types of genetic tests

Not all Genetic Tests are the same

Each person carries 4-5 million genetic variations called polymorphisms. Most of these genetic variations do not cause any disease. Analysis of these common variations can provide very interesting insights on our ancestry, and can also be used to predict future diseases. However, the accuracy of these predictions depends on the technology used.

At first glance, it may appear that every genetic test does the same job. In reality, every genetic test uses a specific technology that has a particular purpose. Cheaper tests generally use single nucleotide polymorphism (SNP) genotyping technology, which tests 1-5 million markers. The other major technology used is sequencing that “reads” your genome anew. There are two levels:

A) Whole Exome Sequencing which analyzes gene coding and adjacent region and covers 30-60 Million bases which are most critical for disease analysis;

B) Whole Genome Sequencing that reads all 3 Billion bases of a genome.

How reliable are disease risk calculations using each technology?

SNP analysis is the most commonly used technology due to its low cost. Sequencing technology is more reliable than SNP genotyping for disease prediction analysis.

Here’s the facts:

1.  SNP cannot detect unknown diseases

Although SNP analyzes millions of variations, it cannot detect the most critical rare variations in your genome. This raises the validity of how SNP companies can claim to calculate disease risk with only partial information on the most prevalent variations, while missing information on novel and very rare mutations.

2. SNP-based Disease Risk Estimates Are Not Valid

The 1000 genomes project estimated that each individual carries about 150-510 extremely rare mutations that alter protein function and may have significant implications on a person’s health. SNP array technology, used by most of genetic companies including 23andme and Pathway Genomics, cannot identify these variations. Therefore, any projections and risk estimates provided by these companies are not clinically valid. The fact that you do not carry one of the three most common variations in the BRCA1/2 genes does not mean that you do not have an increased risk of breast cancer. You still may carry one of over 1600 mutations that may cause the disease.

Furthermore, the calculation of disease risk (known as the odds risk ratio or ORR) relies on empirical data where the frequency of the mutation in affected individuals and controls is known. For example, if the mutation is twice as common in cases than in controls than the ORR will be approximately equal to 2, provided the confidence intervals in sufficiently large sample.

But most of the time we do not know the frequency of novel mutations, simply because it was never seen before.  Including a mutation in the calculation of disease risk can potentially lead to overestimation of the risk, based on the “one in a few millions” distribution.

3.  Disease risk estimates change over time!

Our genomes are more or less fixed – the vast majority of our DNA staying largely the same as you inherited from your parents at the time of inception. However, our understanding of genomes changes over time – every day scientific literature is updated with hundreds of new discoveries linking specific genes and variations to common and rare diseases. The rate of discovery is accelerating with more accessible and affordable sequencing. There is a constantly increasing number of genetic variations linked to a disease which increases the accuracy of genetic diagnostics. Today, over 80 genes explain about a half of breast cancer heritability.

Thus, hundreds of rare and common variations and genetic interactions between these mutations need to be accounted when estimating the risk of disease. In addition, the impact of environmental factors such as diet, exercise, and exposure to toxins needs to be included when estimating the probability of developing severe diseases such as cancer. Unfortunately, today we simply still cannot model all these variations to provide reliable estimates. This is the reason we state on our reports whether we have identified a specific risk factor, such as a severe mutation in a known oncogene, or we did not.

How is Sequencing a better technology? Is it too early to get my genome sequenced?

It’s not too early to get your genome sequenced. The benefits of genome sequencing outweigh the costs. The key is to carefully choose a comprehensive genome analysis for best results. Here’s why:

  • Knowledge of carrier status for genetic disease can ensure healthy children;
  • Sequencing genes predisposing to cancer can identify individuals at higher risk and substantially expand life expectancy through close monitoring and preventative treatments;
  • Understanding of your metabolic profile can improve the efficiency and safety of your medications.

There are many other examples of positive impact of genetic testing, but you have to be aware of the limitations of each technology to truly understand the implications for your health.

What’s next?

If you would like to learn more about the differences in genetic testing technologies, continue reading this related blog post: “How to choose a genetic testing provider”.

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Author: Ruslan Dorfman

SNP Genotyping vs Sequencing

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