Precision medicine: the idea that your genes can tell the best diet, lifestyle, supplementation, disease treatment, and biohacks sounds great in theory. However, in practice, not all data points we’re making use of have solid scientific backing. In addition, most consumers are unaware of the technological and scientific nuances. While I believe personalized medicine and nutrigenomics can be highly beneficial, this article will cover the nuances that explain why we need to exercise healthy skepticism with these tests and their interpretations.
Single Nucleotide Polymorphisms (SNPs) Are NOT the Only Type of Genetic Variants
Polymorphisms and genetic variants are collective terms that include more than just SNPs. For example, you have the following:
Variation in the number of gene copies
Repetitive sequence variations
Addition and subtraction of DNA sequence to the gene
Deletion of genes
Caption: different types of genetic variants in the human genome1
SNPs are the smallest genetic variants because they only involve one base pair. In the human genome, SNPs are found every 1000 base pairs. Eighty percent of all known human variants are SNPs, which may account for the majority of trait differences from person to person.2 However, SNPs are not the only type of genetic variations we have.Keep in mind that currently, the only technology used by 23andme, Geno, and Ancestry are SNP arrays. They only detect SNPs. Therefore, it’s possible to have other larger and more impactful genetic variants than the SNPs you have or lack. SNPs are hardly the be-all and end-all of genetics.
How SNPs Got Associated With Traits and Diseases
Traditional geneticists (like me) identify genes responsible for a trait by mutating the genes and observing the resulting traits. Geneticists also “cross” or mate pairs of animals with the mutations of interest to understand how the mutations transmit through the generations and show up in the offspring. Throughout my academic career, I studied genetics in model organisms, including budding yeasts, flies, and worms.
In contrast, human geneticists have their hands tied because it’s neither ethical nor practical to carry out such genetic experiments in humans — they can only study existing humans. And because your genome has more than 20,000 genes and 3 Giga-base pairs (3,000,000,000) of DNA, finding the mutations that cause diseases or traits is like finding a needle in a haystack.
For humans, the haystack gets more complicated! Some traits and diseases, such as height, depression, cancer, autism, and obesity, are outcomes of multiple variants interacting with each other and the environment. Then, there are also epigenetics and other factors that determine whether the mutations manifest themselves. Importantly, even though the SNPs reside in a gene, they may not change the gene’s genetic expression at all.
In fact, for depression, years of large-scale genetic association studies have failed to reproducibly identify genes that substantially increased the risk!3,4 It wasn’t until interactions with the environment and variability of symptoms were addressed in the study design that they started to find something.5
Analysis of twins and families indicate whether there are genetic components. Generally, if a trait runs in the family, it tends to have a genetic component.
Genome-wide association studies (GWAS) involve comparing the genomes of populations with and without the conditions of interest. Then, a statistical test is performed to identify SNPs and regions that are over-represented among people with the disease and absent in those without the disease.6
Many GWAS have been groundbreaking at identifying variants that contribute to the risk of type 2 diabetes, Parkinson’s disease, heart disorders, obesity, Crohn’s disease, and many types of cancers.
Most SNPs that are tested by direct-to-consumer tests have been identified in genome-wide association studies. These companies use the same technology, the SNP microarray, to identify your SNPs. This technology is relatively affordable and reliable, with a wholesale cost of approximately $40/sample.6 However, the tests are not without problems.
Image source:7 Caveats of Relying on Genetic-Based Health Advice Based on GWAS Data: Risk of Misinterpretation by the General Public
GWAS Do Not Prove Causality or Mechanism
GWAS “associate” a genetic variant with risk of a trait. However, simply because umbrellas are associated with rain does not mean umbrellas cause rain. The SNP could just happen to be there.Instead, finding a SNP inside of a gene being significantly associated with a trait means that you have a few reasonable hypotheses that may explain the association. Some SNPs change the encoded amino acids, while others don’t. You can test the hypotheses with biochemical experiments or by doing a genetic study in a model organism. In fact, a very small subset of SNPs tested by common SNP arrays have experimental proofs of mechanism.
Notably, many SNPs do not affect the function of the genes in which they reside. The human genome is so complex that a SNP may influence the function of a gene 2 million base pairs away. The affected gene may not be the closest gene to the SNP.8 Without direct biochemical measurements, it is impossible to tell whether the SNPs increase, decrease, or do nothing to the gene function.