The Omnigenic Model

theatlantic |  In 1999, a group of scientists scoured the genomes of around 150 pairs of siblings in an attempt to find genes that are involved in autism. They came up empty. They reasoned that this was because the risk of autism is not governed by a small number of powerful genes, which their study would have uncovered. Instead, it’s likely affected by a large number of genes that each have a small effect. Perhaps, they wrote, there might be 15 such genes or more.

Two decades later, that figure seems absurdly and naively low. If you told a modern geneticist that a complex trait—whether a physical characteristic like height or weight, or the risk of a disease like cancer or schizophrenia—was the work of just 15 genes, they’d probably laugh. It’s now thought that such traits are the work of thousands of genetic variants, working in concert. The vast majority of them have only tiny effects, but together, they can dramatically shape our bodies and our health. They’re weak individually, but powerful en masse.

But Evan Boyle, Yang Li, and Jonathan Pritchard from Stanford University think that this framework doesn’t go far enough.

They note that researchers often assume that those thousands of weakly-acting genetic variants will all cluster together in relevant genes. For example, you might expect that height-associated variants will affect genes that control the growth of bones. Similarly, schizophrenia-associated variants might affect genes that are involved in the nervous system. “There’s been this notion that for every gene that’s involved in a trait, there’d be a story connecting that gene to the trait,” says Pritchard. And he thinks that’s only partly true.

Yes, he says, there will be “core genes” that follow this pattern. They will affect traits in ways that make biological sense. But genes don’t work in isolation. They influence each other in large networks, so that “if a variant changes any one gene, it could change an entire gene network,” says Boyle. He believes that these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.

The Stanford trio call this the “omnigenic model.” In the simplest terms, they’re saying that most genes matter for most things.