Biology subjects

Chesi, A.

Publications and source records attributed to Chesi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Cross-trait clustering of sub-threshold sleep genetic signals identifies EGR2 as a conserved regulator of sleep

Idiopathic hypersomnia (IH) is a highly heritable sleep disorder characterized by excessive daytime sleepiness, yet few genetic pathways contributing to hypersomnolence have been identified. To expand genetic discovery beyond the limited number of genome-wide significant loci associated with sleepiness-related traits, we applied multi-trait clustering to sleep-associated genetic variation that did not reach conventional significance thresholds. Integration with our cell-type-specific variant-to-gene mapping prioritized candidate effector genes for cross-species functional screening. Among the strongest candidates was EGR2, which emerged as a distal effector gene at the ADO-EGR2 locus in neurons. Neuronal knockdown of the Drosophila EGR2 ortholog stripe increased sleep duration and sleep consolidation, while mutation of zebrafish egr2 orthologs similarly increased sleep. Together, these findings demonstrate that sleep-regulatory pathways can be identified from genetic signals below conventional significance thresholds and establish EGR2 as a conserved regulator of sleep across species.

neuroscience↗

bioRxiv2025

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development

Genome wide association study (GWAS) reports substantially outpace subsequent functional characterization. Pinpointing the causal effector gene(s) at GWAS loci remains challenging given the non-coding genomic residency of >98% of these signals. We previously implicated effector genes at GWAS loci for the complex and polygenic disorder of human insomnia using a high-resolution cell-specific, chromatin capture-based variant-to-gene mapping protocol, paired with sleep phenotyping in Drosophila. In this study, we leveraged a diurnal vertebrate model with higher genomic conservation, namely zebrafish, to screen our six highest confidence candidate genes and identify those whose loss-of-function impaired sleep characteristics related to human insomnia-like behaviors. Of these genes, we observed that CRISPR-mediated deletion of the zebrafish ortholog of MEIS1 produced nighttime specific sleep fragmentation and increased latency to sleep, pointing to a conserved role for MEIS1 in sleep maintenance. Comparing our human cell-based chromatin accessibility and contact maps with publicly available zebrafish spatial genomic data revealed highly conserved genomic architecture harboring the insomnia GWAS variant of interest. Notably, this genomic conservation was selective for the zebrafish ortholog which contributed to the sleep phenotype, meis1b, while the duplicated ohnolog meis1a proved dispensable. Motivated by this, we characterized the spatio-temporal expression of meis1b in zebrafish, showing it is comparable to human with respect to cerebellar granule progenitors. Ultimately, we found that loss of meis1b impairs cerebellar development. Together, our work provides a powerful model for screening human disorder risk genes for sleep fragmentation using a tractable vertebrate and supports a conserved cerebellar role for MEIS1 in sleep disturbance.

neuroscience↗

bioRxiv2025

Integration of Alzheimer's GWAS, 3D genomics, and single-cell CRISPRi non-coding screen implicates causal variants in a microglial enhancer regulating TSPAN14.

While GWAS have been successful in providing variant-to-trait associations for human complex diseases, functional dissection of the discovered loci has lagged behind. Here, we describe a variant-to-gene (V2G) mapping effort for Alzheimers disease (AD) to implicate causal variants and effector genes from the most recent AD GWAS meta-analyses (101 loci). We leveraged our genomics datasets comprising high-resolution promoter Capture C, ATAC-seq, and RNA-seq from brain-relevant cell types to fine-map AD GWAS variants, identifying 89 candidate causal SNPs and 69 effector genes. We then designed a single-cell CRISPRi screen to perturb candidate regulatory regions (n=74) and assess the transcriptional response in the human microglial cell line, HMC3. Our screen across [~]97,000 cells identified 19 regulatory regions and 19 effector genes. We then elected to functionally dissect our top hit, the TSPAN14 locus, and we show that an intronic region containing AD-associated SNPs rs7080009, rs1870138, and rs1870137 is a microglia-specific enhancer, with the AD risk haplotype increasing its activity. CRISPR precise genomic deletion of this region decreases TSPAN14 expression, alters specific cellular pathways including cell adhesion, and decreases secreted levels of pro-inflammatory cytokines IL-6 and IL-8, which are known biomarkers of aging and AD. Our work provides a systematic framework to map GWAS signals to their effector genes for AD and other brain-related disorders, and provides robust leads to follow up with in-depth functional investigations.

genetics↗

bioRxiv2024

Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

Idiopathic hypersomnia (IH) is a poorly-understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia.

neuroscience↗

bioRxiv2024

Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus

Late-onset Alzheimers disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2, ABI3, and CR1. However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1. We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD CASS4 GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene.

