The Genetics of Endometriosis

Disclaimer: While I am always careful to use reputable, peer-reviewed sources in my writing, I am not a doctor. You should neither take medical advice from me nor from a commercial DNA test. 23andme can tell you with 99% accuracy about the genes it tests for, but it does not test for nearly all of the millions of polymorphisms (a.k.a. variants in your DNA) that make us human beings unique individuals. Always have your 23andme results validated by a genetic counselor before making any medical decisions that could affect your long-term health.

I have always been fascinated by genes, ever since we did those Punnett Squares in the seventh grade (if you know, you know). If I were better at math and science, I would consider a career as a geneticist in a heartbeat.

Unfortunately, that is not my calling in life — but educating people about endometriosis is! So, I thought, why not nerd out about the genetics of endometriosis? For, y’know, educational purposes.

Back in college, David and I took the 23andme DNA test just for fun. (Out of nowhere, I found out I am 20% Greek, which explains my affinity for Mediterranean food.) When you take the 23andme DNA test, you can download your raw DNA file and upload it to all kinds of websites for analysis.

Because I’m a hypochondriac, that’s exactly what I did. But, in my defense, David did it first.

In fact, that DNA test was a big part of what sparked my journey into the medical system. I had been having bowel issues for awhile by then, and found out I was genetically susceptible to Inflammatory Bowel Disease (IBD). The rest, as they say, is history….though that colonoscopy prep still haunts me to this very day.

Every once in awhile, when I get bored, I’ll open my genome in Promethease and start scrolling through just for fun. Do you do that, too, or are you normal?

Out of curiosity, it occurred to me to check and see if I had any genes linked with endometriosis, the one disease I know that I most likely have. After that quick search, I wound up doing a lot of digging…much, much more than I anticipated.

As much as I know I should probably be studying for the GRE right now (I’m taking it in less than a week!), I figured I’d share some of what I learned about the genetics of endometriosis — and my own DNA — with you all.

How Do You Inherit Endometriosis?

Doctors have known for a long time that there is a genetic component to endometriosis. Without looking at specific genes, we know that endometriosis tends to run in families.

But how does endometriosis work for those of us who don’t have a history of endo in our families? If this is you, I’m in the same boat. No one in my family ever had the excruciatingly painful periods that I do — or, if they did, they never complained about it.

That’s where a little thing called gene expression comes into play. This is where genetics starts to get a little complicated, so bear with me!

You see, our genes are only half the battle when it comes to whether or not we develop a disease. Our genetics can increase our risk, but often, they must interact with our environment in a specific way before the disease actually develops.

In short, endometriosis has a genetic component, but it is also deeply linked to our environment. Anything from toxic chemicals in our surroundings to psychological stress can trigger a pathogenic gene response. These genes can also be “turned on” by specific sequences of noncoding DNA, located between pairs of genes.

If you have endometriosis but no one in your family does, it’s likely that they carry the same genetic mutations responsible for the disease — but, unlike yours, their environment did not trigger the development of the disease, or they do not carry the right sequence of noncoding DNA to activate the gene’s expression.

Genes Linked to Endometriosis

The most important thing to understand about endometriosis is that it is a polygenetic disease. That little word tells you a lot about the origins of endo: poly means multiple and genetic means, well, genes — in other words, endometriosis is influenced by more than one gene.

Unlike some other diseases, which are directly caused by mutations in a specific gene or chromosome, you don’t simply inherit one causative “endometriosis gene.” Instead, there is a complex interplay of all the polymorphisms (or genetic variants) present in your DNA that contributes to your endometriosis risk.

What Are Single Nucleotide Polymorphisms (SNPs)?

The genetic variants that contribute to the development of endometriosis are just tiny fragments of your overall genome. Over 99% of the human genome is identical in all human beings. Polymorphisms, those places where your genes vary from person to person, account for about 0.001% of human DNA.

You probably remember from your high school biology class that humans have 23 pairs of chromosomes, tightly-wound segments of DNA that encode everything from your eye color to the consistency of your earwax. Your genes are located on those chromosomes, where they’re made up of different pairs of amino acids that bond with one another. These bonds code for most of the variations in human DNA.

Variations arise from the different nucleotides — represented by A, C, G, and T — or building blocks that can pair with one another at that specific location. The “address” of that location is called a locus (plural: loci), and identifies the specific area of a gene that codes for a particular trait or disease risk. A lot of genetic research focuses on identifying the loci associated with different health conditions. Researchers do this by pinpointing the specific polymorphisms that are frequently shared by people with a disease at those loci.

