Biology subjects

Amos, C.

Publications and source records attributed to Amos, C..

9 recordsLinked to original sources

bioRxiv2026

Single-cell lung eQTL dataset of Asian never-smokers highlights the roles of alveolar cells in lung cancer etiology

Single-cell expression quantitative trait loci (sc-eQTL) analyses are powerful in identifying context-specific susceptibility genes from genome-wide association studies (GWAS) loci. However, few studies have comprehensively investigated cells of lung cancer origin in non-European populations. Here, we built a lung sc-eQTL dataset from 129 Korean women never-smokers with epithelial cell enrichment. eQTL mapping identified 2,229 genes with an eQTL in 33 cell types, including East Asian-specific findings when compared to predominantly European datasets. Integration with single-cell chromatin accessibility data demonstrated an enrichment of cell-type specific eQTLs in cell-type matched candidate enhancers, while shared eQTLs were more frequently found near promoters. Colocalization and transcriptome-wide association study unveiled 36 susceptibility genes from 22 cell types in 22 lung cancer loci, including 10 loci not achieving genome-wide significance in prior GWAS. Around 47% of these genes were from cells of the alveoli, underscoring their importance, especially in lung adenocarcinoma (LUAD) susceptibility. Focusing on the trajectory of alveolar epithelial cell regeneration, we detected 785 cell-state-interacting QTLs, which overlapped with 28% (10) of the identified susceptibility genes. Finally, we experimentally validated East Asian-and alveolar type 2 cell-specific eQTL of TCF7L2 underlying East Asian LUAD locus, 10q25.2. Consistent with its role as a Wnt/{beta}-catenin effector, TCF7L2 displayed significant effect on lung adenocarcinoma cell growth. Our data highlighted context-specific susceptibility genes, especially from alveolar cells of lung, contributing to lung cancer etiology.

genetics↗

bioRxiv2025

Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the endoplasmic reticulum (ER) with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A and FAM102B, and also N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the plasma membrane, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.

cell biology↗

bioRxiv2023

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

genomics↗

bioRxiv2023

Erythroid differentiation dependent interaction of VPS13A with XK at the plasma membrane of K562 cells

Mutations of the bridge-like lipid transport protein VPS13A and of the lipid scramblase XK result in Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) respectively, two similar conditions involving neurodegeneration and deformed erythrocytes (acanthocytes). VPS13A binds XK, suggesting a model in which VPS13A forms a lipid transport bridge between the ER and the plasma membrane (PM) where XK resides. However, studies of VPS13A in HeLa and COS7 cells showed that this protein localizes primarily at contacts of the ER with mitochondria. Overexpression of XK in these cells redistributed VPS13A to the biosynthetic XK pool in the ER but not to PM localized XK. Colocalization of VPS13A with XK at the PM was only observed if overexpressed XK harbored mutations that disengage its VPS13A binding site from an intramolecular interaction. As the acanthocytosis phenotype of ChAc and MLS suggests a role of the two proteins in cells of the erythroid lineage, we explored their localization in K562 cells, which differentiate into erythroblasts upon hemin addition. When tagged VPS13A was overexpressed in hemin treated K562 cells, robust formation of ER-PM contacts positive for VPS13A were observed and their formation was abolished in XK KO cells. ER-PM contacts positive for VPS13A were seldomly observed in undifferentiated K562 cells, in spite of the presence of XK in these cells at concentrations similar to those observed after differentiation. These findings reveal that the interaction of VPS13A with XK at ER-PM contacts requires a permissive state which depends upon cell type and/or functional state of the cell.

cell biology↗

bioRxiv2022

Why are GWASs limp about the X chromosome?

The X-chromosome is among the largest human chromosomes. It differs from autosomes by a number of important features including hemizygosity in males, an almost complete inactivation of one copy in females, and unique patterns of recombination. We used data from the Catalog of Published Genome Wide Association Studies to compare densities of the GWAS-detected SNPs on the X-chromosome and autosomes. The density of GWAS-detected SNPs on the X-chromosome is 6-fold lower compared to the density of the GWAS-detected SNPs on autosomes. Differences between the X-chromosome and autosomes cannot be explained by differences in the overall SNP density, lower X-chromosome coverage by genotyping platforms or low call rate of X-chromosomal SNPs. Similar differences in the density of GWAS-detected SNPs were found in female-only GWASs (e.g. ovarian cancer GWASs). We hypothesized that the lower density of GWAS-detected SNPs on the X-chromosome compared to autosomes is not a result of a methodological bias, e.g. differences in coverage or call rates, but has a real underlying biological reason - a lower density of functional SNPs on the X-chromosome versus autosomes. This hypothesis is supported by the observation that (i) the overall SNP density of X-chromosome is lower compared to the SNP density on autosomes and that (ii) the density of genic SNPs on the X-chromosome is lower compared to autosomes while densities of intergenic SNPs are similar. Author summaryOne of the most striking observations from the Genome Wide Association Studies (GWAS) is that the density of GWAS hits is much lower on X-chromosome compared to autosomes. This was initially explained by technical/analytical reasons such as lower coverage and lack of adequate methods to analyze X-chromosomal SNPs. Since then, a better coverage and better analytical methods to analyze X-chromosomal SNPs were developed. We recently revisited the issue and found that the density of GWAS hits on X-chromosome is at least 5-fold lower compared to autosomes. We demonstrated that the difference cannot be explained by technical or analytical reasons. We proposed a hypothesis of a real biological phenomenon underlying X versus autosomal differences in the density of GWAS-detected SNPs, namely that X-chromosome has a lower density of functional polymorphisms compared to autosomes because of a stronger selection against X-chromosomal mutations since X-chromosomal variants are more exposed to natural selection due to hemizygosity in males and X-chromosome inactivation in females. The hypothesis is supported by the analysis of the densities of intergenic, intronic and exonic SNPs on human chromosomes.

