Buffering and non-monotonic behavior of gene dosage response curves for human complex traits DOI Creative Commons
Nikhil Milind, Courtney J. Smith,

Huisheng Zhu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

A bstract The genome-wide burdens of deletions, loss-of-function mutations, and duplications correlate with many traits. Curiously, for most these traits, variants that decrease expression have the same average direction effect as increase expression. This seemingly contradicts intuition that, at individual genes, reducing should opposite on a phenotype increasing To understand this paradox, we introduce concept called gene dosage response curve (GDRC) relates changes in to expected phenotype. We show GDRCs are systematically biased one trait relative other and, surprisingly, 40% non-monotone, large increases decreases affecting direction. develop simple theoretical model explains bias Our results broad implications complex drug discovery, statistical genetics.

Language: Английский

Buffering and non-monotonic behavior of gene dosage response curves for human complex traits DOI Creative Commons
Nikhil Milind, Courtney J. Smith,

Huisheng Zhu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

A bstract The genome-wide burdens of deletions, loss-of-function mutations, and duplications correlate with many traits. Curiously, for most these traits, variants that decrease expression have the same average direction effect as increase expression. This seemingly contradicts intuition that, at individual genes, reducing should opposite on a phenotype increasing To understand this paradox, we introduce concept called gene dosage response curve (GDRC) relates changes in to expected phenotype. We show GDRCs are systematically biased one trait relative other and, surprisingly, 40% non-monotone, large increases decreases affecting direction. develop simple theoretical model explains bias Our results broad implications complex drug discovery, statistical genetics.

Language: Английский

Citations

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