANCE: In this cohort study, MVPA within the general range of guideline-based recommendations was associated with lower risk of adverse CV outcomes and similar degrees of cardiac remodeling for G+P- carriers compared to noncarriers. Findings support the appropriateness of guideline-based MVPA recommendations for G+P- carriers.

Humans↗

PubMed2025

Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers.

OBJECTIVE: Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities. METHODS: Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression. RESULTS: We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18-1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52-2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10-8) but not RA. There were no statistically significant associations among Black/African American participants. CONCLUSIONS: RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.

Humans↗