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.
Jonathan Pritchard
But last year, while putting together a paper on the recent evolution of height in northern Europeans, Pritchard was forced to rethink that idea.
In the earlier work on the genetics of height, Pritchard and his colleagues were surprised to find that essentially the entire genome influenced height. “It was really unintuitive to me,” he said. “To be honest, I thought that it was probably wrong.” His team spent a long time trying to understand the surprising result.
Instead, he said, “I gradually started to realize that the data don’t really fit the polygenic model.” That work led directly to the current Cell paper, he said. “We started to think, ‘If the whole genome is involved in a complex trait like height, then how does that work?’”
Therapeutic implications
The polygenic model leads researchers to focus on the short list of core genes that function in molecular pathways known to impact diseases. So, therapeutic research typically means addressing those core genes. A common approach to gene discovery is to do larger and larger genomewide association studies, the paper notes, but Pritchard’s team argues against this approach because the sample sizes are expensive and the thousands of peripheral genes uncovered are likely to have tiny, indirect effects. “After you get the first 100 hits,” said Pritchard, “you’ve probably found most of the core genes you’re going to get through genomewide association studies.”
Instead, he recommends switching to deep sequencing the core genes to hunt down rare variants that might have bigger effects. For clinical use, Pritchard said, there’s still a rationale for genomewide association studies: to predict the peripheral gene-based risk factors in individual patients in order to personalize medicine.
Implications for basic science
Pritchard’s omnigenic model promises to take basic biology in new directions and means biologists need to think a lot more about the structure of networks that link together those thousands of peripheral disease genes.
“If this model is right,” said Pritchard, “it’s telling us something profound about how cells work that we don’t really understand very well. And so maybe that puts us a little bit further away from using genomewide association studies for therapeutics. But in terms of understanding how genetics encodes disease risk, it’s really important to understand.”
Learn more:Thousands of genes influence most diseases
The Latest on: Disease genes
- Gene therapy cures patient with sickle cell diseaseon November 30, 2019 at 4:38 pm
Sickle-cell anaemia and beta thalassemia are blood disorders caused when a person inherits mutant versions of the genes that make haemoglobin, the protein in blood that carries oxygen around the body.
- Gene discovery in fruit flies could provide clues to counteract mitochondrial diseaseson November 28, 2019 at 3:47 am
Scientists have identified a protein in fruit flies that can be targeted to reverse the effects of disease-causing mutations in mitochondrial genes. The discovery could provide clues about how to ...
- Gene discovery in fruit flies could help search for new treatments for mitochondrial diseaseon November 27, 2019 at 8:05 am
Scientists have identified a protein in fruit flies that can be targeted to reverse the effects of disease-causing mutations in mitochondrial genes. The discovery could provide clues about how to ...
- Hibernating mammals arouse hope for genetic solutions to obesity, metabolic diseaseson November 26, 2019 at 8:03 am
We believe that understanding the parts of the genome that are linked to hibernation will help us learn to control risks for some these major diseases. A big surprise from our new study is that these ...
- AGTC Grows Preclinical Pipeline with Gene Therapies for Congenital Hearing Loss, Stargardt Diseaseon November 26, 2019 at 5:04 am
Gene therapy developer Applied Genetic Technologies Corp. (AGTC) has expanded its pipeline of orphan disease treatments in recent weeks by partnering with Otonomy to develop an early preclinical ...
- Consistent gene changes in Alzheimer's disease across studieson November 25, 2019 at 10:18 am
A comparison of mouse Alzheimer's disease models shows changes in the number of cells and the genes they express remain consistent throughout all stages of the disease. The new research published in ...
- How AI Is Helping Diagnose Rare Genetic Diseaseson November 25, 2019 at 9:14 am
AI has the power to search through millions of genetic variants at high speed and identify likely ... [+] causes of rare diseases, while also comparing what they find with the existing medical ...
- A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulationon November 25, 2019 at 8:29 am
Fig. 1: Single-nuclei sequencing of human entorhinal cortex recapitulates cell-type-specific marker genes and cell-type-specific changes in Alzheimer’s disease. Fig. 2: Single-nuclei sequencing of ...
- Myriad Genetics' Test Added in Disease Activity Measure Liston November 22, 2019 at 7:52 am
Myriad Genetics, Inc. MYGN announced that its Vectra test was included by the American College of Rheumatology (“ACR”) in its list of recommended disease activity measures for patients with rheumatoid ...
- Alzheimer's Disease Linked to Gene in Studyon November 22, 2019 at 1:31 am
Scientists have identified a gene which they believe could raise the risk of developing Alzheimer's disease. The researchers compared the genomic data from around 5,142 people with Alzheimer's disease ...
via Google News and Bing News