Genome-wide association studies (GWAS) have identified over 41 susceptibility loci associated with Parkinson's Disease (PD) but identifying putative causal genes and the underlying mechanisms remains ...challenging. Here, we leverage large-scale transcriptomic datasets to prioritize genes that are likely to affect PD by using a transcriptome-wide association study (TWAS) approach. Using this approach, we identify 66 gene associations whose predicted expression or splicing levels in dorsolateral prefrontal cortex (DLFPC) and peripheral monocytes are significantly associated with PD risk. We uncover many novel genes associated with PD but also novel mechanisms for known associations such as MAPT, for which we find that variation in exon 3 splicing explains the common genetic association. Genes identified in our analyses belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.
Enormous progress in mapping complex traits in humans has been made in the last 5 yr. There has been early success for prevalent diseases with complex phenotypes. These studies have demonstrated ...clearly that, while complex traits differ in their underlying genetic architectures, for many common disorders the predominant pattern is that of many loci, individually with small effects on phenotype. For some traits, loci of large effect have been identified. For almost all complex traits studied in humans, the sum of the identified genetic effects comprises only a portion, generally less than half, of the estimated trait heritability. A variety of hypotheses have been proposed to explain why this might be the case, including untested rare variants, and gene-gene and gene-environment interaction. Effort is currently being directed toward implementation of novel analytic approaches and testing rare variants for association with complex traits using imputed variants from the publicly available 1000 Genomes Project resequencing data and from direct resequencing of clinical samples. Through integration with annotations and functional genomic data as well as by in vitro and in vivo experimentation, mapping studies continue to characterize functional variants associated with complex traits and address fundamental issues such as epistasis and pleiotropy. This review focuses primarily on the ways in which genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics.
Genome-Wide Association Studies (GWAS) have elucidated the genetic components of Parkinson's Disease (PD). However, because the vast majority of GWAS association signals fall within non-coding ...regions, translating these results into an interpretable, mechanistic understanding of the disease etiology remains a major challenge in the field. In this review, we provide an overview of the approaches to prioritize putative causal variants and genes as well as summarise the primary findings of previous studies. We then discuss recent efforts to integrate multi-omics data to identify likely pathogenic cell types and biological pathways implicated in PD pathogenesis. We have compiled full summary statistics of cell-type, tissue, and phentoype enrichment analyses from multiple studies of PD GWAS and provided them in a standardized format as a resource for the research community (https://github.com/RajLabMSSM/PD_omics_review). Finally, we discuss the experimental, computational, and conceptual advances that will be necessary to fully elucidate the effects of functional variants and genes on cellular dysregulation and disease risk.
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Structural variants (SVs), which are genomic rearrangements of more than 50 base pairs, are an important source of genetic diversity and have been linked to many diseases. However, it remains unclear ...how they modulate human brain function and disease risk. Here we report 170,996 SVs discovered using 1,760 short-read whole genomes from aged adults and individuals with Alzheimer's disease. By applying quantitative trait locus (SV-xQTL) analyses, we quantified the impact of cis-acting SVs on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues. More than 3,200 SVs were associated with at least one molecular phenotype. We found reproducibility of 65-99% SV-eQTLs across cohorts and brain regions. SV associations with mRNA and proteins shared the same direction of effect in more than 87% of SV-gene pairs. Mediation analysis showed ~8% of SV-eQTLs mediated by histone acetylation and ~11% by splicing. Additionally, associations of SVs with progressive supranuclear palsy identified previously known and novel SVs.
Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the ...RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared postmortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex, and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation ...at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large ...transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders.
T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans and its genetic or environmental roots. We analyzed ...gene expression in CD4(+) T cells during unbiased activation or in T helper 17 (T(H)17) conditions from 348 healthy participants representing European, Asian, and African ancestries. We observed interindividual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple T(H)1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, interindividual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.
Invading human leukocyte antigen-G+ (HLA‐G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal ...tissues. Here highly purified HLA‐G+ EVT and HLA‐G− villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA‐G, EGF-Receptor-2, and LIF-Receptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA‐G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25 ᴴᴵFOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal–fetal tolerance, the properties of which are not imitated by HLA‐G–expressing surrogate cell lines.
Significance Fetal extravillous trophoblasts (EVT) invade uterine tissue and interact with maternal immune cells during pregnancy. EVT express human leukocyte antigen-C (HLA-C) and -G (HLA-G). Although polymorphic HLA-C can elicit a maternal immune response, HLA-G has been associated with induction of immune tolerance. We have succeeded in isolating all maternal immune cell types as well as EVT from human placental tissue. These methods were used to elucidate the unique charateristics of EVT as well as their interaction with maternal immune cells. We demonstrate that EVT are specialized cells whose properties are not imitated by HLA‐G–expressing surrogate cell lines. Studies using primary EVT are crucial for understanding maternal–fetal tolerance and development of pregnancy complications such as preeclampsia and miscarriages.
To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4+ T cells and monocytes, ...representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell–specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
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