Gene expression QTL mapping in stimulated iPSC-derived macrophages provides insights into common complex diseases, Panousis et al 2025

[leokitten]

Many disease-associated variants are thought to be regulatory but are not present in existing catalogues of expression quantitative trait loci (eQTL). We hypothesise that these variants may regulate expression in specific biological contexts, such as stimulated immune cells. Here, we used human iPSC-derived macrophages to map eQTLs across 24 cellular conditions.

We found that 76% of eQTLs detected in at least one stimulated condition were also found in naive cells. The percentage of response eQTLs (reQTLs) varied widely across conditions (3.7% − 28.4%), with reQTLs specific to a single condition being rare (1.11%). Despite their relative rarity, reQTLs were overrepresented among disease-colocalizing eQTLs. We nominated an additional 21.7% of disease effector genes at GWAS loci via colocalization of reQTLs, with 38.6% of these not found in the Genotype–Tissue Expression (GTEx) catalogue.

Our study highlights the diversity of genetic effects on expression and demonstrates how condition-specific regulatory variation can enhance our understanding of common disease risk alleles.

Open access

 

[leokitten]

Activated immune cells reveal hidden drivers of autoimmune diseases

By stimulating macrophages—a type of white blood cell—with biological factors that mimic infection, researchers have uncovered genetic drivers of complex diseases such as inflammatory bowel disease (IBD), in one of the largest studies of its kind.

medicalxpress.com

 

[leokitten]

Merged thread due to being very related
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Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk

The majority of immune-mediated disease (IMD) risk loci are located in non-coding regions of the genome, making it difficult to decipher their functional effects in relevant physiological contexts. To assess the extent to which alternative splicing contributes to IMD risk, we mapped genetic variants associated with alternative splicing (splicing quantitative trait loci or sQTL) in macrophages exposed to a wide range of environmental stimuli.

We found that genes involved in innate immune response pathways undergo extensive differential splicing in response to stimulation and detected significant sQTL effects for over 5734 genes across all stimulation conditions. We colocalised sQTL signals for over 700 genes with IMD-associated risk loci from 22 IMDs with high confidence (PP4 ≥ 0.75). Approximately half of the colocalisations implicate lowly-used splice junctions (mean usage ratio <0.1). Finally, we demonstrate how an inflammatory bowel disease (IBD) risk allele increases the usage of a lowly-used isoform of PTPN2, a negative regulator of inflammation.

Together, our findings highlight the role alternative splicing plays in IMD risk, and suggest that lowly-used splicing events significantly contribute to complex disease risk.

Open access

 

[leokitten]

Activated immune cells reveal hidden drivers of autoimmune diseases

A new resource, MacroMap, provides a rich dataset that researchers can use to explore genetic mechanisms behind complex diseases.

www.sanger.ac.uk

 

[leokitten]

If anyone has the energy right now to query MacroMap and to see if anything from DecodeME comes up

 

[forestglip]

Activated immune cells reveal hidden drivers of autoimmune diseases

By stimulating macrophages—a type of white blood cell—with biological factors that mimic infection, researchers have uncovered genetic drivers of complex diseases such as inflammatory bowel disease (IBD), in one of the largest studies of its kind.

medicalxpress.com

Many genetic variants—changes in DNA—associated with disease are thought to influence the extent to which genes are turned on or off. However, these changes are often missing from current databases that map genetic differences that influence gene expression. One reason for this is because studies often use 'resting' cells.

In a new study, researchers from the Sanger Institute sought to understand how genetic differences between people affect the behavior of a type of immune cell, called a macrophage, when stimulated to different conditions and stressors. Macrophages are a form of white blood cell responsible for engulfing and digesting harmful substances or cellular debris.

They found 1,955 instances where gene activity overlapped with genetic variants that are associated with disease, and over half of these—51%—would have been missed using unstimulated cells. For example, a genetic variant associated with coronary artery disease was found to increase the activity of a gene called CTSA, but only when macrophages were stimulated with inflammatory signals.

In a complementary study, which is also part of the MacroMap project and published in Nature Communications, the same team looked at RNA splicing—a process where cells cut and rearrange RNA, which is the instructions from DNA to make proteins.

They found that over 5,000 genes changed their splicing patterns when macrophages were activated by stimuli and that genetic risk factors for autoimmune diseases were linked to differences in splicing.

One genetic change was found to increase the use of a rare version of a gene called PTPN2, which normally helps control inflammation, and so it is suggested that this change may increase the risk of developing IBD.

The data is available on https://www.macromapqtl.org.uk