Published online 18 May 2010 | Nature | doi:10.1038/news.2010.247

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Hunt for genetic causes of diseases narrows targets

The search is on for rare variants that might explain missing heritability.

young woman with asthma inhalerRare genetic variants have been implicated in asthma.TommL/iStockphoto

The falling cost of genome sequencing has kicked off a new phase in the search for the genetic underpinnings of complex diseases such as asthma, diabetes and autism.

Just five years ago, only a handful of genes had been associated with complex traits and diseases. Then, a wave of studies scanning the genomes of hundreds to thousands of individuals at a time began turning up lists of possible suspects. These studies, called genome-wide association (GWA) studies, look for single-letter changes within genes that commonly appear in unrelated individuals with a particular condition. The problem was that the gene variants these projects turned up explained only a small percentage of the heritability thought to underlie such diseases and traits.

Researchers have since grappled with explaining where this 'hidden' variability might lie. Participants at the Biology of Genomes meeting in Cold Spring Harbor, New York, last week presented several approaches that might be used to solve the mystery.

Because they look for gene variants present in large groups of unrelated people, the variants that GWA studies uncover are, by definition, fairly common within a population. Statistically speaking, the method cannot pick up rarer variants — but many have surmised that these variants might have a notable role in disease heritability.

This is backed up by work by Andrew Clark at Cornell University in Ithaca, New York, and his colleagues, presented at last week's meeting. The researchers resequenced two genes associated with diabetes for a sample of almost 14,000 people. Standard models predict that such a large sample would contain about 100 variants for each of these genes, but no one has ever looked that closely; in fact, the researchers found about 600.

Collective responsibility

So how can researchers probe how much of that variation underlies disease? By resequencing just the regions of the genome responsible for carrying the instructions to build proteins — a mere 1% of the genome, known as the exome — Jay Shendure, a genomicist at the University of Washington in Seattle and his colleagues were able to pinpoint uncommon variants responsible for certain rare diseases that are Mendelian in nature — that is, caused by mutations in a single gene (see 'Selective sequencing solves a genetic mystery'). In his talk at last week's meeting, Shendure suggested ways the approach could be extended to teasing out rare variants in more common diseases.

“The pendulum is very clearly swinging towards rare variants.”


Such evidence is already emerging for the role of some rare variants. Carole Ober, a human geneticist at the University of Chicago in Illinois, presented evidence for the involvement in asthma of rare variants in eight genes. She and her colleagues resequenced, from 1,000 people, the coding regions and surrounding sections of a handpicked set of genes previously implicated in the condition. The relationship they uncovered between these genes and the disease was complex. "For some of the genes it wasn't a particular variant, but it was a number of variants collectively" that boosted disease risk, she says.

"The pendulum is very clearly swinging towards rare variants," says Shendure. But whether or not this new phase of the search will uncover stronger, clearer links between genes and diseases than GWA studies have done remains to be seen, he says. "Rare variants may only explain some additional modest amount of heritability."

False dichotomy

Nontheless, more efforts to identify rare variants are getting under way. Researchers hope, for example, that the first wave of data the 1000 Genomes Project, an effort launched in 2008 to catalog human variation by resequencing the genes and exomes of at least 1000 individuals, will provide some insight. Meanwhile, a handful of large-scale resequencing projects have set out to find rare variants in diseases including diabetes, autism and metabolic disorders. One approach is to simply rack up numbers, sequencing at low accuracy the exomes or whole genomes of several thousand patients and controls. Another is to focus on individuals with extreme phenotypes, such as very high or very low cholesterol, to try to enrich the number of disease-associated rare variants likely to be found in the group.

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What that means for the future of traditional GWA studies isn't yet clear. Some researchers believe that the ability to cheaply sequence exomes, and ultimately whole genomes, will soon make the technique obsolete, simply because sequencing will offer much more information. But until sequencing costs drop sufficiently, a quick and dirty search for common variants will remain valuable — particularly as researchers begin to study the genetics of non-European populations, notes Jeffrey Barrett at the Wellcome Trust Sanger Institute in Hinxton, UK. Most of the common variants found so far were identified in people of European descent, and the genetic underpinnings of everything from malaria and AIDS to obesity and cancer may be different in, say, Africa or Asia. "In those cases, GWA is the perfect place to start," says Barrett.

Researchers also caution against creating a false dichotomy between the old and the new where techniques are concerned. "I think different diseases will likely have different genetic architectures, and I think most of them are going to have a mix of common and rare variants," says Ober. What's more, there are many other possibilities for where the mysterious missing heritability may be hiding — from nonlinear combinations of different variants, to environmental effects, to structural components of the genome1. "I think we should have learned our lesson in the sense that we should not be overselling this idea that we will definitely get to the point of predictive medicine," says Shendure. "It might be so complicated that we can't get there." 

  • References

    1. Eichler, E. E. et al. Nature Rev. Genet. 11, 446-450 (2010). | Article
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