Atlas of immune cells explains how genetic variants cause disease

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"Highlights

• Geneticists have long struggled to find the mechanisms by which many disease-linked genetic variants actually cause disease. 
• A new atlas of more than 10 million immune cells from more than 1,100 Finnish blood donors provides a way to connect disease-associated regulatory variants with the genes they control.
• The approach relies on looking at chromatin accessibility — the openness of the DNA around a certain genetic variant — and how that openness correlates with the expression of nearby genes.

...

Now, scientists have developed a new approach to connecting disease-linked regulatory variants to the actual genes they control. Their results, in Nature, reveal that these variants are more likely to influence disease risk if they alter chromatin accessibility — the openness of a section of the genome — in a way that then changes expression of a specific gene, compared to variants that affect only chromatin accessibility or gene expression alone. The finding could help other scientists prioritize the genetic variants that are most important in a particular disease. ...

Across eight broad types of immune cells, the team carried out the full analysis of chromatin accessibility and gene expression for thousands of different disease-linked genes. They then traced the precise molecular mechanisms behind several disease-linked genetic variants. ..."

From the abstract:

"Most disease-associated genetic variants lie in non-coding regions, yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation.

Single-cell molecular quantitative trait locus (QTL) mapping connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression.

Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cells reveals regulatory architectures connecting variants to disease.

From paired single-nucleus assay for transposase-accessible chromatin-sequencing (snATAC–seq) and single-nucleus RNA-sequencing (snRNA-seq) analysis of 10 million peripheral blood mononuclear cells in 1,108 Finnish individuals, we identify 51,083 cis-expression QTLs for 20,829 genes, 338,100 cis-chromatin accessibility QTLs for 210,584 peaks, 119,094 putative causal variants and 593,765 peak–gene links.

Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, with massively parallel reporter assays validating 10,428 fine-mapped molecular QTLs.

At evolutionarily constrained genes, we identify multilayered regulatory buffering, in which chromatin accessibility changes occur with normal effect sizes, but transmission to expression is attenuated through weaker, more numerous enhancer–gene links. This reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion.

Analysis using a massively parallel reporter assay confirms that this buffering acts downstream of the regulatory element, with constraint operating at the chromatin-to-expression interface rather than on intrinsic cis-regulatory activity.

Our atlas provides testable hypotheses for over half of immune disease associations, illustrated by cascades at autoimmune loci (TICAM1 and RHOH) and Finnish-enriched variants (TNRC18 and IL21R)."

Atlas of immune cells explains how genetic variants cause disease | Broad Institute "A new method reveals which genetic variants are most important in disease and how cells “buffer” the expression of genes critical for health."

Population-scale immune multiome atlas reveals regulatory disease mechanisms (no public access)

Population-scale multiome immune cell atlas reveals complex disease drivers (preprint, open access)