A 🧵 on some of my intuitions/priors about the genetics of complex and molecular traits in humans (i.e. what I think of as typical), largely motivated by GWAS/QTL studies over the past decade [citing papers with nice figures where possible]

A mutation in APOL1 that protects against kidney disease. How does it work? Seems to reduce APOL1 pore function Cool new work integrating human genetics with cellular APOL1 function. 👏@alexbickmdphd Eric Green Maze Therapeutics journals.lww.com/jasn/fulltext/…

A variant of APOL1, p.N264K, is associated with reduced risk of CKD and ESKD among carriers of APOL1 high risk variants to levels comparable to individuals with APOL1 low-risk genotypes bit.ly/JASN0219 Caitlyn Vlasschaert Michael Matheny Katalin Susztak Eddie siew Cassy Robinson-Cohen

Here, substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases Science Translational Medicine science.org/doi/10.1126/sc…

If there was only one scientific practice I could teach to every scientist regardless of stage or field I think it would be: look at the data. Spot check it. Find a few data points and trace them through to see if they make sense. Look at the raw data. Don't just do analyses.

Fascinating NYTimes article on quest to understand causes of Kawasaki nytimes.com/2024/02/27/hea…

Nice example of integrating human genetics, functional genomics and protein structure to understand disease biology. Congrats Art Wuster Karol Estrada and team.

Beautiful work from Pietro Fratta, Juan Burrone groups linking TDP-43 to synaptic function with UNC13A as key mediator. Combined with human genetics, strengthens case for UNC13A as promising target for patients with ALS.

We find TDP-43 loss to cause presynaptic defects, which are rescued by ASOs correcting a single cryptic exon in UNC13A. Surprising effect of just one cryptic exon and promising strategy for ALS! Matt Keuss Pete Harley in great collaboration with Juan Burrone Lab biorxiv.org/content/10.110…