While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE ...(database of immune cell expression, expression quantitative trait loci eQTLs, and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org).
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•Cis-eQTLs for 12,254 unique genes were identified in 13 human immune cell types•41% of eGenes showed strong cis-association with genotype in a single cell type•GWAS variants were linked to cell types where their effects are most pronounced•Biological sex was associated with major differences in immune cell gene expression
Surveying gene expression and SNP genotypes across immune cell types from healthy humans reveals cis-eQTLs affecting over half of all expressed genes and demonstrates that variant effects often manifest in cell types other than those with highest gene expression.
Genetics and epigenetics in obesity Rohde, Kerstin; Keller, Maria; la Cour Poulsen, Lars ...
Metabolism, clinical and experimental,
03/2019, Volume:
92
Journal Article
Peer reviewed
Open access
Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. Obesity maybe considered a heritable trait. Identifications of rare ...cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. For example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. Common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general BMI variability. Although GWAS opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. Non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. These factors may interact with genetic predisposition for obesity through epigenetic mechanisms. Thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity.
•Genetic background of monogenic and common (polygenic) forms of obesity•Complex interplay of genetic and non-genetic factors in common obesity•Important recent advances on how epigenetic regulation is involved in obesity.•Potential contribution of genetic and epigenetic factors to precision medicine
•Responsiveness of 655 CFTR variants to elexacaftor/tezacafor/ivacaftor combination.•Results in excellent agreement with FDA label for Trikafta®- approved variants.•Significant treatment response for ...152 unapproved very low-function variants.•Significant response for 140 unapproved variants with >10 % and <50 % normal function.
In 2017, the US Food and Drug Administration initiated expansion of drug labels for the treatment of cystic fibrosis (CF) to include CF transmembrane conductance regulator (CFTR) gene variants based on in vitro functional studies. This study aims to identify CFTR variants that result in increased chloride (Cl−) transport function by the CFTR protein after treatment with the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). These data may benefit people with CF (pwCF) who are not currently eligible for modulator therapies.
Plasmid DNA encoding 655 CFTR variants and wild-type (WT) CFTR were transfected into Fisher Rat Thyroid cells that do not natively express CFTR. After 24 h of incubation with control or TEZ and ELX, and acute addition of IVA, CFTR function was assessed using the transepithelial current clamp conductance assay. Each variant's forskolin/cAMP-induced baseline Cl− transport activity, responsiveness to IVA alone, and responsiveness to the TEZ/ELX/IVA combination were measured in three different laboratories. Western blots were conducted to evaluate CFTR protein maturation and complement the functional data.
253 variants not currently approved for CFTR modulator therapy showed low baseline activity (<10 % of normal CFTR Cl− transport activity). For 152 of these variants, treatment with ELX/TEZ/IVA improved the Cl− transport activity by ≥10 % of normal CFTR function, which is suggestive of clinical benefit. ELX/TEZ/IVA increased CFTR function by ≥10 percentage points for an additional 140 unapproved variants with ≥10 % but <50 % of normal CFTR function at baseline. These findings significantly expand the number of rare CFTR variants for which ELX/TEZ/IVA treatment should result in clinical benefit.
3′ untranslated region (3′UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3′UTRs ...(MPRAu) to sensitively assay 12,173 3′UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3′UTR function, suggesting that simple sequences predominately explain 3′UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3′UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.
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•Assayed thousands of GWAS and adaptation associated 3′UTR variants in 6 cell lines•Nominated hundreds of causal GWAS variants with functional evidence of activity•Characterized mechanistic regulatory motifs at base pair resolution•Used allelic replacement on causal variants for macular degeneration and viral defense
Massively parallel reporter assay for 3′UTRs measures individual regulatory effects of over 12,000 3′UTR variants associated with human disease and evolutionary selection in many cell types, nominating functional genetic variation.
Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of ...the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.
Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly ...understood causal relationship between gut microbiota and intelligence.
We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867). The inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. Considering the close relationship between brain volume and intelligence, we applied 2-step MR to evaluate whether the identified effect was mediated by regulating brain volume (N = 47,316).
We found a risk effect of the genus Oxalobacter on intelligence (odds ratio = 0.968 change in intelligence per standard deviation increase in taxa; 95% CI, 0.952–0.985; p = 1.88 × 10−4) and a protective effect of the genus Fusicatenibacter on intelligence (odds ratio = 1.053; 95% CI, 1.024–1.082; p = 3.03 × 10−4). The 2-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partially mediated by regulating brain volume, with a mediated proportion of 33.6% (95% CI, 6.8%–60.4%; p = .014).
Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.
MVAR: A Mouse Variation Registry El Kassaby, Bahá; Castellanos, Francisco; Gerring, Matthew ...
Journal of Molecular Biology/Journal of molecular biology,
09/2024, Volume:
436, Issue:
17
Journal Article
Peer reviewed
Open access
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•MVAR aggregates and annotates genome variation from large-scale sequencing of different mouse strains and expertly curated variants for phenotypic alleles.•Variant annotation in MVAR ...includes variant type, molecular consequence, impact, and region.•Data in MVAR are accessible in both human- and machine- readable formats.•MVAR serves as both a stand-alone database of mouse genome variation and as a variant annotation service.•MVAR is a platform for facilitating genotype-phenotype associations in the laboratory mouse.•MVAR resource was implemented using a micro-services architecture, providing both interoperability and ease of software maintenance.
The Mouse Variation Registry (MVAR) resource is a scalable registry of mouse single nucleotide variants and small indels and variant annotation. The resource accepts data in standard Variant Call Format (VCF) and assesses the uniqueness of the submitted variants via a canonicalization process. Novel variants are assigned a unique, persistent MVAR identifier; variants that are equivalent to an existing variant in the resource are associated with the existing identifier. Annotations for variant type, molecular consequence, impact, and genomic region in the context of specific transcripts and protein sequences are generated using Ensembl’s Variant Effect Predictor (VEP) and Jannovar. Access to the data and annotations in MVAR are supported via an Application Programming Interface (API) and web application. Researchers can search the resource by gene symbol, genomic region, variant (expressed in Human Genome Variation Society syntax), refSNP identifiers, or MVAR identifiers. Tabular search results can be filtered by variant annotations (variant type, molecular consequence, impact, variant region) and viewed according to variant distribution across mouse strains. The registry currently comprises more than 99 million canonical single nucleotide variants for 581 strains of mice. MVAR is accessible from https://mvar.jax.org.
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