Kenny Westerman

@tamar_sofer at lunch: "Do gene-environment interactions really exist?" A year later, we've collected our thoughts on mechanisms that produce a detectable GxE and when we might care: doi.org/10.1016/j.ajhg… Compliments/criticisms/personal attacks welcome!

Thanks to the many co-authors and TOPMed contributors (including @Riudecanyenc, @deirdre_tobias, and @AlisaManningPhD), and I'd love to hear any feedback and suggestions for future work!

We report: some genetic discovery, some thoughts on statistical power grounded in realistic estimates of diet-related effect sizes and measurement error, and a model for integrating best practices from genetic epidemiology, interaction analysis, and nutritional epidemiology.

Our gene-macronutrient interaction manuscript is out in Diabetes! doi.org/10.2337/db22-0… We set out to find instances of genetic modification of the relationship between dietary macronutrients and glycemia.

@Alan_Couzens How specific are these exercise-related adaptations to the muscles being used, versus whole-body adaptations?

Mitochondria, the powerhouse of the cell, takes time to build. Transcriptional activation, protein synthesis, import, assembly, fission & fusion - all crucial steps that require patience. Remember, good things come to those who wait, even at the cellular level! 🧬⏳ #MitochondrialBiogenesis

Can genetic heritability act as an unbiased metric to compare different phenotype processing methods? Check out our (@kewesterman @AlisaManningPhD et al) latest work applying this to my favorite phenotype (messy diet data). frontiersin.org/articles/10.33…

Thrilled to share that our manuscript on T2D genetic clustering is now published! Soft clustering analysis of type 2 diabetes loci identifies ten physiologically interpretable genetic clusters associated with distinct tissues and clinical outcomes. link.springer.com/article/10.100…

@deirdre_tobias @Riudecanyenc @AmDiabetesAssn @LajousMartin At which point, finally, everything you touch will become causal. Congrats DeeDee!

@Riudecanyenc @AmDiabetesAssn @LajousMartin Thanks Jordi! next step, genetics 🧬

Sweat equity and persistence paid off 🥹 long-time passion project is finally funded! Thank you @AmDiabetesAssn! So excited to work with Drs. @LajousMartin & Dalia Stern on cutting-edge causal inference methods for nutritional epidemiology and T2D prevention. More to come...

We had some very good in person @RallyForNIH meetings with @RepKClark and @RepLynch offices as well as virtually with @SenMarkey & @SenWarren. Thank you all for your steadfast support of the @NIH budget! @DanaFarber @HowardU @ASPPHtweets @GeneticsSociety

But in seriousness, I hope this work encourages discussion about statistical power for gene-diet (and generally, GxE) interactions. Our power calcs here depend substantially on parameter assumptions; what interaction effect sizes are (1) realistic, and (2) practically relevant?

I won't go full tweetorial while on vacation, but check out our new preprint! medrxiv.org/content/10.110… If you like carbohydrates and/or sobering power calculations, this one's for you!

@doctorveera @jacobjchr Our investigation of this isn't published, but was related to what became the triglyceride vignette here: doi.org/10.1038/s41467… The idea of TM6SF2 pleiotropy in genetic effects has been described though, for example: doi.org/10.1002/hep4.1…

@kewesterman @jacobjchr Interesing! Is it published somewhere?

Mendelian Randomization suggests that increased triglyceride levels is protective against alcoholic liver disease. 🤔

Shout-out to co-authors @JBCole150, @AlisaManningPhD, @miriam_udler, and others. You can browse and download our catalog of vQTLs and GxEs on the @AMP_CMDKP (hugeamp.org/research.html?…) -- let us know what you think!

2) We additionally tested for GxEs across all main-effect loci (not just vQTLs), showing that loci with vQTLs were much more enriched for underlying GxEs than standard GWAS loci. This finding supports the original motivation for this project and agrees with existing literature.

Our manuscript on variance-quantitative trait loci and exposome-wide interaction testing is now published! nature.com/articles/s4146…

@jacobjchr @KCKlatt @sguyenet Although this definitely remains in the fundamental category of "p-value threshold worship"!

@jacobjchr @KCKlatt @sguyenet We've used a PCA-based method to generate a specific number of "effective" tests to use for Bonferroni correction -- see Methods section here: doi.org/10.1093/hmg/dd…

Y'all please stop recommending correcting for multiple test corrections when outcomes are non-independent. Got back peer reviews that tried to 'gotchya, rigor!' us with this when we measured the same omega 3 as it moved through different compartments 🙄