Our paper on modified penetrance of coding variants by cis-regulatory variation is out in @NatGenet! Huge thanks and congrats to @stephanecastel who led the analysis nature.com/articles/s4158… . 1/7
The hypothesis is that in individuals who’re heterozygous for a (rare) LoF coding variant, the phenotypic outcome (i.e. penetrance) can be affected by a cis-eQTL allele tweaking the “healthy” haplotype dosage. 2/7 
The key analytical approach is asking whether rare predicted deleterious coding variants are randomly distributed on common eQTL haplotypes. We show that they’re not. 3/7
Analysis of GTEx data shows that the general population is depleted of predicted high penetrance combinations for deleterious coding variants, particularly for strong eQTLs & sensitive genes. This phenomenon doesn’t affect all genes & variants, but a subset that makes sense. 4/7
In autism and cancer cohort data, we show an enrichment of high-penetrance haplotype combos in patients, and protective combos in controls. This is direct evidence of common cis-regulatory variants modifying disease risk. 5/7
Finally, we use CRISPR to show that the eQTL haplotype modified cellular effects of a SNP in the FLCN gene causing the Birt-Hogg-Dube syndrome. We hope that someone follows up with analysis of patients! 6/7
Conclusion: Common regulatory variants can modify the penetrance of rare coding variants, and this effect can be captured in diverse data sets. We need to start integrating human genetics across rare & common variants, building on biological hypotheses of variant effects. 7/7
