Biology subjects

Pell, J.

Publications and source records attributed to Pell, J..

8 recordsLinked to original sources

bioRxiv2025

A T-cell Intrinsic Role for APOL1 Risk Alleles in Allograft Rejection

African Americans have an increased risk of kidney disease due to exonic variants in Apolipoprotein-L1 (G1 and G2). These prevalent variants have also been linked with kidney rejection, but outside of association with African ancestry, underpinning causal mechanisms are unknown. We investigated T-cell function using transgenic mice with physiologic expression of wild type (G0-), G1-, or G2-APOL1. Mice with variant APOL1 showed greater CD8+T-cell activation with expansion of a central memory (TCM) subset. Stimulated G1-CD8+T-cells showed enhanced proliferation and cytokine production, which reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1-mice demonstrated greater CD8+T-cell infiltration and reduced survival. Bulk transcriptome of G1-CD8+T-cells, and single-cell transcriptome of graft infiltrating TCMs, showed enrichment of canonical T-cell receptor (TCR) pathways including Ca2+-signaling. G1-CD8+T-cells demonstrated baseline ER-Ca2+ depletion followed by sustained increases in cytosolic-Ca2+ upon TCR stimulation. G1-CD8+T-cells were more sensitive to Ca2+ chelation, or store-operated Ca2+ entry inhibition, and relatively resistant to calcineurin antagonism vs. G0-CD8+T-cells. Analogously, in a kidney transplant cohort, APOL1-variant recipients developed rejection when they had elevated peripheral TCMs before transplantation and despite significantly higher tacrolimus levels vs G0/G0-AAs with rejection. In summary, we unravel an excitatory T-cell intrinsic mechanism for APOL1 exonic variants, causally linking them with kidney rejection.

immunology↗

bioRxiv2022

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 locus mismatches associated with long-term renal transplant survival

BackgroundLong-term kidney allograft survival remains suboptimal. Emerging evidence indicates donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLA) contribute to graft survival but mechanisms remain unclear, specifically for those mismatches within intronic regions. MethodsWe analyzed genome-wide SNP data of D-R pairs from two well-phenotyped kidney transplant cohorts (median follow-up ~1800 days), Genomics of Chronic Allograft Rejection (GoCAR; n=385) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17; n=146), quantifying genetic mismatches outside of HLA for every D-R pair at variant, gene, and genome-wide scales. ResultsUnbiased genome-wide screen of GoCAR D-R pairs uncovered the LIMS1 locus as the topranked candidate where D-R mismatches associated with death censored graft loss (DCGL). Independent of HLA, a previously unreported relationship between mismatches at a highly linked, intronic haplotype of 30 SNPs was seen as associated with DCGL, with confirmatory association in intra-ancestry D-Rs. Validation testing within the CTOT-01/17 showed similar associations with DCGL. Haplotype D-R mismatches showed a dosage effect, and the introduction of minor alleles in the donor to major allele-carrying recipients showed a greater risk of DCGL. Both the new LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) for the gene GCC2 in recipient immune cells, without alterations in GCC2 or LIMS1 coding sequences. Transcriptome enrichment analyses performed on whole blood and within multiple T cell subsets demonstrated significant associations of GCC2 gene, and of either allelic locus, with regulation of TGF-beta-SMAD signaling, implying a role in Treg function and association with rejection. ConclusionsOur analysis unravels intronic non-HLA SNP mismatches within LIMS1 that do not induce protein sequence variation but associate with DCGL. By acting as cis-eQTLs for GCC2 expression, these SNPs modulates TGF-beta signaling and T cell function, associating with immune events and graft outcomes. The findings have clinical implications for risk assessment and individualized therapy in kidney transplant recipients.

genetics↗

bioRxiv2022

A Genome-Wide Association Analysis of Happiness: Consistent Genetic Effects Across the Lifespan and Across Genetic Ancestries in Multiple Cohorts.

