Biology subjects

Overton, J.

Publications and source records attributed to Overton, J..

5 recordsLinked to original sources

bioRxiv2025

Neuromodulation of risk preferences encoded in human orbitofrontal cortex activity

Human behavior presents a natural range of variation beyond which extreme behavior appears, often as a hallmark of psychiatric conditions. for example, risk preferences, which naturally range from risk-seeking to risk-averse, are characteristically affected in multiple pathologies, e.g. increased risk-taking in gambling disorders. Despite its basic and translational importance, how underlying brain activity reflects and determines behavioral variation is mostly unknown, in part due to the difficulty of directly examining neural activity in decision-relevant brain areas from cohorts of subjects with varying preferences. To address this, we combined human intracranial recordings (n=15 patients) from the orbitofrontal cortex (OFC), a key brain region in economic decision-making, with risky decision-making tasks and computational modeling. We observed significant behavioral variation in risk preferences, which was strongly correlated with low-frequency (delta-theta) oscillatory coherence in OFC. Low-frequency oscillatory phase was coupled to high-frequency activity amplitude, providing a potential neurophysiological mechanism for integrating preferences with trial-by-trial risk computations. Finally, targeted OFC electrical stimulation caused significantly decreased risk-taking behavior and faster reaction times without impairing overall decision-making. These results show a neural correlate for inter-individual variation in decision-making preferences and provide proof-of-principle evidence for modulation of risk-taking behavior through OFC-targeted neurostimulation, paving the way for developing neuromodulatory interventions for pathologies characterized by heightened risk-seeking, such as addiction and gambling disorders. Significance statementWe leverage invasive electrophysiological recordings from human orbitofrontal cortex to demonstrate that low-frequency oscillatory coherence reflects stable inter-individual economic preferences, with targeted neurostimulation causing risk averse behavior. These results provide a neurobiological substrate for interindividual differences in economic decision-making and provide a potential therapeutical avenue for brain disorders characterized by risky behavior.

neuroscience↗

bioRxiv2024

Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.

immunology↗

bioRxiv2023

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

bioRxiv2022

Genotyping, sequencing and analysis of 140,000 adults from the Mexico City Prospective Study

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacan and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native Mexican segments of the genome had lower levels of coding variation, but an excess of homozygous loss of function variants compared with segments of African and European origin. We estimated population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States where the Hispanic/Latino population is predominantly of Mexican descent.

genetics↗

bioRxiv2017

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Inflammatory bowel disease (IBD), clinically defined as Crohns disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents [≥]25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. To determine the role of NOD2 and other genes in pediatric IBD, we performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands who were homozygous or compound heterozygous for rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian recessive inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from the Regeneron Genetics Center (RGC)-Geisinger Health System DiscovEHR study, which links whole exome sequences to longitudinal electronic health records (EHRs) from 51,289 participants. We found that ~7% of cases in this adult IBD cohort, including ~10% of CD cases, can be attributed to recessive inheritance of NOD2 variants, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that 14% of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohns Disease.\n\nAuthor SummaryPediatric onset inflammatory bowel disease (IBD) represents [≥]25% of IBD diagnoses; yet the genetic architecture of early onset IBD remains largely uncharacterized. To investigate this, we performed whole-exome sequencing and rare variant analysis on a cohort of 1,183 pediatric onset IBD patients. We found that 8% of patients in our cohort were homozygous or compound heterozygous for rare or low frequency deleterious variants in the nucleotide binding and oligomerization domain containing 2 (NOD2) gene. Further investigation of whole-exome sequencing of a large clinical cohort of adult IBD patients uncovered recessive inheritance of rare and low frequency NOD2 variants in 7% of cases and that the relative risk for NOD2 variant homozygosity has likely been underestimated. While it has been reported that having >1 NOD2 risk alleles is associated with increased susceptibility to Crohns Disease (CD), our data formally demonstrate what has long been suspected: recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Our data suggest that a subset of IBD-CD patients with early disease onset is characterized by recessive inheritance of NOD2 alleles, which has important implications for the screening, diagnosis, and treatment of IBD.

genetics↗