Tom Soare

GitHub - insitro/AllelicSeries: Implementation of gene-level rare coding variant association tests targeting allelic series: cases where increasingly deleterious mutations have increasingly large phen... Implementation of gene-level rare coding variant association tests targeting allelic series: cases where increasingly deleterious mutations have increasingly large phenotypic effects. - insitro/All...

COAST-SS is available in an updated AllelicSeries R package (github.com/insitro/Alle...). Congrats to all coauthors @zmccaw.bsky.social, Jianhui Gao, Rounak Dey, Simon Tucker, Yiyan Zhang, Jessica Gronsbell, Xihao Li, Emily Fox, @codushlaine.bsky.social and the Research Team @insitro.bsky.social!

Further, because COAST-SS operates on summary statistics instead of individual-level genotypes, it can complete a genome-wide scan 100x faster than the original COAST.

Of the 108 candidate allelic series identified in our analysis, 80 had prior rare variant support, and 23 of the remaining 28 associations had common variant support. The remaining 5 associations, all with HDL, are reported here for the first time.

In a combined analysis of UKB and MVP with a sample size of up to 840K, we identify 108 Bonferroni-significant genes associated with lipid traits, including 41 for HDL (below), more than doubling the number of genes identified in our previous analyses.

Though we recommend using LD calculated in a relevant sample, due to the low LD among rare variants, the test remains valid even when variants are assumed to be in linkage equilibrium.

In simulations and real data, we show that COAST-SS is robust to how linkage disequilibrium (LD) is specified.

Here we present COAST-SS, which enables detection of allelic series genes based entirely on per-variant GWAS summary statistics.

An allelic-series rare-variant association test for candidate-gene discovery Allelic series are collections of variants that lead to a gradation of possible phenotypes. We introduce COAST (Coding-Variant Allelic-Series Test), a test that identifies genes where increasingly del...

The original COAST method (www.cell.com/ajhg/fulltex... enables identification of dose-response relationships between genes and phenotypes (“allelic series genes”), empowering rare variant association testing, but requires access to individual-level genetic and phenotypic data.

A scalable framework for identifying allelic series from summary statistics Genes where a dose-response relationship exists between functionality and phenotypic impact are appealing therapeutic targets, as the effects of pharm…

We’re excited to share a new article from @insitro.bsky.social (first author @zmccaw.bsky.social) in @ajhgnews.bsky.social, introducing a summary-statistic-based implementation of the COding-variant Allelic Series Test, COAST-SS: www.sciencedirect.com/science/arti...

We’re @ #ASHG to share our work that uses high-content phenotypic data, genetics & AI/ML to unblock new biology.

@sominenihk.bsky.social presents work to identify a key gene as a clinical driver of #MASLD

@twsoare.bsky.social presents on #AMD & how we use OCT scans to better predict disease risk

Today insitro announces an exciting new collaboration with insighteyehub.bsky.social at Moorfields Eye Hospital, London, through the development of a novel #AI foundation model to identify and to support #drugdiscovery. Learn more: www.businesswire.com/news/home/20...

@tkaraletsos.bsky.social, Daphne Koller, Hugues Aschard, @mendelrandom.bsky.social, @dgmacarthur.bsky.social, @codushlaine.bsky.social, and additional members of the team at @insitro.bsky.social !

Congrats to the team and our collaborators! @zmccaw.bsky.social, Rounak Dey, Hari Somineni, David Amar, @smukherjee89.bsky.social, Kaitlin Sandor, ...

In summary, associations with ratio traits are not specific to the ratio per se. Practitioners considering GWAS on ratios should examine the motivation for forming the ratio. We provide guidance on how to approach GWAS of related pairs of traits in light of analysis objectives.

In the case where the denominator is heritable and collider bias is a concern, we propose additionally adjusting for a leave-one-chromosome-out polygenic score (LOCO-PGS) of the denominator, which we show corrects for collider bias due to genetic background.

Instead of a ratio model, we propose a model that adjusts for the denominator as a covariate, e.g. to detect the genetic effect on weight while holding height constant. Loci from weight adjusted for height GWAS were enriched for adiposity-related signals more so than loci from the BMI GWAS.

Examining ratio traits commonly used in clinical practice and genetic association testing, such as waist-to-hip ratio and albumin-to-creatinine ratio, we find that loci detected by the ratio model are enriched for denominator signals.

Top “hits” from ratio trait GWASs can be driven entirely by the denominator. This means, for example, that attempts to find genes associated with BMI may return genes associated entirely with height (only), and not weight.

With high-dimensional omics and imaging data, there is a temptation to test all pairs of ratios to increase power. We caution against this approach; GWAS on ratio traits may increase the number of significant associations, but it does so by conflating signals for the numerator and denominator.

Pitfalls in performing genome-wide association studies on ratio traits Any variant associated with either numerator or denominator will associate with the ratio in GWAS of sufficient size. Associations with ratio traits are thus not specific to the ratio. Instead, we rec...

Excited to share a new paper from @insitro.bsky.social (first author @zmccaw.bsky.social ) in @hggadvances.bsky.social vances.bsky.social on scrutinizing the practice of using a ratio trait (numerator / denominator) for GWAS.

www.cell.com/hgg-advances...