The Omnigenic Model Of Complex Human Traits

quantamagazine |  The question most of genetics tries to answer is how genes connect to the traits we see. One person has red hair, another blonde hair; one dies at age 30 of Huntington’s disease, another lives to celebrate a 102nd birthday. Knowing what in the vast expanse of the genetic code is behind traits can fuel better treatments and information about future risks and illuminate how biology and evolution work. For some traits, the connection to certain genes is clear: Mutations of a single gene are behind sickle cell anemia, for instance, and mutations in another are behind cystic fibrosis.

But unfortunately for those who like things simple, these conditions are the exceptions. The roots of many traits, from how tall you are to your susceptibility to schizophrenia, are far more tangled. In fact, they may be so complex that almost the entire genome may be involved in some way, an idea formalized in a theory put forward last year.

Starting about 15 years ago, geneticists began to collect DNA from thousands of people who shared traits, to look for clues to each trait’s cause in commonalities between their genomes, a kind of analysis called a genome-wide association study (GWAS). What they found, first, was that you need an enormous number of people to get statistically significant results — one recent GWAS seeking correlations between genetics and insomnia, for instance, included more than a million people. 

Second, in study after study, even the most significant genetic connections turned out to have surprisingly small effects. The conclusion, sometimes called the polygenic hypothesis, was that multiple loci, or positions in the genome, were likely to be involved in every trait, with each contributing just a small part. (A single large gene can contain several loci, each representing a distinct part of the DNA where mutations make a detectable difference.)

How many loci that “multiple” description might mean was not defined precisely. One very early genetic mapping study in 1999 suggested that “a large number of loci (perhaps > than 15)” might contribute to autism risk, recalled Jonathan Pritchard, now a geneticist at Stanford University. “That’s a lot!” he remembered thinking when the paper came out.

Over the years, however, what scientists might consider “a lot” in this context has quietly inflated. Last June, Pritchard and his Stanford colleagues Evan Boyle and Yang Li (now at the University of Chicago) published a paper about this in Cell that immediately sparked controversy, although it also had many people nodding in cautious agreement. The authors described what they called the “omnigenic” model of complex traits. Drawing on GWAS analyses of three diseases, they concluded that in the cell types that are relevant to a disease, it appears that not 15, not 100, but essentially all genes contribute to the condition. The authors suggested that for some traits, “multiple” loci could mean more than 100,000.