Single nucleotide polymorphisms (SNPs) — pronounced “snips” — are the most common variations in human DNA, and represent a place where two people may have different nucleotides at the same locus due to genetic mutations passed down through human DNA. Many SNPs are shared by people whose ancestors originate from the same place. Geneticists have found over 100 million unique SNPs in populations across the world.

Genetic research related to endometriosis identifies SNPs that may be responsible for the development of endometriosis in some people, but not others. Where there is an SNP, there are typically three different combinations of nucleotides, or genotypes, possible for a human being. For example, if the possible nucleotides at that locus are C and T, a person can have the genotype C,C; the genotype C,T; or the genotype T,T.

What is a Risk Allele?

In genetics, each of the possible nucleotides at an SNP is referred to as an allele. The “risk allele” is the nucleotide linked to the development of a disease or trait. For example, say the above SNP codes for an increased risk of developing endometriosis. If T is the risk allele, then C,C is the “normal” genotype that does not increase endometriosis risk. Someone with the genotype C,T may or may not have an increased risk of developing endo, while someone with the genotype T,T would definitely have an increased risk of developing endo.

Whether or not you can inherit a trait or condition from a heterogenous genotype — meaning you carry one “normal” allele and one risk allele — depends on whether the trait is dominant or recessive. You probably remember learning about dominant and recessive genes in middle school, but here’s a refresher: if a trait is dominant, you only need one risk allele to develop it. If it is recessive, you need two.

Someone who carries one risk allele of a recessive trait is considered a carrier, meaning you cannot develop the condition yourself but may pass it down to your children. In order to pass a recessive trait onto your child, both parents must be carriers of at least one recessive trait, and the child must inherit two risk alleles to develop the condition.

Along with the complicated dynamics of gene expression, recessive patterns of inheritance are another reason why you might develop endo, even if no one else in your family has it. If you’re the first in your family with endometriosis, it might mean that your other family members are carriers of one or more risk alleles linked to the disease. Because you inherited two risk alleles instead of just one, you developed the recessive trait predisposing you to endo, while your other family members did not.

SNPs and Risk Alleles Associated with Endometriosis

The genetic differences across the human population arising from SNPs are small but mighty, and play an important role in who develops endometriosis (and who does not).

As an endo warrior, you don’t need me to tell you that research for our condition is drastically underfunded and underperformed. For a disease affecting 1 in 10 women, we know surprisingly little about the genetics of endometriosis. However, some recent studies have scraped the surface of identifying the reasons why some people develop endo while others do not.

By far the most influential genetic study of endometriosis was the 2012 study “Genome-wide association meta-analysis identifies new endometriosis risk loci,” published in the journal Nature Genetics. This study used a sample size of over 4,500 Japanese and European endometriosis patients to identify seven loci strongly linked to endometriosis. This study replicated the results of previous genetic research linking two of the loci to endometriosis and identified five novel loci that had not previously been identified.

The “endo genes” identified in this study are:

  • rs7521902 (risk allele A). This SNP is located on chromosome 1, on a gene called LOC105376850. Little is known about the gene beyond its well-established link to endometriosis, so it’s unclear why this SNP increases the risk of endo.
  • rs13394619 (risk allele G). This SNP is located on chromosome 2, on a gene caled GREB1. GREB1 plays an important role in coding for the proteins that bind to estrogen receptors. As a result, it plays an important role in the growth of endometriosis, as well as estrogen-dependent breast and prostate cancers.
  • rs4141819 (risk allele C). This SNP is located on chromosome 2, on a gene called LOC105374786. This SNP is linked, in particular, with Stage III and IV endometriosis involving the ovaries.
  • rs7739264 (risk allele T). This SNP is located on chromosome 6, on a gene called LOC100506885. Little is known about the gene beyond its link to endometriosis, so it’s unclear why this SNP increases the risk of endo.
  • rs12700667 (risk allele A). This SNP is located on chromosome 7, on an inter-genic region. A previous Australian study linked it with moderate-to-severe endometriosis. The Nature Genetics study linked it with endo in general, as did a 2013 replication study.
  • rs1537377 (risk allele C). This SNP is located on chromosome 9. The results of the Nature Genetics study were replicated in a 2015 study that confirmed the genome-wide significance of the SNP in conferring endometriosis risk.
  • rs10859871 (risk allele C). This SNP is located on chromosome 12, near a gene called VEZT. VEZT is a gene that encodes for a specific protein involved in the joining of cells at the membrane, which makes sense given that endometriosis is a proliferative process. This particular SNP is widely accepted as the SNP with the strongest link to endometriosis, and the results of the Nature Genetics study have been replicated many times. The A,C genotype is associated with a 1.2x higher risk of endometriosis, and the C,C genotype is associated with a 1.4x higher risk of endometriosis.

