by Catherine Weiner
figures by Michael Gerhardt
A decade ago, the idea of analyzing your DNA from the comfort of your own home seemed like science fiction. Tests required several weeks, thousands if not millions of dollars, and a lab of highly specialized PhDs. Today, thanks to technical advances and companies like 23andMe, you can perform this analysis for $199.
The U.S. Food and Drug Administration (FDA) recently approved the first direct-to-consumer genetic testing for ten medical diseases and conditions, including late-onset Alzheimer’s and celiac disease. Approval of the kit marks a dramatic shift from a 2013 decision in which the FDA banned 23andMe’s reporting on disease risks. The FDA’s change of heart opens the floodgates for other companies to expand their repertoire of available tests. As tests become more available and public interest in personalized genetics grows, what should you know to be an informed at-home geneticist?
How does the test work?
DNA is the set of blueprints inside every cell in our body. These instructions are written as an alphabet containing four letters called nucleotides: ‘A’, ‘T’, ‘C’, and ‘G’. Across the human population, these DNA blueprints are largely the same. In fact, about 99.5% of the 3.5 billion A’s, T’s, C’s, and G’s of DNA between any two people are identical. The 1 million sites of DNA in which one letter has been substituted for another—for example, a place where an A in one person is a C in another—are called SNPs (single nucleotide polymorphisms, pronounced ‘snips’). It is the small fraction of SNPs that makes every individual unique. It is also this small fraction that companies like 23andMe analyze.
These companies record the information at ~500,000 individual DNA sites with technology known as SNP-arrays. These arrays are pre-loaded with thousands of standardized DNA regions that are known to be associated with human disease. Thanks to advances in chemical synthesis technology, the thousands of DNA regions to be tested are physically attached to a chip smaller than your hand. When a customer is ready for genetic testing, they simply spit into a receptacle and mail in their saliva sample. The customer’s DNA is then isolated from this sample, fragmented, and placed on the SNP-array. When a fragment of the customer’s DNA matches the DNA region on the SNP-array, it attaches to the chip, isolating the consumer’s disease-associated DNA regions. The identity of the letter of each SNP can then be determined with newly developed high-sensitivity cameras. Using this technique, 23andMe determines which letters are present at informative DNA sites as opposed to the entire DNA, allowing them to dramatically reduce costs while still reporting each customer’s most important disease risks.
What is the link between DNA and disease?
The letters present in DNA code come together to form genetic words or ‘genes.’ Analogously to how each word has a unique definition in English, each gene has a specific function in cells. Therefore, altering a letter in a gene can dramatically change its function, just as changing letters in a word alter its definition. Most SNPs are innocuous and fall in regions of DNA where changing a letter will have no effect. However, some SNPs can affect a person’s susceptibility to different diseases.
For example, in the late 1990s, scientists discovered a gene, named Factor V, required to stop the blood clotting process. A SNP in Factor V was quickly identified that prevented this gene from stopping the clotting process, meaning that a Factor V gene harboring this SNP caused blood to clot more than usual. Around the same time, it was noted that patients who developed deep vein thrombosis (DVT), a blood clot in the lower extremities that can often lead to stroke, had an increased chance of carrying the same SNP that encodes for the broken Factor V gene. After this initial breakthrough, further epidemiological and biological studies have characterized the genetic underpinnings of DVT. Today, we understand that nearly 5% of the population is affected by this disorder and that having the SNP that leads to a nonfunctional Factor V increases a person’s risk of excess blood clotting by seven fold.
However, linking a single SNP to a complex human disease is not always straightforward. Just as with Factor V, the association between a SNP and a disease is often uncovered by comparing DNA information collected from hundreds of affected patients to the same information collected from unaffected individuals. If a particular SNP is significantly more common among patients with a given disease or disorder, scientists may conclude that this SNP is associated with that condition. It is important to note that correlation of a SNP with a disease outcome does not mean that the SNP causes the disease.
What diseases are now tested?
The original health reports conducted by 23andMe reported on approximately 200 gene-disease associations. However, the FDA was concerned with the accuracy of the testing and the ability of consumers to interpret their results without a professional geneticist. In a letter to the Wall Street Journal, the FDA Commissioner Margaret Hamburg explained the reasoning for the 2013 ban: “The agency’s desire to review these particular tests is solely to ensure that they are safe, do what they claim to do, and that the results are communicated in a way that a consumer can understand.” She went on to explain that without further evidence linking the claims of the report to actual scientific backing, a false positive result could harm consumers who seek out unnecessary treatment or undergo an unnecessary burden.
After further research validating the accuracy of each SNP and demonstrating that consumers understand more than 90% of their results without professional counseling, 23andMe has recently won approval to test for ten human diseases and conditions in which there is a clear scientific link between a particular SNP (or set of SNPs) and a disease outcome (Table 1).
Why only ten diseases?
Human disease is a complicated puzzle, and many pieces must fit together in order for an individual to be affected. Genetic factors, such as SNPs, are only one piece of this puzzle. Environmental and lifestyle choices must also be considered. Given the complexity of many diseases, scientists struggle to identify key links between the genetic differences throughout the human population and the risk of disease certain genetic variants actually carry. The FDA plans to put in place a pipeline to ease approval of additional diseases for SNP testing as research in this area improves; however, no decisions on how this will be implemented have been made at this time.
What is next?
Companies like 23andMe hope to empower the public by providing accessible genomic information. With these data, people can begin to understand the potential risks carried by their DNA and adjust their lifestyles accordingly to reduce their probability of developing particular disorders. They can also be advocates for their own health and actively seek out professional opinions on results they may find worrying. A continued increase in interest and understanding of personal genetics among the general public will add to growing pressure on the pharmacology and medical communities to begin incorporating these approaches into their daily practice. It is not impossible to imagine that, within our lifetime, most people will have genetic testing performed and that such testing will lead to increased personalization of medical treatment.
Catherine Weiner is a third year PhD candidate in the Molecules, Cells, and Organisms Program at The Department of Molecular and Cellular Biology, Harvard University.
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Learn more about the ten diseases:
Late-onset Alzheimer’s disease; Parkinson’s disease; Early-onset primary dystonia; Celiac disease; Alpha-1 antitrypsin deficiency (AATD); Gaucher disease type I; Glucose-6-phosphate dehydrogenase deficiency (G6PD); Hereditary hemochromatosis; Factor XI deficiency; Factor V Leiden