genetics↗

bioRxiv2024

GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblasts (hFOBs). The BMD relevance of hFOBs was supported by heritability enrichment from stratified LD-score regression involving 98 cell types grouped into 15 tissues. 23 genes showed perturbation in the screen, with four (ARID5B, CC2D1B, EIF4G2, and NCOA3) exhibiting consistent effects upon siRNA knockdown on three measures of osteoblast maturation and mineralization. Lastly, additional heritability enrichments, genetic correlations, and multi-trait fine-mapping revealed unexpectedly that many BMD GWAS signals are pleiotropic and likely mediate their effects via non-bone tissues. Extending our CRISPRi screening approach to these tissues could play a key role in fully elucidating the etiology of BMD.

genomics↗

bioRxiv2023

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

biochemistry↗

bioRxiv2023

Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2

The ch12q13 obesity locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via an influence on cis-regulation within the genomic region. We implicated rs7132908 as a putative causal variant at this locus leveraging a combination of our inhouse 3D genomic data, public domain datasets, and several computational approaches. Using a luciferase reporter assay in human primary astrocytes, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. Motivated by this finding, we went on to generate isogenic human embryonic stem cell lines homozygous for either rs7132908 allele with CRISPR-Cas9 homology-directed repair to assess changes in gene expression due to genotype and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. We observed that the rs7132908 obesity risk allele influenced the expression of FAIM2 along with other genes, decreased the proportion of neurons produced during differentiation, up-regulated cell death gene sets, and conversely down-regulated neuron differentiation gene sets. We have therefore functionally validated rs7132908 as a causal obesity variant which temporally regulates nearby effector genes at the ch12q13 locus and influences neurodevelopment and survival.

genetics↗

bioRxiv2023

Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q

Although genome wide association studies (GWAS) have been crucial for the identification of loci associated with sleep traits and disorders, the method itself does not directly uncover the underlying causal variants and corresponding effector genes. The overwhelming majority of such variants reside in non-coding regions and are therefore presumed to impact the activity of cis-regulatory elements, such as enhancers. Our previously reported variant-to-gene mapping effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophila and zebrafish, implicated PIG-Q as a functionally relevant gene at the insomnia WDR90 locus. However, importantly that effort did not characterize the corresponding underlying causal variant at this GWAS signal. Specifically, our genome-wide ATAC-seq and high-resolution promoter-focused Capture C datasets generated in this cell setting brought our attention to a shortlist of three tightly neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium in a candidate intronic enhancer region of WDR90 that contacted the open PIG-Q promoter. The objective of this study was to investigate the influence of the proxy SNPs collectively and then individually on PIG-Q modulation and to pinpoint the causal "regulatory" variant among the three SNPs. Starting at a gross level perturbation, deletion of the entire region harboring all three SNPs in human iPSC-derived neural progenitor cells via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Q transcripts. Results from more refined individual luciferase reporter assays for each of the three SNPs in iPSCs revealed that the intronic region with the rs3752495 risk allele induced a [~]2.5-fold increase in luciferase expression (n=10). Importantly, rs3752495 also exhibited an allele specific effect, with the risk allele increasing the luciferase expression by [~]2-fold compared to the non-risk allele. In conclusion, our variant-to-function approach and subsequent in vitro validation implicates rs3752495 as a causal insomnia risk variant embedded at the WDR90-PIG-Q locus.

genomics↗

bioRxiv2022

Zebrafish screen of high-confidence targets at insomnia GWAS loci implicates MEIS1, SKIV2L, and ARFGAP2 as conserved regulators of sleep-wake behaviors

Recent large-scale human genome-wide association studies (GWAS) for insomnia have identified more than 200 significant loci. The functional relevance of these loci to the pathogenesis of insomnia is largely unknown. GWAS signals are typically non-coding variants, which are often arbitrarily annotated to the nearest protein-coding gene; however, due to 3D chromatin structure, variants can interact with more distal genes driving their function. The distal gene may, therefore, represent the true causal gene influencing the phenotype. By integrating our high-resolution chromatin interaction maps from neural progenitor cells with phenotypic data from a Drosophila RNAi screen, we prioritized candidate genes that we hypothesized would have deep phylogenetic conservation of sleep function. To determine the conservation of these candidate genes in the context of vertebrate sleep and their relevance to insomnia-like behaviors, we performed CRISPR-Cas9 mutagenesis in larval zebrafish for six highly conserved candidate genes and examined sleep-wake behaviors using automated video-tracking. CRISPR mutation of zebrafish orthologs of MEIS1 and SKIV2L produced insomnia-like behaviors, while mutation of ARFGAP2 impaired activity and development in our larval zebrafish model, demonstrating the importance of performing functional validation of GWAS-implicated effector genes to reveal genes influencing disease-relevant mechanisms.

genetics↗

bioRxiv2021

Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a variant-to-gene mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly, Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q), a gene that encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)- anchor biosynthesis. We show that flies deficient for PIG-Q have longer sleep during both day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated the PIG-Q locus in zebrafish and identified similar increases in sleep to those observed in Drosophila, confirming deep homology of PIG-Q mediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism-based prioritization, revealing a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.

