GWAS sounds like some exotic African or South American disease that we learned about in medical school. But it isn’t. Before I divulge what it means, you have to promise to stick with me to the end as GWAS is already revolutionizing medicine “as we know it.” This is important because it is likely to touch you personally in the near future.


What is GWAS?

It stands for Genome-wide Association Study, which is already realizing the long dream of researchers and doctors of personalized medicine. Just imagine: you are battling the midriff bulge that just won’t go away, despite the most draconian diets imaginable. Why do some people maintain their weight while feasting with abandon, and you, poor soul, gain weight just by looking at food? The answer my friend is written in the genes.  This we knew intuitively for a long time, and we even used it as a ready excuse to give up the battle of the bulge.

The problem is that complex diseases and other biological phenomena (behavior, for instance) are not controlled by one or two genes; they are controlled by multiple genes, each one making only a minor or moderate contribution. But even that is too simple: many of these genes require that they interact with others in order to exert their influence. You can see how impossibly complex it would be if you had to discover one gene at a time, and then study all possible interactions with the other genes. In fact, the only diseases that had their genetic link deciphered were the ones in which a mutation in a single gene occurred. A well-known example is Huntington disease, a devastating neurological disorder which came into prominence because it afflicted folksinger, Woody Guthrie.

In the 1990’s 2 genes were discovered that conferred susceptibility to breast and, to a lesser extent, ovarian cancers: BRCA1 and BRCA2. But these susceptibility genes were found primarily among Ashkenazi Jews. Most women with breast cancer or ovarian cancer did not have these genes. This led to the conclusion that complex diseases like cancer or diabetes are polygenic diseases.

Enter the invention of GWAS. Recent technological advances have provided platforms that allow hundreds of thousands of SNPs (single nucleotide polymorphism, pronounced SNIPS, which are gene variants, or mutations) to be analyzed in association studies, thus providing a basis for identifying moderate risk variants without prior knowledge of position or function. This is like saying that you could recognize whether a face is a man’s or a woman’s without knowing the individual bones, muscles, blood vessels etc. that in the aggregate make a face.  In other words, we don’t have to analyze every component of the face—instead, we recognize the pattern.


Pattern recognition is the basis of GWAS.  How is it done?

To carry out a genome-wide association study, researchers use two groups of participants: people with the disease being studied and similar people without the disease. Researchers obtain DNA from each participant, usually by drawing a blood sample or by rubbing a cotton swab along the inside of the mouth to harvest cells.

Each person’s complete set of DNA, or genome, is then purified from the blood or cells, placed on tiny chips and scanned on automated laboratory machines. The machines quickly survey each participant’s genome for strategically selected markers of genetic variation (or SNIPS). If certain genetic variations are found to be significantly more frequent in people with the disease compared to people without the disease, the variations are said to be “associated” with the disease. The associated genetic variations can serve as powerful pointers to the region of the human genome where the disease-causing problem resides.


What are the fruits of this technique?

We are witnessing a veritable avalanche of GWAS studies, linking diseases with their genetic mutations. The first one, in 2005, reported on age-related macular degeneration, an eye disease that is a major cause of blindness in older adults. And what a surprise it was: the gene identified as the culprit was a variant that makes a protein called Complement Protein H, which has to do with inflammation. Until then, inflammation was not even on the radar screen as a cause for this disease.

In short order, genetic linkages were discovered for obesity, type 2 diabetes, Crohn’s disease, prostate cancer, and breast cancer. And a study published in Nature Genetics this week identified the genetic mutation that is responsible for a common migraine.


The promise of individualized medicine: how will these findings be translated into clinical practice?

Take the recent discovery of the genetic variant that is responsible for a common migraine. It turns out that a genetic mutation of the gene EEAT2 interferes with the removal of glutamic acid, a neurotransmitter, from the synapse. Until now the treatment of a migraine focused on analgesia and on vasoconstriction since a migraine was associated with vasodilatation. But this could be only a secondary cause of the disease: increased neuronal activity due to building up of glutamic acid could cause increased demand for nutrients and oxygen, hence the vasodilatation. Now drug developers could concentrate on the real cause of the disease and nip it in the bud.

What’s next? Active research is going on in different cancers, type 2 diabetes, and other common, genetically complex diseases. How exciting!

Stay tuned.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.