Since then, much of the research has focused on confirming the results of this genome-wide meta-anaysis, rather than identifying novel susceptibility loci for endometriosis. However, in 2017, 23andme published a study of results collected from its customers that found five new loci associated with the development of endometriosis.

The “endo genes” 23andme identified were:

  • rs1250241 (risk allele T). This SNP is located on chromosome 2, on a gene called FN1. FN1 codes for a protein called fibronectin, which is involved in cell adhesion. Certain types of fibronectin also prevent tumor growth and metastasis. This link makes sense since endometriosis is a proliferative process, and it has been surmised that genes regulating tumor growth may be defective in patients with endo.
  • rs1971256 (risk allele C). This SNP is located on chromosome 6, on an inter-genic region involving the genes RMND1 and CCDC170. RMND1 plays a role in translating messenger RNA (mRNA) into the proteins of the mitochondrial ribosome, while CCDC170 is a relatively mysterious protein-encoding gene that has been linked to breast cancer in addition to endo.
  • rs71575922 (risk allele G). This SNP is located on chromosome 6, on a gene called SYNE1. SYNE1 codes for a protein expressed in the skeletal and smooth muscle. This protein plays an especially important role in the brain, making its link to endo particularly interesting. It’s also worth noting that another 23andme study found a strong link between this gene and the development of uterine fibroids.
  • rs74491657 (risk allele G). This SNP is located on chromosome 7, on an inter-genetic band of the chromosome called 7p12. Notably, 7p12 contains the gene EGFR. EGFR stands for epidermal growth factor receptor, the protein it encodes for. EGFR activates the processes of cell growth and division, making it a logical link to endometriosis.
  • rs74485684 (risk allele T). This SNP is located on chromosome 11, near a gene called FSHB. FSHB codes for a component of follicle stimulating hormone (FSH), which plays an important role in regulating the menstrual cycle and reproductive organs. Appropriately, this SNP has also been linked to heavy menstrual flow.

What’s My Genotype?

The only definitive way to figure out your genotype is to have testing performed by a genetic counselor — but since these SNPs are correlational, not causational, for endometriosis, most doctors probably won’t suggest genetic counseling for endo.

If you are curious about your genetic risk for endometriosis, you can always take a direct-to-consumer DNA test like 23andme or Ancestry DNA. Personally, I took 23andme’s Ancestry test and skipped the Health test because it was so expensive. Instead, I downloaded the raw DNA file from 23andme and uploaded it to Promethease.

Promethease is a literature retrieval service — meaning that it won’t interpret your DNA or put you in touch with genetic counseling, but it will show you the conditions your DNA is linked to and studies that support those links. You pay $12 one time and receive lifelong access to your report, which I think is worth it.

Once you’re in Promethease, you can use the search function to type in the endometriosis SNPs above. Then, you’ll want to look at your genotype to see if you have a risk allele for endometriosis. Let me show you an example from my DNA report:

As you can see, I searched for rs10859871, the SNP most closely linked to endometriosis risk. My genotype is A,C. The risk allele is C, so my risk of endometriosis is 1.2x higher than average. However, combined with other genes that increase my risk, my overall risk of endometriosis may be much higher than this. That’s why it’s important to review more than one SNP to get a clear picture of your endo risk.

When using Promethease, I recommend completely disregarding the additional information, such as the “repute” of the gene or the SNP wiki entry it generates. Because anyone can edit the SNP wiki, it can contain a lot of misleading information — such as the retrograde menstruation theory you see above, which has since been disproven! Instead, I recommend you click on “more info” and carefully review the supporting studies linked in the wiki entry for the most accurate scientific information.

By reviewing my raw DNA, I found out that I have six genetic risk factors for endometriosis, not including the new ones discovered by 23andme. While it’s important to keep in mind that consumer DNA tests like 23andme are flawed, and that having these genes doesn’t guarantee you have endo, I think it’s incredibly fascinating to see how something as intangible as our DNA so strongly influences our reality.

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