genetics↗

bioRxiv2021

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

genomics↗

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↗

bioRxiv2021

A UVB-responsive common variant at chr7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor gene (AHR)

Genome-wide association studies have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP, and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). As ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWAS identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor gene (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. As AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus, and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression, and altering melanocyte growth phenotypes upon exposure.

genetics↗

bioRxiv2020

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits

SummaryThe hypothalamus regulates metabolic homeostasis by influencing behavior, energy utilization and endocrine systems. Given its role governing health-relevant traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function should yield insights into these traits and diseases. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generated a chromatin architecture atlas of an established embryonic stem cell (ESC)-derived hypothalamic-like neuron (HN) model across three stages of in vitro differentiation. We profiled accessible chromatin and identified physically interacting contacts between gene promoters and their putative cis-regulatory elements (cREs) to characterize changes in the gene regulatory landscape during hypothalamic differentiation. Next, we integrated these data with GWAS loci for multiple traits and diseases enriched for heritability in these cells, identifying candidate effector genes and cREs impacting transcription factor binding. Our results reveal common target genes for these traits, potentially identifying core hypothalamic developmental pathways. Our atlas will enable future efforts to determine precise mechanisms underlying hypothalamic development with respect to specific disease pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2019

Human follicular helper T cell promoter connectomes reveal novel genes and regulatory elements at SLE GWAS loci

Systemic lupus erythematosus (SLE) is a complex inflammatory disease mediated by autoreactive antibodies that damages multiple tissues in children and adults. Genome-wide association studies (GWAS) have statistically implicated hundreds of loci in the susceptibility to human disease, including SLE, but the majority have failed to identify the causal variants or the effector genes. As a physicochemical approach to detecting functional variants and connecting them to target genes, we generated comprehensive, high-resolution maps of SLE variant accessibility and gene connectivity in the context of the three-dimensional chromosomal architecture of human tonsillar follicular helper T cells (TFH), a cell type required for the production of anti-nuclear antibodies characteristic of SLE. These spatial epigenomic maps identified a shortlist of over 400 potentially functional variants across 48 GWAS-implicated SLE loci. Twenty percent of these variants were located in open promoters of highly-expressed TFH genes, while 80% reside in non-promoter genomic regions that are connected in 3D to genes that likewise tend to be highly expressed in TFH. Importantly, we find that 90% of SLE-associated variants exhibit spatial proximity to genes that are not nearby in the 1D sequence of the genome, and over 60% of variants skip the nearest gene to physically interact only with the promoters of distant genes. Gene ontology confirmed that genes in spatial proximity to SLE variants reside in highly SLE-relevant networks, including accessible variants that loop 200-1000 kb to interact with the promoters of the canonical TFH genes BCL6 and CXCR5. CRISPR-Cas9 genome editing confirmed that these variants reside in novel, distal regulatory elements required for normal BCL6 and CXCR5 expression by T cells. Furthermore, SLE-associated SNP-promoter interactomes implicated a set of novel genes with no known role in TFH or SLE disease biology, including the homeobox-interacting protein kinase HIPK1 and the Ste kinase homolog MINK1. Targeting these kinases in primary human TFH cells inhibited production of IL-21, a requisite cytokine for production of class-switched antibodies by B cells. This 3D-variant-to-gene mapping approach gives mechanistic insight into the SLE-associated regulatory architecture of the human genome.

genomics↗

bioRxiv2018

Clinical and Functional Characterization of Melanocortin 4 Receptor genetic variants in African American and/or Hispanic children with severe early onset obesity.

ContextMutations in melanocortin receptor (MC4R) are the most frequent cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from minority populations in the United States.\n\nObjectiveThis study aims to identify the prevalence of MC4R mutations in children with severe early onset obesity of African-American and/or Latina ancestry.\n\nDesign and SettingIndividuals were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome and/or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand -melanocyte stimulating hormone.\n\nParticipantsThree hundred and twelve children (1-18 years, 50% girls) with body mass index (BMI) > 120% of 95th percentile of CDC 2000 growth charts at an age < 6 years, with no known pathological cause of obesity were enrolled.\n\nResultsEight rare MC4R mutations (2.6%) were identified in this study (R7S, F202L (n=2), M215I, G252D, V253I, I269N, F284I), three of which have not been previously reported (M215I, G252D, F284I). The pathogenicity of the variants was confirmed either by prior literature reports, or by functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort.\n\nConclusionsWhile the prevalence of MC4R mutations in this cohort was similar to that reported in obese children of European ancestry, some of the variants were novel.

genetics↗

bioRxiv2018

Genetic And Epigenetic Fine Mapping Of Complex Trait Associated Loci In The Human Liver

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

genetics↗