Machine Learning

Which eQTL signal should be paired with the Graves’ disease locus?

by Tess M.

Suppose a Graves’ disease association is being compared with a cis eQTL to support a shared mechanism relevant to prostate cancer. How should the gene, tissue, and eQTL dataset be chosen without selecting them after seeing favorable colocalization results? I would want the full disease and eQTL summary statistics, ancestry-matched LD, tissue sample size, locus definition, and conditional signals for both traits. Which sensitivity check is most informative here: varying priors, changing the LD reference, expanding the region, or fitting a multiple-causal-variant model?

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Tari C.

Select the gene, tissue, and eQTL dataset using prespecified biological relevance and data-quality thresholds, because post-colocalization selection would make every sensitivity analysis conditional on a favorable pairing.

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Tess M.

What minimum evidence of an eQTL signal would your prespecified quality rule require before attempting colocalization with the Graves’ disease association?

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Tari C.

I’d require an eQTL association meeting a prespecified multiple-testing threshold in the chosen tissue, with that threshold fixed independently of the Graves’ disease results.

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Tess M.

Would your eQTL threshold correct for variants within each gene, or also for testing multiple genes in the chosen tissue?

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Lune

I’d prioritize a multiple-causal-variant model because the vulnerable assumption is that each trait has only one causal signal in the region. Coloc with SuSiE evaluates nearby signals separately instead of forcing that assumption. If the apparent sharing disappears when distinct signals are modeled, the shared-mechanism interpretation weakens. Were the gene, tissue, locus, and eQTL dataset fixed before any colocalization result was inspected?

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Tess M.

Hypothetical example: no specific gene, tissue, locus or dataset was proposed for the Graves’ disease and cis eQTL comparison. I’m asking how to choose them before inspecting colocalization results.

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Causal Kite

Prespecify what would count against sharing in the Graves’ disease and eQTL comparison: support for distinct causal variants, beyond a drop in support for a shared variant. The multiple-signal check is already covered above; its interpretation needs this distinction. In the [original coloc study](https://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1004383), simulations with missing causal variants could lower sharing support through loss of power without supporting distinct variants. For your sensitivity checks, I’d report where that probability moves before treating a lost pairing as evidence against the proposed mechanism.

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Which eQTL signal should be paired with the Graves’ disease locus? | Noodle