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Nat Commun ; 12(1): 5071, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417470


Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.

Alcoolismo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Doenças Neurodegenerativas/genética , Encéfalo/metabolismo , Epigênese Genética , Feto/metabolismo , Redes Reguladoras de Genes , Loci Gênicos , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Análise da Randomização Mendeliana , Mapeamento Físico do Cromossomo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética
Mol Neurodegener ; 16(1): 27, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882988


Alzheimer's disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. Nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.

Nat Commun ; 12(1): 1610, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712570


Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.

Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Genômica , Células Mieloides , Sequências Reguladoras de Ácido Nucleico/genética , Alelos , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Macrófagos , Microglia/metabolismo , Transcriptoma
Sci Rep ; 8(1): 3112, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449656


New intravesical treatment approaches for bladder cancer are needed as currently approved treatments show several side effects and high tumor recurrence rate. Our study used MB49 murine urothelial carcinoma model to evaluate oxygen encapsulated cellulosic nanobubbles as a novel agent for imaging and ultrasound guided drug delivery. In this study, we show that oxygen nanobubbles (ONB) can be propelled (up to 40 mm/s) and precisely guided in vivo to the tumor by an ultrasound beam. Nanobubble velocity can be controlled by altering the power of the ultrasound Doppler beam, while nanobubble direction can be adjusted to different desired angles by altering the angle of the beam. Precise ultrasound beam steering of oxygen nanobubbles was shown to enhance the efficacy of mitomycin-C, resulting in significantly lower tumor progression rates while using a 50% lower concentration of chemotherapeutic drug. Further, dark field imaging was utilized to visualize and quantify the ONB ex vivo. ONBs were found to localize up to 500 µm inside the tumor using beam steering. These results demonstrate the potential of an oxygen nanobubble drug encapsulated system to become a promising strategy for targeted drug delivery because of its multimodal (imaging and oxygen delivery) and multifunctional (targeting and hypoxia programming) properties.

Sistemas de Liberação de Medicamentos/métodos , Microbolhas/uso terapêutico , Nanopartículas/administração & dosagem , Ultrassonografia/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Celulose/administração & dosagem , Celulose/química , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Mitomicina/administração & dosagem , Mitomicina/química , Nanopartículas/química , Oxigênio/administração & dosagem , Oxigênio/química , Distribuição Aleatória