Biology subjects

Eid, M.

Publications and source records attributed to Eid, M..

7 recordsLinked to original sources

bioRxiv2026

Genomic SEM reveals shared genetic architecture and expands locus discovery for locomotor activity in heterogeneous stock rats

Locomotor response to a novel environment is a heritable, addiction-relevant behavioral phenotype in rodents. We characterized its genetic basis in 9,341 male and female heterogeneous stock (HS) rats from eight studies. Locomotor activity was heritable across studies, while pairwise genetic correlations were positive but variable, indicating shared yet nonidentical genetic influences. Given nonuniform genetic architecture, we compared three complementary approaches to locus discovery that analyzed SNP effects 1) on a pooled locomotor phenotype (MEGA), 2) across studies under a fixed-effect model (METAL), or 3) on a shared genetic factor (Genomic SEM). To ensure comparability, all three locus-discovery approaches were applied to a common subset of seven studies. Together, these approaches identified 38 loci, with both convergence and method-specific discovery across analyses. Genomic SEM identified 31 loci, compared to 8 for MEGA and 13 for METAL. To interpret the loci, we integrated brain molecular QTLs, predicted coding and splice consequences, and open-field locomotor phenotypes from knockouts of orthologous mouse genes. Our results highlighted established neurobehavioral candidates spanning locomotor and reward-related biology (Negr1 and Lmo4), serotonergic signaling (Htr1b), and GABAergic signaling (Gabrg2), as well as relatively novel genes including Tcerg1l, Pcdh10, and Tmem132e. Our results illustrate how Genomic SEM can integrate genetically correlated yet heterogeneous behavioral measures and enable discovery of loci underlying their shared genetic architecture, highlighting its utility for complex-trait studies in rodents.

genetics↗

bioRxiv2026

Genome-wide association study in Heterogeneous Stock rats identifies genetic loci associated with aversion-based learning and cocaine aversion

Addiction is a complex and heritable trait which progresses through several developmental stages, each of which is presumably influenced by multiple partially overlapping genetic factors. Cocaine initially produces rewarding effects, followed by aversive effects including anxiety, craving, anhedonia, and withdrawal. These aversive effects have been suggested to contribute to the etiology of cocaine use disorders (CUD), as repeated exposure is thought to desensitize the rewarding effects and sensitize the aversive effects through a process involving both aberrant reward-based learning and aberrant avoidance-based learning. We examined the genetic basis of aversion learning using both food-based and cocaine-based behavioral assays in outbred Heterogenous Stock (HS) rats. A total of 1,074 HS rats (35.3% male) underwent runway operant cocaine-seeking, food-based progressive ratio and punishment testing, and locomotion testing. These phenotypes were significantly heritable (with h2 estimates as high as 0.307) and identified significant (p < 0.05) genetic loci related to avoidance-based learning including from the punishment task on Chromosomes 2, 3, 5, and 6, and the cocaine-operant runway latency task on Chromosome X. 172 positional candidate genes were identified from significant and suggestive loci, including Cdh10, Cdh12, Cdh18 which have previously been associated with smoking initiation from human GWAS, Adcy3, Cfap206, and Drc1 which are associated with primary neuronal cilia, as well as SNPs associated with novelty-related and social interaction phenotypes in independent samples of HS rats. Our results suggest that these aversion learning phenotypes are themselves complex heritable traits influenced by multiple genetic loci, which may pleiotropically affect other aspects of addiction biology.

genetics↗

bioRxiv2026

Integrated inference of cancer gene expression from cell-free plasma chromatin

Gene expression is a defining determinant of tumor identity, behavior, and therapeutic response, yet remains challenging to measure noninvasively. Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on [~]270,000 gene-sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on >15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred NECTIN4 expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.

genomics↗

bioRxiv2025

SNAP: Streamlined Nextflow Analysis Pipeline for Immunoprecipitation-Based Epigenomic Profiling of Circulating Chromatin