We present a genome-wide association study of a general happiness measure in 118,851 participants from the UK Biobank. Using BOLT-LMM, we identify 3 significant loci with a heritability estimate of 0.8%. Linkage disequilibrium score regression was performed on the big five personality traits finding significant associations with lower neuroticism and higher extraversion and conscientiousness. Using a novel approach, we construct LDpred-inf polygenic risk scores in the Adolescent Brain Cognitive Development (ABCD) cohort and the Add Health cohort. We detected nominally significant associations with several well-being measures in ABCD and significant correlations with a happiness measure in Add Health. Additionally, we tested for associations with several brain regions in a white British subsample of UK Biobank finding significant associations with several brain structure and integrity phenotypes. We demonstrated a genetic basis for general happiness level and brain structure that appears to remain consistent throughout the lifespan and across multiple ancestral backgrounds. Author summaryAt the genetic level, there has been little investigation into whether people may have a baseline happiness level which varies from person to person. Here we perform a genetic analysis in the UK Biobank to identify three genetic loci that associate with general happiness level and preform genetic correlations of our results with the Big Five personality traits, identifying significant correlations with neuroticism, conscientiousness and extraversion. We use the resulting summary statistics to create LDpred-inf polygenic risk scores in UK biobank identifying several brain metrics and regions associate with genetic loading for general happiness level. We also use a novel method to create LDpred-inf polygenic risk scores in two other cohorts, ABCD and Add Health. We found significant correlations with an independent happiness measure in Add Health and nominally significant correlations with several well-being measures in ABCD in both those of European Ancestry and all other ancestries found in these cohorts. We also attempted to replicate our UK Biobank MRi finding in ABCD. We conclude there is evidence that individuals have a general happiness level that is in part genetic which spans across age and ancestry.

genetics↗

bioRxiv2022

Comparative evaluation of glomerular morphometric techniques reveals differential technical artefacts between FSGS and normal glomeruli

Morphometric estimates of mean glomerular volume (MGV) have clinical implications, over and above histologic data. However, MGV estimation is time-consuming, could waste tissue sections and requires expertise limiting its utility in retrospective clinical studies. MethodsWe evaluated MGV using both plastic and paraffin-embedded tissue from control and FSGS mice (n=10 each) using the gold-standard Disector/Cavalieri technique (Vglom-Cav) and other reported techniques [2- or 3-profile technique, Weibel-Gomez method (W-G)]. Within Vglom-Cav we examined the precision of MGV estimation while using MGVs obtained from 5- or 10-individual glomeruli measurements vs the true mean (20 glomeruli). ResultsIn both FSGS and controls, we identified an acceptable precision of 10-glomerular sampling vs true MGV within Vglom-Cav technique [88 (79-94) % of MGV obtained were within 10% of the true MGV]. The 5-glomerular sampling was less precise [70 (56, 81) % of MGV obtained were within 10% of true MGV]. In plastic based techniques, 2- or 3-profile MGVs showed greater concordance with Vglom-Cav, than W-G MGV. The new 3-profile technique offered incremental benefit to the existing 2-profile method (improved Lins concordance in control and FSGS animals). We observed a consistent reduction of Vglom values within control animals (52+/-0.06%) in paraffin-embedded tissue (vs corresponding methods in plastic) demonstrating a clear shrinkage artefact due to tissue processing. FSGS glomeruli showed significantly less and more variable shrinkage artefact likely due to glomerular fibrosis. ConclusionWe report the precision of 5- or 10-glomerular sampling for MGV estimation using controls and FSGS animals. We demonstrate and quantify the shrinkage bias in MGV during tissue processing for paraffin-embedding that also differentiated control animals and FSGS. Our findings have implications for experimental studies using glomerular morphometry.

pathology↗

bioRxiv2019

Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits.

ObjectivesAtherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultra-sound measurement of the carotid artery intima-media thickness (cIMT) can be used to measure vascular remodelling, which is indicative of atherosclerosis. Genome-wide association studies have identified a number of genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here we conducted genome-wide association analyses in UK Biobank (N=22,179), the largest single study with consistent cIMT measurements.\n\nApproach and resultsWe used BOLT-LMM to run linear regression of cIMT in UK Biobank, adjusted for age, sex, genotyping platform and population structure. In white British participants, we identified 4 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a female-specific locus on Chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body-mass index and glucometabolic traits were also observed.\n\nConclusionThese findings replicate previously reported associations, highlight novel biology and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

genetics↗

bioRxiv2018

PCSK9 genetic variants, life-long lowering of LDL-cholesterol and cognition: a large-scale Mendelian randomization study

AimsPCSK9 inhibitors lower LDL cholesterol and are efficacious at reducing risk of vascular disease, however questions remain about potential adverse effects on cognitive function. We examined the association of LDL cholesterol-lowering genetic variants in PCSK9 with continuous measures of cognitive ability\n\nMethods and ResultsSix independent SNPs in PCSK9 were used in up to 337,348 individuals from the UK Biobank who underwent measures of cognitive ability (fluid reasoning, reaction time, trial making test and digit symbol coding. Scaled to a 50mg/dL lower LDL cholesterol, the PCSK9 allele score was associated with a lower risk of CHD (odds ratio 0.73; 95% CI: 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nominally associated with worse log reaction time (0.04 standard deviations; 95%CI: 0.00, 0.08; P=0.038). Although no strong associations of the PCSK9 allele score were identified with any cognitive trait, the imprecision around the estimates meant that we could not exclude a similar magnitude of effect of genetic inhibition of PCSK9 to that seen with established risk factors, including APOEe4 or smoking status for any of the individual cognition traits. Point estimates for the PCSK9 allele score and cognition traits were all on the harmful side of unity.\n\nConclusionsUsing currently available data in UK Biobank, we are not able to rule out meaningful associations of PCSK9 genetic variants with cognition traits. These data highlight the need for further large-scale genetic analyses and, in parallel, continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

epidemiology↗

bioRxiv2017

Genome-Wide Analysis Of 113,968 Individuals In UK Biobank Identifies Four Loci Associated With Mood Instability.

Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria (RDoC) approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently-associated loci (on chromosomes eight, nine, 14 and 18), and a common single nucleotide polymorphism (SNP)-based heritability estimate of approximately 8%. We found a strong genetic correlation between mood instability and MDD (rg=0.60, SE=0.07, p=8.95 x 10-17) and a small but significant genetic correlation with both schizophrenia (rg=0.11, SE=0.04, p=0.01) and anxiety disorders (rg=0.28, SE=0.14, p=0.04), although no genetic correlation with BD, ADHD or PTSD. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF), and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

neuroscience↗

bioRxiv2016

Cannabis use and risk of schizophrenia:a Mendelian randomization study

Cannabis use is observationally associated with an increased risk of schizophrenia, however whether the relationship is causal is not known. To determine the nature of the association between cannabis use on risk of schizophrenia using Mendelian randomization (MR) analysis, we used ten genetic variants previously identified to associate with cannabis use in 32,330 individuals. Genetic variants were used in a MR analyses of the association of genetically determined cannabis on risk of schizophrenia in 34,241 cases and 45,604 controls from predominantly European descent. Estimates from MR were compared to a metaanalysis of observational studies reporting effect estimates for ever use of cannabis and risk of schizophrenia or related disorders. Genetically determined use of cannabis was associated with increased risk of schizophrenia (OR of schizophrenia for users vs. non-users of cannabis: 1.37; 95%CI, 1.09 to 1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.50 (95% CI, 1.10 to 2.00; P-value for heterogeneity = 0.88). The genetic instrument did not show evidence of pleiotropy on MR-Egger (Egger test, P-value=0.292) nor on multivariable MR accounting for tobacco exposure (OR of schizophrenia for users vs. nonusers of cannabis, adjusted for ever vs. never smoker: 1.41; 95% CI, 1.09-1.83). Furthermore, the causal estimate remained robust to sensitivity analyses. These findings strongly support a causal association between genetically determined use of cannabis and risk of schizophrenia. Such robust evidence may inform public health message about the risks of cannabis use, especially regarding its potential mental health consequences.

epidemiology↗