evolutionary biology↗

bioRxiv2019

Physical activity and risk of lung cancer: a two-sample Mendelian randomiza-tion study

AO_SCPLOWBSTRACTC_SCPLOWObservational studies have suggested that physical activity might lower the risk of lung cancer in former and current smokers but not in never smokers. Using genetic instruments for self-reported and accelerometer-measured physical activity traits implemented through two-sample Mendelian randomization (MR), we sought to strengthen the evidence for causality. We used 18 genome-wide significant (P < 5x10-8) single nucleotide polymorphisms (SNPs) for self-reported moderate-to-vigorous physical activity and seven SNPs for accelerometer-measured ( average acceleration) physical activity from up to 377,234 UK Biobank participants and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR analysis suggested no effect of self-reported physical activity (odds ratio (OR) [95% confidence interval (CI)] = 0.67 [0.42-1.05], P-value = 0.081, Q-value = 0.243) and accelerometer-measured activity (OR [95% CI] = 0.98 [0.93-1.03], P-value = 0.372,Q-value = 0.562) on lung cancer. There was no evidence for associations of physical activity with histologic types and lung cancer in ever and never smokers. Replication analysis using genetic instruments from a different genome-wide study and sensitivity analysis to address potential pleiotropic effects led to no substantive change in estimates. These findings do not support a protective relationship between physical activity and the risk of lung cancer. SignificanceThe present study provides little evidence that recommending physical activity would help to prevent lung cancer.

genetics↗

bioRxiv2019

Risk of multiple primary cancer diagnosis over age in families of Li-Fraumeni syndrome: a single institution perspective

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging due to limited data availability and the difficulty of accounting for the characteristic effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach, we estimated penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort (number families=189; Single primary cancer, or SPC=771; MPC=87). We then validated the risk prediction performance using an independent clinical cohort of TP53 tested individuals from MD Anderson (SPC=102; MPC=58). Our penetrance estimates are dependent on TP53 genotype, sex, and, importantly, age of diagnosis (AoD) for the first PC. We observed the later the AoD is, the shorter the gap time is for this person to be diagnosed with a second PC. We achieved an Area under the ROC curve (AUC) of 0.77 for predicting individual outcomes of MPC vs. SPC. In summary, we have provided the first set of penetrance estimates for SPC and MPC for TP53 mutation carriers, and demonstrated its accuracy for cancer risk assessment. Our open-source R package, LFSPRO, provides future risk estimates for SPC and MPC among TP53 germline mutation carriers.\n\nSignificanceOur tool can be used to support clinical counseling of LFS cancer survivors for better health management.

genetics↗

bioRxiv2019

Risk of differential cancer types over age in families with Li-Fraumeni syndrome: a validation study using multi-center cohorts

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. An accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals of LFS. Our competing risk-based statistical model incorporates the pedigree structure efficiently into the penetrance estimation and corrects for the ascertainment bias. A set of TP53 penetrance for three cancer types (breast, BR/sarcoma, SA/others, OT) involved in LFS is then estimated from 186 pediatric-sarcoma families collected at MD Anderson Cancer Center. The penetrance was then validated on a mixed cohort of clinically ascertained families with cancer (total number of families=668). The age-dependent onset probability distributions of specific cancer types are different. For breast cancer, the TP53 penetrance goes up at an earlier age than the reported BRCA1/2 penetrance. We validated the prediction performance of the penetrance estimates via two independent cohorts combined (BR=85, SA=540, OT=158). We obtained areas under the ROC curves (AUCs) of 0.92 (BR), 0.75 (SA), and 0.81 (OT). Our R package, LFSPRO, provides risk estimates for the diagnosis of breast cancer, sarcoma, other cancers or death before cancer diagnosis in future.\n\nSignificanceCancer-specific penetrance can facilitate clinical characterization of LFS and will contribute to the management of families at high risk of LFS.

genetics↗

bioRxiv2018

Appraising the causal relevance of DNA methylation for risk of lung cancer

DNA methylation changes in peripheral blood have been identified in relation to lung cancer risk. However, the causal nature of these associations remains to be fully elucidated. Meta-analysis of four epigenome-wide association studies (918 cases, 918 controls) revealed differential methylation at 16 CpG sites (FDR < 0.05) in relation to lung cancer risk. A two-sample Mendelian randomization analysis, using genetic instruments for methylation at 14 of the 16 CpG sites, and 29,863 cases and 55,586 controls from the TRICL-ILCCO lung cancer consortium, was performed to appraise the causal role of methylation at these sites on lung cancer. This approach provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites play a causal role in lung cancer development, including for cg05575921 AHRR, where methylation is strongly associated with lung cancer risk. Further studies are needed to investigate the causal role played by DNA methylation in lung tissue.

epidemiology↗