Biology subjects

Vance, J. M.

Publications and source records attributed to Vance, J. M..

13 recordsLinked to original sources

bioRxiv2026

Enhanced Hi-C Capture Analysis reveals complex regulatory architecture at the PICALM-EED locus for Alzheimer Disease

ObjectiveBoth the phosphatidylinositol binding clathrin assembly protein gene (PICALM) and the embryonic ectoderm development gene (EED) have been implicated as causal genes driving a genome-wide association for Alzheimer disease (AD) risk. We employed a new virtual approach using genome-wide chromatin interactions (Hi-C) called enhanced Hi-C Capture Analysis (eHiCA) to identify the genes and regulatory regions that are driving this important AD risk association. MethodsHi-C data from the frontal cortex of eight AD patients, as well as inducible pluripotent stem cell-derived microglia and spheroids of AD and control patients were used. We applied 14 eHiCA baits each containing a GWAS SNP to identify the cis regulatory interactions in this GWAS locus at a 5kb resolution. ResultsThe baits derived from the GWAS associated haplotype primarily interacted with the PICALM promoter and the large cis-regulatory elements cluster (CREe) lying upstream of the EED promoter. The EED promoter interacts with PICALM gene body and promoter region but not directly with the associated risk haplotype. Although the AD-associated variants segregate together as a haplotype in the population, each bait exhibited distinct functional chromatin interactions. InterpretationThe PICALM gene is the primary driver of the association in microglia along with the CREe locus. Different SNPs in a segregating haplotype can display different physical Hi-C interactions. This study demonstrates that eHiCA can help resolve the casual genes driving complex GWAS associations, opening new pathways to study Alzheimer disease and other disorders.

genomics↗

bioRxiv2025

Disrupted Lipid Homeostasis as a Pathogenic Mechanism in ABCA7-Associated Alzheimers Disease Risk

INTRODUCTIONABCA7 (ATP-binding cassette sub-family A member 7) encodes a lipid transporter linked to Alzheimers disease (AD). While common variants confer modest risk in Europeans, a 44-base pair deletion (rs142076058; p.Arg578Alafs) is a strong risk factor in African Americans (AA). Despite this, the biological consequences of this ancestry-specific variant are not well understood. METHODSWe expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess localization and lipid metabolism. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were compared with isogenic controls. RESULTSThe truncated ABCA7 localized to the plasma membrane similarly to wild type but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons. DISCUSSIONThese findings show that the AA-specific ABCA7 deletion disrupts lipid regulation despite normal localization, suggesting a mechanistic link between impaired lipid homeostasis and increased AD risk. This work underscores the importance of ancestry-specific studies in AD research. HighlightsO_LITruncated ABCA7 protein remains stable and correctly localizes to the plasma membrane in HEK293T cells. C_LIO_LITruncated ABCA7 disrupts lipid droplet regulation in HepG2 cells. C_LIO_LIABCA7 shows the highest expression in neurons among brain cell types. C_LIO_LIABCA7 truncation impairs lipid metabolism in neurons. C_LI

neuroscience↗

bioRxiv2025

Finding ancestry-specific chromatin architecture in Alzheimer's disease

Genetic risk for Alzheimers Disease (AD) varies across populations. We hypothesized that three-dimensional (3D) genome architecture variations could offer novel epigenetic understanding of ancestry-specific genetic risk. Herein, we performed Hi-C analyses of frontal cortex from APOE {varepsilon}4/{varepsilon}4 individuals with African (AF) or European (EU) ancestry who also had single nuclei ATAC-seq and RNA-seq data available. Ancestry-specific 3D genome architecture was found at both compartment and chromatin loop levels. EU genomes have more active compartments than AF genomes, consistent with our previous report of higher chromatin accessibility in EU than AF genome. Of the over one million chromatin loops identified by the DeepLoop pipeline, we called 12,082 putative EU-specific and 2885 putative AF- specific loops. The AF-specific loops are smaller (median size =158 kb) and likely represent promoter-enhancer interactions, while EU-specific loops are larger (median size = 496 kb) and enriched for CTCF loops. We found that differently expressed genes between AF and EU ancestries were significantly enriched at the putative ancestry-specific loop loci (Fisher-test; p<2.2x10-16; OR=5.13). High confidence HiC-QTLs (N=38) were identified after filtering with CTCF consensus sequence and chromatin accessibility-QTLs. Our study demonstrates variations in 3D genome structure between ancestries, which may contribute to the ancestry-specific genetic risk.

genetics↗

bioRxiv2024

African origin haplotype protective for Alzheimer's disease in APOEϵ4 carriers: exploring potential mechanisms

