🤯 The black death killed 30-60% of Europe so it's reasonable to think it affected the allele frequency spectrum.

Absolutely incredible @Nature paper using ancient DNA pre-post the black death to show positive selection of immune genes due to the plague (Fig2d-g). It's so impressive they got 206 ancient DNA samples pre-, during, and post- plague in not 1, but 2 cities (so they could replicate the findings). I'm honestly gobsmacked at how cool this paper is. Huge congrats to Jennifer Klunk, @TaurVil, @LB_Barreiro and co.🎉

Last in this #ASHG21 late breaking plenary session is Bailey Martin-Giacalone presenting on germline variants in cancer predisposition genes predict survival for children with rhabdomyosarcoma #ASHG21 Martin-Giacalone: Want to look at germline (not somatic) variants associated with rhabdomyosarcoma (RMS ).

Exome-sequenced 615 RMS cases and 9963 adult controls.

Next up in the #ASHG21 late breaking plenary session is Elisa De Franco (@Elisa_EDF) presenting loss of primate-specific gene ZNF808. #ASHG21 @Elisa_EDF: studying mice can provide insights into human biology, but there are differences. Mice have 2 genes for insulin (Ins1, Ins2), humans have 1 (INS).

Next up in the #ASHG21 plenary session is Jonathan Sebat (@sebatlab) covering WGS of #Autism combining common and rare variants. #ASHG21 @sebatlab: Found more de novo variants in cases than controls, rare inherited variants overtransmitted to cases, polygenic scores overtransmitted to cases. As such, all 3 categories are associated with #Autism risk.

#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

Really impressive talk on noncoding #constraint in #gnomAD genomes from Siwei Chen (@konradjk's lab).

#ASHG21 Chen: Calculated constraint on 1kb windows using Z scores.

How do known non-coding elements (like enhancers) look when viewed through the lens on constraint?

#ASHG21

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

Suyash Shringarpure (@suyashss) from @23andMeResearch presented a fantastic #raredisease study: "Novel genetic associations for rare diseases with GWAS and trans-ethnic analysis of self-reported medical data"

#ASHG21

medrxiv.org/content/10.110… .@suyashss: It's well known that self-reported data works very well for common diseases, but what about rare diseases? The assumption is that it wouldn't work.

The other common assumption is that rare disease requires sequencing to find rare causal variants.
#ASHG21

Next up is Randy Parish presenting SR-TWAS: Leveraging multiple reference panels to improve TWAS power by ensemble machine learning

#ASHG21 Parish: Transcriptome-wide association study (TWAS) is a popular technique to integrating reference transcriptomic data with GWAS data for conducting gene-based association studies

#ASHG21

Next up in the "Novel associations take novel statistical methods" platform, @_jennaBallard (@Luke0connor's lab) is presenting "Pleiotropic decomposition regression to characterize multi-trait genetic architecture"

#ASHG21 Ballard: Pleiotropy is widespread in GWAS and can be mechanistically informative - providing information about systems that are common and different across disparate traits.

#ASHG21

Huge congrats to @jdbackman, Manuel Ferreira, @gabecasis, @RegeneronDNA, and co. on @Nature 450k exome @uk_biobank paper 🎉🎉🎉

Especially exciting to see ALL ancestries analyzed (not just EUR like most other UKB exome papers thus far)
nature.com/articles/s4158… Across 454k individuals, they found 12.3M variants (99.6% MAF<1%). This is:
- 1.3x the coding variation in TOPMed & gnomAD combined
- 8x what could be found from TOPMed imputation of UKB (info >0.3)

Large study of protein-coding variants from @biogen by @ben_b_sun, @heikorunz and co. in 653K individuals (392K EUR @uk_biobank exomes & 260K @FinnGen_FI imputed genotypes) across 744 phenotypes medrxiv.org/content/10.110… Testing individual coding variants (so no burden tests), they found 975 associations (P<5e-8), 715 at Bonferroni threshold (P<2e-9). Most associations in missense variants (although unclear whether that is enriched above expectation), and 1/3 were novel.

Our #COVID19 pan-ancestry exome-wide meta-analysis across 586,157 individuals (20,952 SARS-CoV-2 positive cases, 4928 hospitalized, 1304 severe) is now out in @AJHGNews.

What did we find? To be frank, not much, but here's a 🧵.

cell.com/ajhg/fulltext/… Within 3 cohorts with #COVID19 phenotypes (@uk_biobank, @GeisingerHealth, @PennMedicine), we analyzed rare variants (MAF<0.5%; ~7million) and burden tests within each ancestry separately and meta-analyzed our results. Incorporating non-EUR data increased our case N by ~10%.

Survived another ASHG plenary talk :)

In case you missed it, I presented results on behalf of @Regeneron from a trans-ancestry #COVID19 meta-analysis of common and rare variants + gene burden tests in >883k imputed samples and >592k exomes.
#ASHG20 Using REGENIE developed by @joellembatchou and @marchini (SAIGE gave us some bizarre results with rare variants) to run our common and rare variant GWASes, we found 2 loci associated with susceptibility and 3 loci with hospitalization. #ASHG20

Up next in the first #ASHG20 plenary session is my former Daly lab colleague, @HHeyne, presenting work from @FinnGen_FI on "Recessive effects of 82,516 coding variants in 176,899 Finns." Bottleneck in Finland makes the Finnish population and @FinnGen_FI ideal for understanding ultra-rare variants that stochastically rose in frequency #ASHG20

1st Plenary #ASHG20 session: Meredith Course identified a human-specific 69bp repeat expansion in the last exon of WDR7.

This repeat was associated with ALS (repeats in ALS cases are on average longer in ALS cases than controls). Longest repeat observed was 86bp. #ASHG20 Observed periodicity in the WDR7 repeat and found that it expands in multiples of 2 in the 3' - 5' direction. #ASHG20

Up next is @joellembatchou from @Regeneron presenting REGENIE - a computationally efficient whole genome regression for quantitative and binary traits #ASHG20

biorxiv.org/content/10.110… Both BOLT and SAIGE are fantastic LMMs for quantitative and binary traits respectively, but have high memory requirements and long computational times. #ASHG20