Thread by @thatdnaguy

#ASHG20 EDF
Transcription factor regulation of genetic variant effects across tissues and individuals.
Elise D. Flynn.
@EliseScience

#ASHG20 EDF Know that eQTLS are enriched in cis-regulatory elements. Can be context specific, where effect is only seen with certain stimulations. May be seen in many contexts with variable effects.

#ASHG20 EDF eQTLs may be exerting effects by transcription factor binding. i.e. some alleles have higher affinity for binding to TFs. Can also think about this effect at different expression levels of transcription factors. i.e. minimum threshold of TF expression to see effect.

#ASHG20 EDF May also see saturation of both alleles if the expression level of the TF is sufficiently high, i.e. it doesn't matter if one is better at very low levels or very high TF levels.

#ASHG20 EDF Used GTEx v8. What are TF regulators of QTLs? 6.5M common GTEx vars --> 2.9M fine mapped QTL in any tissue --> 473k overlap with a TF as tested by ChIP-Seq signals.

#ASHG20 EDF Calculate eQTL effect in each tissue, correlate with the expression level of the TF in that tissue. ~420k TF-eQTL correlations after correction. Does it correlate with TF level? Example of effect in adipose tissue with EGR1.

#ASHG20 EDF Different effect in skin - genetic effect by allele, but no change based on expression of the TF. 58k interactions seen in any tissue. 3k 2+ tissues. 8k also correlated across tissues.

#ASHG20 EDF Do the predicted TF-eQTL interactions overlap with known binding sites? Across tissues were enriched for overlap with known binding. Within tissue was not correlated well with known TF binding sites.

#ASHG20 EDF High confidence interactions they're following up - 10.5k interactions across 4.1k genes supported by at least 2 lines of evidence.

#ASHG20 EDF Example - PU.1 vs. LIPA eQTL. LIPA eQTL colocalizes with coronary artery disease locus. Evidence for PU.1 regulation of rs1320496. Alt has higher affinity. Allele specific binding in the ENCODE ChIP-Seq data.

#ASHG20 EDF Locus shows multiple associated loci linked. Mutagenesis experiments show multiple independent effects of these SNPs rather than just a single effect of the lead SNP.