APOE{varepsilon}4 is the strongest genetic risk factor for Alzheimers disease (AD) with approximately 50% of AD patients carrying at least one APOE{varepsilon}4 allele. Our group identified a protective interaction between APOE{varepsilon}4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOE{varepsilon}4 homozygotes by approximately 75%. The protective variant lies 2Mb from APOE in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes (PSGs) and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in APOE{varepsilon}4 carriers and supports the importance of including all ancestries in AD research.

genetics↗

bioRxiv2024

Methylation Clocks Do Not Predict Age or Alzheimer's Disease Risk Across Genetically Admixed Individuals

Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimers disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2,500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.

genomics↗

bioRxiv2024

Gene expression and chromatin accessibility comparison in iPSC-derived microglia in African, European, and Amerindian genomes in Alzheimer's patients and controls.

Alzheimers disease (AD) risk differs between population groups, with African Americans and Hispanics being the most affected groups compared to non-Hispanic Whites. Genetic factors contribute significant risk to AD, but the genetic regulatory architectures (GRA) have primarily been studied in Europeans. Many AD genes are expressed in microglia; thus, we explored the impact of genetic ancestry (Amerindian (AI), African (AF), and European (EU)) on the GRA in iPSC-derived microglia from 13 individuals ([~]4 each with high global ancestry, AD and controls) through ATAC-seq and RNA-seq analyses. We identified several differentially accessible and expressed genes (2 and 10 AD-related, respectively) between ancestry groups. We also found a high correlation between the transcriptomes of iPSC-derived and brain microglia, supporting their use in human studies. This study provides valuable insights into genetically diverse microglia beyond the analysis of AD.

genomics↗

bioRxiv2023

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c.3113C>G) was found to segregate with disease in a multigenerational family with late onset Alzheimers disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing and the resulting isogenic pair of iPSC lines were differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3D morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant. HighlightsO_LIThe AD risk variant TTC3 p.S1038C reduces the expression levels of TTC3 C_LIO_LIThe variant modifies the expression of AD specific genes BACE1, INPP5F, and UNC5C C_LIO_LINeurons with the variant are enriched for genes in the PI3K-Akt pathway C_LIO_LIiPSC-derived neurons with the alteration have increased neurite length and branching C_LIO_LIThe variant interferes with actin cytoskeleton and is ameliorated by Cytochalasin D C_LI

genetics↗

bioRxiv2022

Ancestry-related differences in chromatin accessibility and gene expression of APOE4 are associated with Alzheimer disease risk

BackgroundEuropean local ancestry (ELA) surrounding APOE4 is associated with a higher risk for Alzheimer Disease (AD) compared to African local ancestry (ALA). We previously demonstrated significantly higher APOE4 expression in ELA vs ALA in the frontal cortex of APOE4/4 AD patients. Differences in chromatin accessibility could contribute to these differences in APOE4 expression. MethodsWe performed single nuclei Assays for Transposase Accessible Chromatin sequencing (snATAC-seq) and single nuclei RNA sequencing (snRNA-seq) from frozen frontal cortex of six ALA and six ELA AD patients, all homozygous for local ancestry and APOE4. ResultsWe demonstrated that APOE4, including its promoter area, has greater chromatin accessibility in ELA vs ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility and expression in ELA in astrocytes were enriched for synaptic function, cholesterol processing and astrocyte reactivity. ConclusionOur results suggest that increased chromatin accessibility of APOE4 in astrocyte with the ELA contributes to the observed elevated APOE4 expression, corresponding to the increased AD risk in ELA vs ALA APOE4/4 carriers.

neuroscience↗

bioRxiv2021

Converging evidence for differential regulatory control of APOEε4 on African versus European haplotypes

INTRODUCTIONThe difference in APOE{varepsilon}4 risk for Alzheimer disease (AD) between different populations is associated with APOE{varepsilon}4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOE{varepsilon}4 haplotypes for areas of differential regulation. METHODSWe performed two enhancer Massively Parallel Reporter Assay (MPRA) approaches, supplemented with single fragment reporter assays. We utilized Capture C analyses to support interactions with the APOE promoter. RESULTSThe TOMM40 intron 2 and 3 region showed increased enhancer activity in the European/Japanese versus African LA haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. DISCUSSIONBoth differential regulatory function and Capture C data support an intronic region in TOMM40 as contributing to the differential APOE expression between African and European/Japanese LA.

genomics↗

bioRxiv2020

Increased APOEϵ4 expression is associated with reactive A1 astrocytes and the difference in Alzheimer Disease risk from diverse ancestral backgrounds

