Biology subjects

Broce, I.

Publications and source records attributed to Broce, I..

4 recordsLinked to original sources

bioRxiv2025

Old vs. New Local Ancestry Inference in HCHS/SOL: A Comparative Study

Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. Studies of genetic association in these admixed populations often use methods such as admixture mapping, which relies on inferred counts of "local" ancestry, i.e., of the source ancestral population at a locus. Local ancestries are inferred using external reference panels that represent ancestral populations, making the choice of inference method and reference panel critical. This study used a dataset of Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to evaluate the "old" local ancestry inference performed using the state-of-the-art inference method, RFMix, alongside "new" inferences performed using Fast Local Ancestry Estimation (FLARE), which also used an updated reference panel. We compared their performance in terms of global and local ancestry correlations, as well as admixture mapping-based associations. Overall, the old RFMix and new FLARE inferences were highly similar for both global and local ancestries, with FLARE-inferred datasets yielding admixture mapping results consistent with those computed from RFMix. However, in some genomic regions the old and new local ancestries have relatively lower correlations (Pearson R < 0.9). Most of these genomic regions (86.42%) were mapped to either ENCODE blacklist regions, or to gene clusters, compared to 7.67% of randomly-matched regions with high correlations (Pearson R > 0.97) between old and new local ancestries.

genetics↗

bioRxiv2023

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., C9orf72 gene network) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. ResultsA total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. ConclusionsConsidered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

neuroscience↗

bioRxiv2018

Lipid associated polygenic enrichment in Alzheimer’s disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimers disease (AD) pathogenesis. Beyond the [isin]4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimers risk.

genetics↗

bioRxiv2017

Laterality of the frontal aslant tract (FAT) explains externalizing behaviors through its association with executive function.

We investigated the development of a recently-identified white matter pathway, the frontal aslant tract (FAT) and its association to executive function and externalizing behaviors in a sample of 129 neurotypical children ranging in age from 7 months to 19-years. We found that the FAT could be tracked in 92% of those children, and that the pathway showed age-related differences into adulthood. The change in white matter microstructure was very rapid until about 6-years, and then plateaued, only to show age-related increases again after the age of 11-years. In a subset of those children (5-18-years; n = 70), left laterality of the microstructural properties of the FAT was associated with greater attention problems as measured by the Child Behavior Checklist (CBCL). However, this relationship was fully mediated by higher executive dysfunction as measured by the Behavior Rating Inventory of Executive Function (BRIEF). This relationship was specific to the FAT--we found no relationship between laterality of the white matter of the brain in general and attention problems, or executive function. These findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.\n\nSignificance StatementTo investigate the function of a recently-identified white matter fiber pathway, the frontal aslant tract (FAT), we tracked the pathway in 129 typically developing children using diffusion-weighted magnetic resonance imaging (DW-MRI). We then examined whether laterality of the tract is associated with attention problems and executive function. We found that reduced right laterality of the tract was associated with greater executive dysfunction, which predicted increased reports of attention problems. The findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.

neuroscience↗