Genetic links to infertility for women

The statistics on infertility are astounding. According to the CDC, estimates show 12% of US women have impaired fertility. For women over age 30, that statistic rises to 25%![ref][ref] Your genes may be playing a role in your infertility — and knowing which genetic variants you carry may help you figure out solutions to try.

What are the causes of infertility? Are they hereditary?

Some of the causes of infertility for women can be categorized as follows:

  • hormonal issues: thyroid problems, PCOS, HPA axis dysregulation, reproductive hormone dysregulation
  • structural issues: fibroids, blocked fallopian tubes, other structural abnormalities
  • ovarian insufficiency or premature menopause
  • recurrent miscarriages
  • and more

This article highlights some of the common genetic variants that may play a role in infertility. It is just a starting point… My hope is that it gives you enough information to get started on figuring out the root cause of your problems conceiving.

Everything here is for informational purposes only, based on research studies on genetics and fertility. Please talk with your doctor for medical advice or seek help from a fertility coach or expert. 

A crash course in reproduction:

A lot of people think of pregnancy in basic terms: sperm meets egg and 9 months later you have a baby. Birds do it, bees do it. Heck, even trees do it, in their own way.

But when you get down to the specific details, it gets a lot more complicated…

Ovarian follicle:

At puberty, women have around 300,000 to 400,000 follicles in their ovaries. These primordial follicles are tiny fluid-filled sacs that contain the oocyte (immature egg cell). Over the course of a woman’s reproductive years, only 400 – 500 eggs will reach maturity.

Hormones stimulate the development of some of the follicles each month. Usually only one will reach maturity each month, at which point ovulation occurs. (The other follicles are broken down and reabsorbed.)

That egg cell that gets released at ovulation is what can get fertilized by the sperm, resulting in pregnancy if all goes well. The egg needs to be healthy with no DNA damage.

Reproductive hormone levels:

For all of this to happen, the reproductive hormones need to be at the right levels and at the right time. Follicle-stimulating hormone (FSH) rises at the right time to stimulate the immature follicles to begin to mature. Without FSH, the immature follicles will go through apoptosis (cell death).

When the follicle reaches a certain size, it will start secreting estrogen. This causes a surge in gonadotrophin-releasing hormone (GnRH).

The surge in GnRH causes a surge in luteinizing hormone (LH) secretion, which triggers ovulation.

Decreased fertility:

As women age, they have fewer follicles in their ovaries, eventually reaching the end of the reproductive span at menopause. A hormone called AMH (anti-mullerian hormone) is often used as a marker of ‘ovarian reserve’, an estimate of available eggs.

But the ovaries aren’t like a gumball machine, spitting out good gumballs (eggs) up until the last one comes out. Oxidative damage, insults to the cells, etc. cause egg quality to decline as we age.

Conditions that can decrease fertility rates include PCOS (polycystic ovarian syndrome), hypothyroidism, diabetes, and autoimmune diseases.

The risk of recurrent miscarriages also increases with age. Blood clots can increase the risk of recurrent miscarriages, and several genetic variants cause increased clotting.


Genetic variants that impact fertility:

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How does the MTHFR variant impact fertility for women?

The MTHFR gene codes for a key enzyme in the methylation cycle. It is the final step for converting folate into the form the body uses, methylfolate. While most women know that folate is important to a growing baby, the MTHFR gene can also impact other aspects of fertility.

Research shows that the MTHFR C677T and A1298C variants impact fertility in a couple of specific ways.

Carriers of two copies of the C677T variant have altered reproductive hormone levels (FSH and AMH) that impact egg number and quality. This can also alter the hormone amount needed during IVF.[ref][ref][ref]

Carrying two copies of the C677T and/or A1298C variants are linked to a higher risk of recurrent miscarriages in many (but not all) studies.[ref][ref][ref][ref]

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: one copy of MTHFR C677T allele (heterozygous), MTHFR enzyme efficiency reduced by 40%
  • A/A: two copies of MTHFR C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • G/T: one copy of A1298C allele (heterozygous), MTHFR enzyme efficiency slightly reduced
  • G/G: two copies of A1298C (homozygous), MTHFR efficiency reduced

Members: Your genotype for rs1801131 is .