APOE{varepsilon}4 African local genomic ancestry (LA) confers less risk for Alzheimer disease (AD) relative to European LA (LA) carriers. Single nucleus RNA sequencing from AD-APOE{varepsilon}4/4 frontal cortex found European LA carriers have a 1.45-fold greater APOE{varepsilon}4 expression (p< 1.8 E10-313) and are associated with a unique A1 reactive astrocyte cluster. This suggests a potential mechanism for the increased risk for AD seen in European LA carriers of APOE{varepsilon}4.

genomics↗

bioRxiv2020

Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE {varepsilon}4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in{varepsilon} 4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to [~]80 of Amerindian ancestry provides a unique opportunity to assess the role of Amerindian ancestry in Alzheimer disease. In this study we assess the effect of the ApoE {varepsilon}4 allele on AD in the Peruvian population. A total of 78 AD cases and 128 unrelated cognitive healthy controls were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE {varepsilon}4 allele on Alzheimer disease was tested using a logistic regression model by adjusting for age, gender, and population substructure (first three principal components). Logistic regression results showed that ApoE {varepsilon}4 allele is significantly associated with AD in Peruvian population with the high-risk effect (OR = 5.02, CI: 2.3-12.5, p-value = 2e-4). The average values of the local ancestries surrounding the ApoE gene (chr19:44Mb-46Mb) have the highest proportion of Amerindian (60.6%), followed by European (33.9%) and African (5.5%) ancestral backgrounds. Our results showed that the risk for AD from ApoE {varepsilon}4 in Peruvians is higher than we have observed in non-Hispanic White populations. Given the high admixture of Amerindian ancestry in the Peruvian population, it suggests that the Amerindian local ancestry is contributing to a strong risk for AD in ApoE {varepsilon}4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE {varepsilon}4 and the ancestral backgrounds located around the genomic region of ApoE gene.

genetics↗

bioRxiv2020

Linkage Analysis in Caribbean Hispanic Families with Puerto Rican Ancestry Idenitfies an Alzheimer Disease Locus on chromosome 9.

BackgroundThe ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing Alzheimer disease through linkage and segregation-based approaches. MethodsAs part of the Puerto Rican Alzheimer Disease Initiative, whole genome sequencing data were generated for 100 individuals (61 affected) from 23 Puerto Rican families. To identify the genetic loci likely to carry risk variants, we performed a parametric multipoint affected individuals-only linkage analysis using MERLIN software. Following the linkage analysis, we identified the consensus region (heterogeneity logarithm of the odds score (HLOD) > 5.1), annotated variants using Ensembl Variant Effect Predictor, and combined annotation dependent depletion score (CADD). Finally, we prioritized variants according to allele frequency (< 0.01), function (CADD > 10), and complete segregation among affected individuals. ResultsA locus at 9p21 produced a linkage HLOD score of 5.1 in the parametric affecteds-only multipoint affected individuals-only model supported by 9 families. Through the prioritization step, we selected 36 variants (22 genic variants). Candidate genes in the regions include C9orf72, UNC13B, and ELAVL2. ConclusionsLinkage analysis of Caribbean Hispanics Puerto Rican families confirmed previously reported linkage to 9p21 in non-Hispanic White and Israeli-Arap families. Our results suggest several candidates in the region as conferring AD risk. Identified putative damaging rare variants in multiplex families indicates the critical role of rare variation in Alzheimer disease etiology.

genetics↗

bioRxiv2019

Mutant MFN2/fzo-1 selectively removes mitochondrial DNA heteroplasmy in Caenorhabditis elegans and in Charcot-Marie-Tooth patients

Deleterious and intact mitochondrial DNA (mtDNA) mutations frequently co-exist (heteroplasmy). Such mutations likely survive and are inherited due to complementation via the intra-cellular mitochondrial network. Hence, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. To test this hypothesis, we assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions ({Delta}mtDNA) in the background of mutant mitofusin. Firstly, these animals displayed severe embryonic lethality and developmental delay. Strikingly, these phenotypes were relieved during subsequent generations in association with complete {Delta}mtDNA removal. Moreover, the rates of deletion loss negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. While introducing the {Delta}mtDNA into a fzo-1;pdr-1 (PARKIN ortholog) double mutant, we observed skew in the mendelian distribution of progeny, in contrast to normal distribution in the {Delta}mtDNA;fzo-1 mutant, and severely reduced brood size. Notably, the {Delta}mtDNA was lost across generations in association with improved phenotypes. This underlines the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. Finally, while investigating heteroplasmy patterns in three Charcot-Marie-Tooth disease type 2A pedigrees, which carry a mutated mitofusin 2, we found a single potentially deleterious heteroplasmic mutation, whose levels were selectively reduced in the patient versus healthy maternal relatives. Taken together our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection, while inherited from generation to generation.

genetics↗