Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

Nature Communications · 2026-01-12 · 2 citations

Idiopathic hypersomnia (IH) is a poorly understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia. Cross-species studies show that loss of the synaptic adhesion molecules beat-Ia/CADM2 causes excessive sleepiness by disrupting development of wake-promoting NPF/NPY brain circuits. Targeting NPY signaling may offer treatment for human hypersomnia.

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

Molecular Cell · 2026-01-01 · 4 citations

GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

Genome biology · 2025-10-03

BACKGROUND: Over 1100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. RESULTS: We execute a CRISPRi screen in human fetal osteoblasts (hFOBs) with single-cell RNA-seq read-out for 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci. The BMD relevance of hFOBs is supported by heritability enrichment from stratified LD-score regression involving 98 cell types grouped into 15 tissues. Twenty-three genes show perturbation in the screen, with four (ARID5B, CC2D1B, EIF4G2, and NCOA3) exhibiting consistent effects upon siRNA knockdown on three measures of osteoblast maturation and mineralization. Lastly, additional heritability enrichments, genetic correlations, and multi-trait fine-mapping unexpectedly reveal that many BMD GWAS signals are pleiotropic and likely mediate their effects via non-bone tissues. CONCLUSIONS: Our results provide a roadmap for how single-cell CRISPRi screens may be applied to the challenging task of resolving effector gene identities at all BMD GWAS loci. Extending our CRISPRi screening approach to other tissues could play a key role in fully elucidating the etiology of BMD.

Integrated genomic analysis and CRISPRi implicates EGFR in Alzheimer’s disease risk

npj Dementia · 2025-12-16

Abstract Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 41 candidate causal variant-effector gene pairs and assessed their impact using enhancer–promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD-related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.

Integration of Alzheimer’s GWAS, 3D genomics, and single-cell CRISPRi non-coding screen implicates causal variants in a microglial enhancer regulating <i>TSPAN14</i>

bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-01 · 2 citations

ABSTRACT While GWAS have been successful in providing variant-to-trait associations for human complex diseases, functional dissection of the discovered loci has lagged behind. Here, we describe a variant-to-gene (V2G) mapping effort for Alzheimer’s disease (AD) to implicate causal variants and effector genes from the most recent AD GWAS meta-analyses (101 loci). We leveraged our genomics datasets comprising high-resolution promoter Capture C, ATAC-seq, and RNA-seq from brain-relevant cell types to fine-map AD GWAS variants, identifying 89 candidate causal SNPs and 69 effector genes. We then designed a single-cell CRISPRi screen to perturb candidate regulatory regions (n=74) and assess the transcriptional response in the human microglial cell line, HMC3. Our screen across ∼97,000 cells identified 19 regulatory regions and 19 effector genes. We then elected to functionally dissect our top hit, the TSPAN14 locus, and we show that an intronic region containing AD-associated SNPs rs7080009, rs1870138, and rs1870137 is a microglia-specific enhancer, with the AD risk haplotype increasing its activity. CRISPR precise genomic deletion of this region decreases TSPAN14 expression, alters specific cellular pathways including cell adhesion, and decreases secreted levels of pro-inflammatory cytokines IL-6 and IL-8, which are known biomarkers of aging and AD. Our work provides a systematic framework to map GWAS signals to their effector genes for AD and other brain-related disorders, and provides robust leads to follow up with in-depth functional investigations.

Integrated genomic analysis and CRISPRi implicates <i>EGFR</i> in Alzheimer’s disease risk

medRxiv · 2025-06-26 · 1 citations

Abstract Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 42 candidate causal variant-effector gene pairs and assessed their impact using enhancer-promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.

The gSOS Polygenic Score is Associated with Bone Density and Fracture Risk in Childhood

medRxiv · 2025-04-23

Abstract The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N=1,727); and (2) children with genetic data for research at the Children’s Hospital of Philadelphia (CHOP; N=10,301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity and fracture accumulation (none or ≥1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal bone mineral density (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by dual energy X-ray absorptiometry and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). gSOS associated with higher aBMD Z-scores across 7 skeletal sites [e.g., a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher lumbar spine aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 12% and 16% reduced likelihood of self-reported fracture in the BMDCS (OR=0.84, 95% CI: 0.74, 0.95) and a recorded fracture in the CHOP EHR (OR=0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan. Lay summary In adults, the polygenic risk score gSOS associates with reduced fracture risk. This study evaluates the relationship of gSOS to bone density and fractures in two groups of children. We found that a 1 standard deviation increase in gSOS was associated with higher bone density at multiple skeletal sites. In our two groups of children, a 1 standard deviation increase in gSOS associated with reduced odds of fracture in children by 12% (95% CI: 0.82, 0.95) and 26% (95% CI: 0.74, 0.95). Having a higher gSOS may enhance bone accretion in early life, and protect against fracture across the lifespan.

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Genome biology · 2025-12-08 · 1 citations

Abstract Background Insight into the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but this alone does not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. Results Here, we generate 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrate this data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. The majority of variants implicated by these cis-regulatory architectures are trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, leading to enrichment of similar biological networks. While this suggests a high level of genetic diversity and complexity that converges at the level of target gene and cell type, some trait-specific pathways representing potential areas for disease-specific intervention were identified. We pharmacologically validate squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach and supported by prior eQTL data in multiple sclerosis and systemic lupus erythematosus, as a novel immunomodulatory drug target controlling T cell inflammatory cytokine production and aiding B cell antibody production in a human lymphoid organoid model. Conclusions These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types. Graphical Abstract

Mapping chromatin interactions at melanoma susceptibility loci uncovers distant cis-regulatory gene targets

The American Journal of Human Genetics · 2025-05-22 · 6 citations

The gSOS polygenic score is associated with bone density and fracture risk in childhood

Journal of Bone and Mineral Research · 2025-10-14 · 2 citations

The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N = 1727) and (2) children with genetic data for research at the Children's Hospital of Philadelphia (CHOP; N = 10 301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity, and fracture accumulation (none or ≥1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal BMD (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by DXA and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). Genetic quantitative ultrasound speed of sound associated with higher aBMD Z-scores across 7 skeletal sites [eg, a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher LS aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 24% reduced likelihood of self-reported fracture in the BMDCS (OR = 0.76, 95% CI: 0.66, 0.88) and a 12% reduced likelihood of a recorded fracture in the CHOP EHR (OR = 0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan.