Post

I'm excited to share that our work studying gene dosage response curves (GDRCs) is now out in Cell Genomics (@cellpress.bsky.social). www.cell.com/cell-genomic... [1/n]

cell.comBuffering of gene dosage response curves for human complex traitsMilind et al. explore why loss-of-function variants and duplications tend to have average effects in the same direction on 94 complex traits. Using gene dosage response curves (GDRCs), they gather evi...

Nikhil Milind

@nikhilmilind.dev

26 May

With amazing collaborators @courtsmithrun.bsky.social, @huishengzhu.bsky.social, @tamigj.bsky.social, and my mentors @jeffspence.github.io and @jkpritch.bsky.social. [2/n]

Nikhil Milind

@nikhilmilind.dev

We observed that the average effect of gene deletions (LoF) and gene duplications was positively correlated across traits. We use the GDRC to conceptualize what types of gene dosage architectures may explain this pattern. [3/n]

26/5/26, 11:59 pm0 reposts1 like

Nikhil Milind

@nikhilmilind.dev

26 May

We find that this pattern is explained by trait buffering, which is the propensity for GDRCs to be buffered against modifying the trait in one particular direction over the other. [4/n]

Nikhil Milind

@nikhilmilind.dev

26 May

We propose a simple model of an upstream "dysregulation" phenotype that may explain why GDRCs organize themselves in this manner. [5/n]

Nikhil Milind

@nikhilmilind.dev

27 May

I think GDRCs are a conceptually pleasing way to tie together various estimates of gene effect that are used in the field (e.g., burden tests, TWAS). [6/n]

Nikhil Milind

@nikhilmilind.dev

27 May

In the paper, we introduced new quantities related to GDRCs: monotonicity and trait buffering. These are somewhat challenging to interpret, so I have a short blog post explaining them: nikhilmilind.dev/posts/interp... [7/n]

nikhilmilind.devNikhil Milind