Atlas of 10 million immune cells from 1,108 Finnish individuals links noncoding variants to disease
Researchers profiled chromatin accessibility and gene expression in the same nuclei from 10 million peripheral blood mononuclear cells, drawn from 1,108 Finnish individuals. Variants that completed the chromatin-to-expression cascade showed twice the disease colocalization of variants with chromatin-only effects. Massively parallel reporter assays validated 10,428 fine-mapped molecular QTLs. At evolutionarily constrained genes, chromatin changes had normal effect sizes, but transmission to expression was attenuated, a pattern the authors call multilayered regulatory buffering. The paper illustrates cascades at the autoimmune loci TICAM1 and RHOH.
The authors say the atlas gives testable hypotheses for over half of immune disease associations. It also reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion.
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