Biology subjects

Dube, U.

Publications and source records attributed to Dube, U..

5 recordsLinked to original sources

bioRxiv2019

Overlapping Genetic Architecture between Parkinson Disease and Melanoma

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10 to 0.24; P = 4.09 x 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10-04), and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

genetics↗

bioRxiv2019

Single- nuclei RNA sequencing from human brain to study for Mendelian and sporadic AD

Alzheimer Disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single cell resolution. To do so, we generated unsorted single-nuclei RNA-sequencing data from brain tissue. We leveraged tissue donated from a carrier of a Mendelian genetic mutation and two family members who suffer from AD, but do not have the same mutation. We evaluated alternative alignment approaches to maximize the titer of reads, genes and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses. We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from human brains recapitulate the expression profile of Disease Associated Microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data it is critical to control for biases introduced by donor specific expression profiles. In conclusion, we propose a collection of best practices to generate a highly-detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.

genomics↗

bioRxiv2019

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

BackgroundIn previous studies, we observed decreased neuronal and increased astrocyte proportions in AD cases in parietal brain cortex by using a deconvolution method for bulk RNA-seq. These findings suggested that genetic risk factors associated with AD etiology have a specific effect in the cellular composition of AD brains. The goal of this study is to investigate if there are genetic determinants for brain cell compositions.\n\nMethodsUsing cell type composition inferred from transcriptome as a disease status proxy, we performed cell type association analysis to identify novel loci related to cellular population changes in disease cohort. We imputed and merged genotyping data from seven studies in total of 1,669 samples and derived major CNS cell type proportions from cortical RNAseq data. We also inferred RNA transcript integrity number (TIN) to account for RNA quality variances. The model we performed in the analysis was: normalized neuronal proportion [~] SNP + Age + Gender + PC1 + PC2 + median TIN.\n\nResultsA variant rs1990621 located in the TMEM106B gene region was significantly associated with neuronal proportion (p=6.40x10-07) and replicated in an independent dataset. The association became more significant as we combined both discovery and replication datasets in multi-tissue meta-analysis (p=9.42x10-09) and joint analysis (p=7.66x10-10). This variant is in high LD with rs1990622 (r2 = 0.98) which was previously identified as a protective variant in FTD cohorts. Further analyses indicated that this variant is associated with increased neuronal proportion in participants with neurodegenerative disorders, not only in AD cohort but also in cognitive normal elderly cohort. However, this effect was not observed in a younger schizophrenia cohort with a mean age of death < 65. The second most significant loci for neuron proportion was APOE, which suggested that using neuronal proportion as an informative endophenotype could help identify loci associated with neurodegeneration.\n\nConclusionThis result suggested a common pathway involving TMEM106B shared by aging groups in the present or absence of neurodegenerative pathology may contribute to cognitive preservation and neuronal protection.

neuroscience↗

bioRxiv2018

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15x10-15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

genomics↗

bioRxiv2018

Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

Alzheimers disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the effects of brain cellular composition are often ignored in high-throughput molecular studies. We developed and optimized a cell-type specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. We found that neuronal and astrocyte proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1 or PSEN2 presented lower neurons and higher astrocytes proportions compared to sporadic AD. Similarly, the APOE {varepsilon}4 allele also showed decreased neurons and increased astrocytes compared to AD non-carriers. On the contrary, carriers of variants in TREM2 risk showed a lower degree of neuronal loss than matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-seq studies for cell composition, and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.

genetics↗