Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci

Cannon, Maren E.; Mohlke, Karen L.

doi:10.1016/j.ajhg.2018.10.001

Cited by 97 publications

(83 citation statements)

References 134 publications

(146 reference statements)

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“…These results revealed cis and trans regulators of a previously unrecognized mechanism that activates the endogenous INS gene. Transcriptional regulatory DNA variants play a central role in human disease 44 , yet so far most efforts have investigated their function in experimental systems that do not consider their in vivo impact [45][46][47] . This is a major limitation, because it is currently clear that gene regulation entails a complex interplay between elements that are difficult to reproduce outside of an in vivo context, including chromatin structure, epigenetic chemical modifications, or noncoding RNAs.…”

Section: Discussionmentioning

confidence: 99%

Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Akerman

Maestro

Grau

et al. 2020

Preprint

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Despite the central role of chromosomal context in gene transcription, human noncoding DNA variants are generally studied outside of their endogenous genomic location. This poses major limitations to understand the true consequences of causal regulatory variants. We focused on a cis-regulatory mutation (c.-331C>G) in the INS gene promoter that is recurrently mutated in unrelated patients with recessive neonatal diabetes. We created mice in which a ~3.1 kb human INS upstream region carrying -331C or -331G alleles replaced the orthologous mouse Ins2 region. This human sequence drove cell-specific transcription in mice. It also recapitulated poised chromatin during pancreas development and active chromatin in differentiated bcells. The c.-331C>G mutation, however, blocked active chromatin formation in differentiated b-cells. We further show that another neonatal diabetes gene product, GLIS3, had a singular pioneer-like ability to activate INS chromatin in non-pancreatic cells, which was hampered by the c.-331C>G mutation. This in vivo analysis of human regulatory defects, therefore, uncovered cis and trans components of a mechanism that is essential to activate the endogenous INS gene.

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Section: Discussionmentioning

confidence: 99%

Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Akerman

Maestro

Grau

et al. 2020

Preprint

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“…GWASs have been used to identify causal variants, disease pathways, and upstream or downstream regulators in various complex diseases. ( 33 ) However, functional characterization of mechanisms at GWAS loci is a multifaceted challenge. The post‐GWAS approach is currently not satisfactory for identifying critical molecular targets in these complex diseases.…”

Section: Discussionmentioning

confidence: 99%

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets. (Hepatology Communications 2020;4:724-738). P rimary biliary cholangitis (PBC) is a rare chronic autoimmune cholestatic liver disease that predominantly affects middle-aged females. PBC is characterized by lymphocytic cholangitis and gradual destruction of the small intrahepatic bile ducts, which leads to fibrosis, cirrhosis, and

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“…Methods for multi-site mapping of tightly linked causal variants need to be further explored. One strategy is to incorporate functional evidence from ENCODE or evolutionary conservation into the mapping algorithm (25,26), though this strategy seems to be more productive for promoter-proximal than distal elements.…”

Section: Discussionmentioning

confidence: 99%

TreeMap: A Structured Approach to Fine Mapping of eQTL Variants

Liu

Chandrashekar

Zeng

et al. 2020

Preprint

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Motivation: Expression quantitative trait loci (eQTL) harbor genetic variants modulating gene transcription. Fine mapping of regulatory variants at these loci is a daunting task due to the juxtaposition of causal and linked variants at a locus as well as the likelihood of interactions among multiple variants. This problem is exacerbated in genes with multiple cis-acting eQTL, where superimposed effects of adjacent loci further distort the association signals. Results:We developed a novel algorithm, TreeMap, that identifies putative causal variants in cis-eQTL accounting for multisite effects and genetic linkage at a locus. Guided by the hierarchical structure of linkage disequilibrium, TreeMap performs an organized search for individual and multiple causal variants. Via extensive simulations, we show that TreeMap detects co-regulating variants more accurately than current methods. Furthermore, its high computational efficiency enables genome-wide analysis of long-range eQTL. We applied TreeMap to GTEx data of brain hippocampus samples and transverse colon samples to search for eQTL in gene bodies and in 4 Mbps gene-flanking regions, discovering numerous distal eQTL. Furthermore, we found concordant distal eQTL that were present in both brain and colon samples, implying long-range regulation of gene expression.Availability: TreeMap is available as an R package enabled for parallel processing at https://github.com/liliulab/treemap.

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Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci

Cited by 97 publications

References 134 publications

Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

TreeMap: A Structured Approach to Fine Mapping of eQTL Variants

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