Biology subjects

Perry, J. R. B.

Publications and source records attributed to Perry, J. R. B..

11 recordsLinked to original sources

bioRxiv2024

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated. MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

genomics↗

bioRxiv2024

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

The nuclear receptor Liver X Receptor- (LXR) activates lipogenic gene expression in hepatocytes. Its inhibition has therefore been proposed as a strategy to treat metabolic-dysfunction-associated steatotic liver disease (MASLD). In order to understand the impact of reducing LXR activity on human health we first examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXR) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXR in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXR, carriers of damaging mutations in LXR had reduced serum triglycerides ({beta}=-0.13 s.d. {+/-}0.03, P=2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated concentrations of serum liver enzymes (e.g. ALT: {beta}=0.17s.d. {+/-}0.03, P=1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P=1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Homozygous knock-in mice rapidly developed severe hepatitis and fibrotic liver injury following exposure to western diet despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was completely rescued by viral over-expression of wildtype LXR specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXR knockout mice showed some evidence of hepatocyte injury under similar dietary conditions, the phenotype of the LXRW441R/W441R mouse was much more severe, suggesting that dominant negative mutations that actively co-repress target genes can result in pathological impacts significantly more severe than those seen with simple absence of the receptor. In summary, our results show that loss of function mutations in LXR occur in at least 1/450 people and are associated with evidence of liver dysfunction. These findings implicate LXR in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.

genetics↗

bioRxiv2023

Profiling human hypothalamic neurons reveals a candidate combination drug therapy for weight loss

Obesity substantially increases the risk of type 2 diabetes, cardiovascular disease, and other diseases, making it a leading preventable cause of death in developed countries. It has a strong genetic basis, with obesity-associated genetic variants preferentially acting in the brain. This includes the hypothalamic pro-opiomelanocortin (POMC) neurons that inhibit food intake and are stimulated by drugs that agonise glucagon-like 1 peptide receptor (GLP1R) including Semaglutide (Ozempic/Wegovy). We therefore hypothesised that drugs which selectively activate human POMC neurons would suppress appetite and promote weight loss, and that focusing on drugs already approved for use would facilitate rapid clinical translation. We therefore generated POMC neurons from human pluripotent stem cells (hPSCs) and identified enriched genes that were genetically associated with obesity and targeted by approved drugs. We found that human POMC neurons are enriched in GLP1R, reliably activated by Semaglutide, and their responses are further increased by co-administration of Ceritinib, an FDA-approved drug potently and selectively inhibiting anaplastic lymphoma kinase (ALK). Ceritinib reduced food intake and body weight in obese but not lean mice, and upregulated the expression of GLP1R in the mouse hypothalamus and hPSC-derived human hypothalamic neurons. These studies reveal a new potential therapeutic strategy for reducing food intake and body weight, and demonstrate the utility of hPSC-derived hypothalamic neurons for drug discovery.

neuroscience↗

bioRxiv2023

Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis

Adipogenesis is a multi-stage process essential for healthy fat storage and metabolic regulation. While early regulatory mechanisms are well characterized, the control of late-stage adipocyte differentiation remains poorly understood. Integrating CAGE-seq, promoter capture Hi-C, and a high-throughput siRNA screen of druggable genes, we report here that chromatin architecture rewiring promotes gene regulation changes essential for terminal adipogenesis. We identified nine clusters of dynamic promoter-anchored chromosomal interactions, many involving distal enhancers. Functional screening of genes engaged in these interactions revealed 19 novel regulators of late adipogenesis, including proteins with peptidase and ubiquitin ligase activity. Human genetic variant-to-gene mapping, coupled with cross-species chromatin interaction and synteny analyses, highlighted new gene-trait associations relevant to lipid traits (FXYD5, LAP3, SGPP1) and type 2 diabetes (FBXO17, FN3KRP, ZFAND6, TTC3). Our findings define the 3D gene regulatory landscape of late adipogenesis. The molecular links uncovered here provide mechanistic insight into metabolic disease risk and potential interventions.

genetics↗

bioRxiv2022

A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein translation

Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report the first whole genome, multiparametric CRISPR anti-aging screen, identifying 43 new genes that can reverse multiple aging phenotypes in progeria. The screen was implemented in fibroblasts from Nestor- Guillermo Progeria Syndrome (NGPS) patients, carrying a homozygous p.Ala12Thr mutation in barrier-to-autointegration factor (BAF A12T). The hits were enriched for genes involved in protein translation, protein and RNA transport and osteoclast formation. We further confirmed that BAF A12T drives increased protein translation and translational errors that could directly contribute to premature aging in patients. This work has highlighted the power of multiparametric whole genome synthetic rescue screens to identify new anti-aging genes and uncover novel biology behind progeria-associated cellular dysfunction. One-Sentence SummaryA whole genome multiparametric screen in progeria identifies new pathways that can reverse cellular aging phenotypes.

molecular biology↗

bioRxiv2022

Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Clonal hematopoiesis (CH) - age-related expansion of mutated hematopoietic clones - can differ in frequency and cellular fitness. Descriptive studies have identified a spectrum of events (coding mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-existence of different CH events raises key questions as to their origin, selection, and impact. Here, we report analyses of sequence and genotype array data in up to 482,378 individuals from UK Biobank, demonstrating shared genetic architecture across different types of CH. These data highlighted evidence for a cellular evolutionary trade-off between different forms of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. Furthermore, we observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Individuals carrying these overlapping somatic mutations had a large increase in risk of future hematological malignancy (HR=17.31, 95% CI=9.80-30.58, P=8.94x10-23), which is significantly elevated compared to individuals with non-overlapping CHIP and autosomal mCAs (Pheterogeneity=8.83x10-3). Finally, we leverage the shared genetic architecture of these CH traits to identify 15 novel loci associated with blood cancer risk.

genetics↗

bioRxiv2020

Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity

Age at first sexual intercourse (AFS) and age at first birth (AFB) have implications for health and evolutionary fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we identify 370 independent signals, 11 sex-specific, with a 5-6% polygenic score (PGS) prediction. Heritability of AFB shifted from 9% [CI=4-14] for women born in 1940 to 22% [CI=19-25] in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility, and spermatid differentiation. Polycystic Ovarian Syndrome leads to later AFB, linking with infertility. Late AFB is protective against later-life disease and associated with parental longevity. Higher childhood socioeconomic circumstances and those in the highest PGS decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, for understanding longevity, and guiding experimentation into mechanisms of infertility.

genetics↗

bioRxiv2018

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on womens lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P < 5 x 10-8)4-6. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis - another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.

genomics↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗

bioRxiv2017

A genome-wide polygenic approach to HIV uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

Polygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.\n\nWe used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.\n\nThese results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.\n\nAuthor SummaryThe biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individuals genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

genomics↗

bioRxiv2017

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Genetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 169,331, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 34 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory over excitatory neurons for bipolar disorder but excitatory over inhibitory neurons for schizophrenia and body mass index, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for Alzheimer's disease, which we validated with independent chromatin data. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.

genetics↗