Biology subjects

Whelan, C. D.

Publications and source records attributed to Whelan, C. D..

9 recordsLinked to original sources

bioRxiv2026

Atlas of Proteomic Technologies: an evidence-based framework for selecting and combining commercial proteomics platforms

High-throughput proteomics now spans several technologies that differ in biological breadth, precision, specificity, sensitivity, cost, and method(s) of quantification; however, investigators currently lack an evidence-based framework to select or combine platforms. Here, we present the Atlas of Proteomic Technologies (APT) - a curated resource that evaluates six commercial platforms across ten analytical dimensions using published head-to-head evidence, expert evaluation, and iterative peer review. APT hosts two decision tools: the Help Me Choose tool maps a study's primary aim(s), scale, sample matrix, and technical constraints to a calibrated, weight-adjustable platform ranking, and the Help Me Combine tool ranks complementary platform pairs by their net-new protein coverage and user-specified technical priorities. Both tools were tested exhaustively across all possible combinations and behave in a balanced, merit-based manner. APT is openly accessible at https://aptatlas.org, providing downloadable tool specifications, seeded analysis scripts, and complete protein coverage lists, ensuring every score and recommendation is inspectable and reproducible.

bioinformatics↗

bioRxiv2022

Influences of rare protein-coding genetic variants on the human plasma proteome in 50,829 UK Biobank participants

Combining human genomics with proteomics is becoming a powerful tool for drug discovery. Associations between genetic variants and protein levels can uncover disease mechanisms, clinical biomarkers, and candidate drug targets. To date, most population-level proteogenomic studies have focused on common alleles through genome-wide association studies (GWAS). Here, we studied the contribution of rare protein-coding variants to 1,472 plasma proteins abundances measured via the Olink Explore 1536 assay in 50,829 UK Biobank human exomes. Through a variant-level exome-wide association study (ExWAS), we identified 3,674 rare and significant protein quantitative trait loci (pQTLs), of which 76% were undetected in a prior GWAS performed on the same cohort, and we found that rare pQTLs are less likely to be random in their variant effect annotation. In gene-based collapsing analyses, we identified an additional 166 significant gene-protein pQTL signals that were undetected through single-variant analyses. Of the total 456 protein-truncating variant (PTV)-driven cis-pQTLs in the gene-based collapsing analysis, 99.3% were associated with decreased protein levels. We demonstrate how this resource can identify allelic series and propose biomarkers for several candidate therapeutic targets, including GRN, HSD17B13, NLRC4, and others. Finally, we introduce a new collapsing analysis framework that combines PTVs with missense cis-pQTLs that are associated with decreased protein abundance to bolster genetic discovery statistical power. Our results collectively highlight a considerable role for rare variation in plasma protein abundance and demonstrate the utility of plasma proteomics in gene discovery and unravelling mechanisms of action.

genomics↗

bioRxiv2021

Genetic map of regional sulcal morphology in the human brain

The human brain is a complex organ underlying many cognitive and physiological processes, affected by a wide range of diseases. Genetic associations with macroscopic brain structure are emerging, providing insights into genetic sources of brain variability and risk for functional impairments and disease. However, specific associations with measures of local brain folding, associated with both brain development and decline, remain under-explored. Here we carried out detailed large-scale genome-wide associations of regional brain cortical sulcal measures derived from magnetic resonance imaging data of 40,169 individuals in the UK Biobank. Combining both genotyping and whole-exome sequencing data ([~]12 million variants), we discovered 388 regional brain folding associations across 77 genetic loci at p<5x10-8, which replicated at p<0.05. We found genes in associated loci to be independently enriched for expression in the cerebral cortex, neuronal development processes and differential regulation in early brain development. We integrated coding associations and brain eQTLs to refine genes for various loci and demonstrated shared signal in the pleiotropic KCNK2 locus with a cortex-specific KCNK2 eQTL. Genetic correlations with neuropsychiatric conditions highlighted emerging patterns across distinct sulcal parameters and related phenotypes. We provide an interactive 3D visualisation of our summary associations, making complex association patterns easier to interpret, and emphasising the added resolution of regional brain analyses compared to global brain measures. Our results offer new insights into the genetic architecture underpinning brain folding and provide a resource to the wider scientific community for studies of pathways driving brain folding and their role in health and disease.

