Making leaps and bounds in 10 years of genome-wide association studies

A Broad Institute cartoon explains what SNPs have to do with genome-wide association studies
A clip from a Broad Institute infographic explains what researchers look for during genome-wide association studies. Download full infographic here. Credit: Susanna Hamilton/Karen Zusi of the Broad Institute.

In 2007, when the first genome-wide association studies (GWAS) got underway, researchers began to realize just how poorly they had previously been able to predict which genes might be related to certain diseases.

“I think we were all surprised how bad our candidate gene lists were,” said Joel Hirschhorn, MD, PhD, in a recent podcast with the Broad Institute of MIT and Harvard. Hirschhorn, a pioneer in GWAS, now leads the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium, which has analyzed the genomes of hundreds of thousands of people over the last several years.

Joel Hirschhorn, a pioneer in genome-wide association studies
Joel Hirschhorn

Hirschhorn is also a member of the Broad, the director of the Center for Basic and Translational Obesity Research at Boston Children’s Hospital and professor of pediatrics and genetics at Boston Children’s and Harvard Medical School.

GWAS first got its roots in the Human Genome Project, which revealed that although humans are 99.9 percent genetically alike, variation was rampant in the remaining 0.1 percent of an individual’s genome. Most of these genetic variations are single-letter DNA changes called single-nucleotide polymorphisms (SNPs), which on their own are not drastic enough to trigger disease. But, in combination with other SNPs and environmental factors, these DNA variants could contribute to disease.

An upward slope of learning

A Broad story about the evolution of GWAS over the last decade reports that once technologies enabled detection of genome-wide variations, Hirschhorn and his colleagues were “surprised by the number and diversity of DNA changes uncovered.”

“For pretty much every polygenic trait and every disease that we looked at with GWAS, more samples gave us more and more discovered loci, in a surprisingly linear fashion,” Hirschhorn told the Broad.

As GWAS generated more data, Hirschhorn says critics of the approach wondered how anything meaningful would result from the efforts.

“If every gene in the genome is associated, how can that possibly teach us anything about biology?” critics argued, according to Hirschhorn.

That’s why Hirschhorn says a key next step is identifying which regions of the genome might contain SNPs of particular interest, which genes those DNA variants impact and how that changes the way that proteins, cells or tissues function.

Still, Hirschhorn says there has been an “upward slope in terms of what we’re learning.”

Earlier this year, the GIANT Consortium conducted GWAS on more than 700,000 people, discovering 83 DNA changes that influence human height, as well as several genes that affect previously-unknown biological pathways involved in skeletal growth.

“Even larger sample sizes will be needed to completely understand the genetic and biologic basis of human growth and multifactorial diseases,” Hirschhorn said, revealing that an expanded, 2-million-plus-person GWAS study on height is already underway.

Read the Broad Institute’s story on the evolution of GWAS or listen to a podcast with Joel Hirschhorn.