Researchers say that disease genes are spread uniformly across the genome, not clustered in specific molecular pathways

Jonathan Pritchard (center) and his colleagues, Yang Li (left) and Evan Boyle, discuss their recent work positing that almost any gene can influence disease.
Steve Fisch

Thousands of genes influence most diseases

In a provocative new perspective piece, Stanford researchers say that disease genes are spread uniformly across the genome, not clustered in specific molecular pathways, as has been thought.

A core assumption in the study of disease-causing genes has been that they are clustered in molecular pathways directly connected to the disease. But work by a group of researchers at the Stanford University School of Medicine suggests otherwise.

The gene activity of cells is so broadly networked that virtually any gene can influence disease, the researchers found. As a result, most of the heritability of diseases is due not to a handful of core genes, but to tiny contributions from vast numbers of peripheral genes that function outside disease pathways.

Any given trait, it seems, is not controlled by a small set of genes. Instead, nearly every gene in the genome influences everything about us. The effects may be tiny, but they add up.

The work is described in a paper published June 15 in Cell. Jonathan Pritchard, PhD, professor of genetics and of biology, is the senior author. Graduate student Evan Boyle and postdoctoral scholar Yang Li, PhD, share lead authorship.

The researchers call their provocative new understanding of disease genes an “omnigenic model” to indicate that almost any gene can influence diseases and other complex traits. In any cell, there might be 50 to 100 core genes with direct effects on a given trait, as well as easily another 10,000 peripheral genes that are expressed in the same cell with indirect effects on that trait, said Pritchard, who is also a Howard Hughes Medical Institute investigator.

Each of the peripheral genes has a small effect on the trait. But because those thousands of genes outnumber the core genes by orders of magnitude, most of the genetic variation related to diseases and other traits comes from the thousands of peripheral genes. So, ironically, the genes whose impact on disease is most indirect and small end up being responsible for most of the inheritance patterns of the disease.

“This is a compelling paper that presents a plausible and fascinating model to explain a number of confusing observations from genomewide studies of disease,” said Joe Pickrell, PhD, an investigator at the New York Genome Center, who was not involved in the work.

From a polygenic to omnigenic model

Until recently, said Pritchard, he thought of genetically complex traits as conforming to a polygenic model, in which each gene has a direct effect on a trait, whether that trait is something like height or a disease, such as autism.