genomics↗

bioRxiv2020

Pairwise genetic interactions modulate lipid plasma levels and cellular uptake

Genetic interactions (GIs), the joint impact of different genes or variants on a phenotype, are foundational to the genetic architecture of complex traits. However, identifying GIs through human genetics is challenging since it necessitates very large population sizes, while findings from model systems not always translate to humans. Here, we combined exome-sequencing and genotyping in the UK Biobank with combinatorial RNA-interference (coRNAi) screening to systematically test for pairwise GIs between 30 lipid GWAS genes. Gene-based protein-truncating variant (PTV) burden analyses from 240,970 exomes revealed additive GIs for APOB with PCSK9 and LPL, respectively. Both, genetics and coRNAi identified additive GIs for 12 additional gene pairs. Overlapping non-additive GIs were detected only for TOMM40 at the APOE locus with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate both, plasma and cellular lipid levels via additive and non-additive effects and nominates drug target pairs for improved lipid-lowering combination therapies.

genetics↗

bioRxiv2020

The burden of rare protein-truncating genetic variants on human lifespan

Genetic predisposition is believed to contribute substantially to the age at which we die. Genome-wide association studies (GWAS) have implicated more than 20 genetic loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss-of-function. Through whole-exome sequencing of 238,239 UK Biobank participants, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified exome-wide (P<2.5e-6) significant associations between BRCA2, BRCA1, TET2, PPM1D, LDLR, EML2 and DEDD2 PTV-burden with human lifespan. Gene and gene-set PTV-burden phenome-wide association studies (PheWAS) further highlighted the roles of these genes in cancer and cardiovascular disease as relevant for overall survival. The overlap between PTV-burden and prior GWAS results was modest, underscoring the value of sequencing in well-powered cohorts to complement GWAS for identifying loci associated with complex traits and disease.

genetics↗

bioRxiv2020

Dynamics of Brain Structure and its Genetic Architecture over the Lifespan

Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.

genetics↗

bioRxiv2019

Hippocampal subfield volumes are uniquely affected in PTSD and depression: International analysis of 31 cohorts from the PGC-ENIGMA PTSD Working Group

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.\n\nMethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115; Mage=38.9{+/-}13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.\n\nResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail ({beta}=-0.13) and CA1 ({beta}=-0.09) after adjusting for covariates and multiple testing (adjusted ps (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 ({beta}=-0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls ({beta}=-0.12, q=0.012), C-PTSD-only ({beta}=-0.17, q=0.001), and Depression-only ({beta}=-0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.\n\nConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

neuroscience↗

bioRxiv2018

Smaller Hippocampal CA-1 Subfield Volume in Posttraumatic Stress Disorder

BackgroundSmaller hippocampal volume in patients with PTSD represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features.\n\nMethodsCase-control cross-sectional study of US military veterans (n=282) from the Iraq and Afghanistan era were grouped into PTSD (n=142) and trauma-exposed controls (n=140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3-Tesla. Segmentation with Free Surfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model.\n\nResultsSignificantly lower subfield volumes were associated with PTSD in left CA1 (p=.01; d=.21; uncorrected), CA3 (p=.04; d=.08; uncorrected), and right CA3 (p=.02; d=.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD [F4, 221=3.32, p = 0.07] is present and the other subfield findings are non-significant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD associated differences in global hippocampal shape were non-significant.\n\nConclusionsThe present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.

neuroscience↗

bioRxiv2017

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

Oscillations in neuronal activity are widely thought to play a crucial role in information processing and cortical communication 1-8. Brain oscillations have been widely investigated as biomarkers of psychiatric disorders and variation in normal human behavior 9, 10, including intelligence 11, 12, schizophrenia 13, 14, attentional deficits 15, 16, and substance use 17, 18. Beyond the biomarker, oscillatory activity may indeed cause variation in behavior, as it has been shown that disrupting oscillatory activity by blocking GABAergic fast-spiking interneurons in the frontal cortex of mice impairs behavioral flexibility8, consistent with ...

genetics↗