Biology subjects

Griswold, A.

Publications and source records attributed to Griswold, A..

4 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↗

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

coMethDMR: Accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies

Recent technology has made it possible to measure DNA methylation profiles in a cost-effective and comprehensive genome-wide manner using array-based technology for epigenome-wide association studies. However, identifying differentially methylated regions (DMRs) remains a challenging task because of the complexities in DNA methylation data. Supervised methods typically focus on the regions that contain consecutive highly significantly differentially methylated CpGs in the genome, but may lack power for detecting small but consistent changes when few CpGs pass stringent significance threshold after multiple comparison. Unsupervised methods group CpGs based on genomic annotations first and then test them against phenotype, but may lack specificity because the regional boundaries of methylation are often not well defined. We present coMethDMR, a flexible, powerful, and accurate tool for identifying DMRs. Instead of testing all CpGs within a genomic region, coMethDMR carries out an additional step that selects co-methylated sub-regions first. Next, coMethDMR tests association between methylation levels within the sub-region and phenotype via a random coefficient mixed effects model that models both variations between CpG sites within the region and differential methylation simultaneously. coMethDMR offers well-controlled Type I error rate, improved specificity, focused testing of targeted genomic regions, and is available as an open-source R package.

bioinformatics↗

bioRxiv2018

N-terminal degradation activates the Nlrp1b inflammasome

Intracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptotic cell death. The anthrax lethal factor metalloprotease and small molecule DPP8/9 inhibitors both activate the Nlrp1b inflammasome, but the molecular mechanism of Nlrp1b activation is not known. Here, we used genome-wide CRISPR/Cas9 knockout screens to identify genes required for Nlrp1b-mediated pyroptosis, and discovered that lethal factor induces cell death via the N-end rule proteasomal degradation pathway. Lethal factor directly cleaves Nlrp1b, which induces the N-end rule-mediated degradation of the Nlrp1b N-terminus and thereby frees the Nlrp1b C-terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the Nlrp1b N-terminus, but, in contrast, not through the N-end rule pathway. Overall, these data reveal that N-terminal degradation is the common mechanism for activation of this innate immune sensor protein.\n\nOne Sentence SummaryProteasome-mediated degradation of the Nlrp1b N-terminus releases the Nlrp1b C-terminus to activate caspase-1 and induce pyroptotic cell death.

immunology↗