Thread by @jakphd

#ASHG21 first up in the late breaking plenary session is Wenhan Lu looking at pleiotropy in the UKB exomes available at genebass.org

#ASHG21 Lu: observe large-scale pleiotropy across individual variants and genes.
24 genes have >10 independent phenotypic associations

#ASHG21 Lu: Group 491 ICD diseases into 41 domains.
Example: LDLR and ADH1B each have multiple gene associations across different domains

#ASHG21 Lu: 35 genes show an allelic series. allelic series of pLoF variants in ATM are associated with cancer diagnosis.

#ASHG21 Lu: many associations are found across phenotypes, but due to r2<0.5, there will still be residual correlation.

Developed a test for allelic heterogeneity, make the assumption that all variants are independent (no LD; MAF<1% [probably a lower MAF is required here])

#ASHG21 Lu: test only works for QTs. find more significant associations with missense variants than pLoFs.

Example: ALB associated with both albumin and calcium. Find an allelic series of missense variants are associated with calcium and albumin, but no allelic series with LoF

#ASHG21 Lu: great use of synonymous variants as a negative control for assessing their novel statistical tests. It's remarkable how well synonymous variants have worked (and continue to do so) as a really good negative control