Epigenomic profiling of circulating chromatin is a powerful and minimally invasive approach for detecting and monitoring disease, but there are no bioinformatics pipelines tailored to the unique characteristics of cell-free chromatin. We present SNAP (Streamlined Nextflow Analysis Pipeline), a reproducible, scalable, and modular workflow specifically designed for immunoprecipitation-based methods for profiling cell-free chromatin. SNAP incorporates quality control metrics optimized for circulating chromatin, including enrichment score and fragment count thresholds, as well as direct estimation of circulating tumor DNA (ctDNA) content from fragment length distributions. It also includes SNP fingerprinting to enable sample identity verification. When applied to cfChIP-seq and cfMeDIP-seq data across multiple cancer types, SNAPs quality filters significantly improved classification performance while maintaining high data retention. Independent validation using plasma from patients with osteosarcoma confirmed the detection of tumor-associated epigenomic signatures that correlated with ctDNA levels and reflected disease biology. SNAPs modular architecture enables straightforward extension to additional cell-free immunoprecipitation-based assays, providing a robust framework to support studies of circulating chromatin broadly. SNAP is compatible with cloud and high-performance computing environments and is publicly available at https://github.com/prc992/SNAP/. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/694452v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@47c734org.highwire.dtl.DTLVardef@674af8org.highwire.dtl.DTLVardef@16ae938org.highwire.dtl.DTLVardef@1f57a01_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy.

genomics↗

bioRxiv2019

Multiple elements of addiction vulnerability are independently heritable in rats

BackgroundAlthough cocaine is powerfully rewarding, only a fraction of drug-exposed individuals actually transition to become drug-dependent users, possibly due in part to genetic influences, as addictions are among the most heritable of human neuropsychiatric disorders. Consistent with addiction being a complex disorder, prior studies have noted many factors that predict addiction vulnerability, such as drug-induced aversive effects, behavioral responses to novelty, and sensitivity to punishment.\n\nMethodsWe tested different inbred strains of rats, as well as selectively bred Sprague-Dawley (SD) or Heterogeneous Stock (HS) rats, on cocaine avoidance, sensitivity to punishment, and locomotor responses to novelty, and calculated heritability estimates of these behaviors. We tested animals on additional control tasks (progressive ratio, shock avoidance) to control for alternate interpretations of addiction-like behaviors.\n\nResultsConditioned avoidance to cocaine varied greatly between individual rats as measured using either the runway operant task or conditioned place aversion (CPA). Cocaine avoidance responded rapidly to selective breeding, yielding heritability estimates of 0.70 and 0.58 in SD and HS rats. Resistance to punishment was also highly heritable in inbred rats (estimated h2 = 0.62), and varied independently of cocaine avoidance despite both behaviors being mediated by the RMTg. Furthermore, cocaine avoidance correlated positively with cocaine-induced c-Fos induction in the RMTg, negatively with initial rates of acquisition of intravenous cocaine self-administration, and positively with both cued and cocaine-primed reinstatement.\n\nConclusionsCocaine avoidance and resistance to punishment are strongly and independently heritable behaviors that may both control different aspects of individual propensity to acquire and maintain drug-seeking.

neuroscience↗

bioRxiv2018

Generality and opponency of rostromedial tegmental (RMTg) roles in valence processing

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine (DA) neurons, has been hypothesized to encode aversive stimuli. However, this encoding pattern has only been demonstrated for a limited number of stimuli, and its influence on the ventral tegmental (VTA) responses to aversive stimuli is untested. Here, we found that RMTg neurons show average inhibitions to rewarding stimuli and excitations to aversive stimuli of greatly varying sensory modalities and timescales. Notably, negative valence-encoding neurons are particularly enriched in subpopulations projecting to the VTA versus other targets. Additionally, RMTg neurons also dynamically encode \"opponent\" changes in motivational states induced by removal of sustained stimuli. Finally, excitotoxic RMTg lesions impair conditioned place aversion to multiple aversive stimuli, and greatly reduce aversive stimulus-induced inhibitions in VTA neurons, particularly in putative DA-like neurons. Together, our findings indicate a broad RMTg role in encoding aversion and potentially driving DA responses and behavior.

neuroscience↗