omnigenicity - senecio7の日記

Boyle EA, Li YI & Pritchard JK 2017 The omnigenic model: response from the authors. J Psychiat Brain Sci 2:S8.

one of our goals in writing this paper was to highlight an apparent paradox in human genetics
most of the heritability for a typical complex trait is driven by genetic variation at loci that seem unrelated to the trait in question
the lack of a clear explanation for this seeming paradox is a major conceptual gap in modern human genetics

prior to the GWAS era, many researchers conceptualized complex traits in a very similar paradigm
they expected that complex traits would be driven by variants in multiple genes, each with proportionally smaller effect sizes
there was a clear expectation that if those genes could be found, they would lead directly to disease-relevant biology

typical complex traits are hugely polygenic, such that
(1) the largest-effect variants confer only modest risk and, together, explain only a small fraction of the heritability
(2) huge numbers of variants make non-negligible contributions to heritability
(3) the signal is spread surprisingly broadly across the genome
for example, most 100kb windows contain variants that measurably affect height
(4) there is only weak enrichment of heritability in genes with putatively relevant gene functions
(5) while signals are strongly enriched in chromatin that is active in relevant cell types, there is little difference between the enrichment of cell type-specific chromatin vs. generically active chromatin such as constitutive promoters of housekeeping genes
since around 2006, our shared understanding of the architecture of complex traits has been completely transformed

essentially any gene with regulatory variants in at least one tissue that contributes to disease pathogenesis is likely to have nontrivial effects on risk for that disease
since core genes are hugely outnumbered by peripheral genes, a large fraction of the total genetic contribution to disease comes from peripheral genes that do not play direct roles in disease

"gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes"

we tried to leave the definition of core genes open
it seems unlikely to us that a single definition can cover all cases in all complex traits
if a precise definition is needed, we suggested that core genes may be defined as the (minimal) set of genes such that "conditional on the genotype and expression levels of all core genes, the genotypes and expression levels of peripheral genes no longer matter"
in the near future, the combination of GWAS data and expression data in large case-control samples will enable tests to distinguish core and peripheral genes by this definition