Thread by @jakphd

Next up is my @RegeneronDNA colleague, Julie Horowitz, presenting "Common and rare variant analysis of 21K psoriasis cases and 623K controls identifies novel, protective associations in several genes in the type 1 interferon #ASHG21

Horowitz: Previous GWAS of psoriasis have identified >60 loci, but no large scale sequencing of psoriasis has been performed to identify 1) very rare variants and 2) burden tests.

#ASHG21

Horowitz: Leveraging data from >5 cohorts and 4 ancestries (EUR, AFR, SAS, AMR), they performed a trans-ancestry meta-analysis across a total of 21k cases and 623k controls.

#ASHG21

Horowitz: These analyses replicated previous common variants from GWAS. Burden tests of rare LoF and missense variants identified 3 genes, all within the interferon pathway.

#ASHG21

Horowitz: First gene identified from burden tests was IFIH1. Burden tests using both LoF-only and LoF+missense both yield significant protective associations.

#ASHG21

Horowitz: Burden test of rare LoF+missense variants are protective in TRIM65, which encodes an E3 ligase that interacts with IFIH1 (as discussed in the previous tweet). Most of the signal in this burden test is driven by a single missense variant.

#ASHG21

Horowitz: Last gene burden comes from LoF+missense in ADAR that increases risk (OR=1.97; P<9.7e-9) - in contrast to the previous two associations that were protective.

#ASHG21