Which genes increase miscarriage risk due to blood clots?

There are several genetic variants that increase the risk of blood clots and conditions such as deep vein thrombosis. These genetic variants also increase the risk of recurrent miscarriages due to clotting. This does NOT mean that everyone who carries these variants will have a miscarriage. It is something to talk with your doctor or fertility specialist about.

Note that the 23andMe and AncestryDNA raw data is marketed for informational purposes, not clinical testing. So if your raw data shows that you carry one of the risk factors below, you should talk with your doctor and consider possibly getting a second test done for verification before making medical decisions.

Factor V Leiden (read more here):

Check your genetic data for rs6025 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: one copy of factor V Leiden, increased risk of miscarriage[ref][ref]
  • T/T: two copies of factor V Leiden, increased risk of miscarriage[ref][ref]

Members: Your genotype for rs6025 is .

Prothrombin G20210A variant (read more here):

Check your genetic data for rs1799963, (G20210A) (23andMe v4, v5 i3002432 ; AncestryDNA):

  • A/A: increased risk of blood clots, stroke; increased miscarriage risk[ref][ref][ref]
  • A/G: increased risk of blood clots; increased miscarriage risk
  • G/G: typical

Members: Your genotype for i3002432 is .

PCOS and infertility:

PCOS (polycystic ovary syndrome) makes it harder for some women to conceive. Women with PCOS can have anovulatory or irregular menstrual cycles as well as hormonal dysregulation.[ref][ref]

PCOS is thought to be partially genetic, with about 70% of the disease risk due to genetic factors.

There are quite a few genes that contribute to the risk of PCOS.

LHCGR gene:

Variants in the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene are associated with an increased risk of PCOS and variations in the insulin response. The LHCGR is the receptor for both luteinizing hormone (LH), which triggers ovulation, and human chorionic gonadotropin (hCG), which maintains pregnancy.

Check your genetic data for rs13405728 (23andMe v4, v5; AncestryDNA)

  • A/A: typical
  • A/G: increased insulin levels in PCOS, but decreased overall risk of PCOS in Asian pops
  • G/G: increased insulin levels in PCOS[ref], but decreased overall risk of PCOS in Asian pops.[ref]

Members: Your genotype for rs13405728 is .

Check your genetic data for rs2293275 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk (3 – 4 fold) of PCOS[ref][ref][ref]
  • C/T: increased risk for PCOS
  • C/C: typical risk of PCOS

Members: Your genotype for rs2293275 is .

DENND1A gene:

Too much DENND1A increases androgen hormone synthesis in the cells in the ovaries.

Check your genetic data for rs10818854 (23andMe v4, v5; AncestryDNA):

  • A/A: increased (2x) risk of PCOS[ref][ref]
  • A/G: increased risk of PCOS
  • G/G: typical

Members: Your genotype for rs10818854 is .

FSHB gene:

Follicle-stimulating hormone gene. The LH:FSH ratio is important in PCOS.

Check your genetic data for rs11031006 (23andMe v4, v5; AncestryDNA):

  • A/A: increased LH levels[ref]
  • A/G: increased LH levels
  • G/G: typical LH levels

Members: Your genotype for rs11031006 is .

FSHR gene:

The FSHR gene codes for the follicle-stimulating hormone receptor.

Check your genetic data for rs6166 (23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • C/T: typical risk of PCOS
  • C/C: increased risk of PCOS[ref][ref]

Members: Your genotype for rs6166 is .

ADIPOQ gene:

Adiponectin (ADIPOQ) is created by fat cells and helps to regulate energy metabolism and insulin.

Check your genetic data for rs2241766 (23andMe v4, v5):

  • T/T: increased (1.9x) risk of PCOS[ref]
  • G/T: typical risk of PCOS
  • G/G: typical risk of PCOS

Members: Your genotype for rs2241766 is .

Check your genetic data for rs1501299 (23andMe v4, v5; AncestryDNA):

  • T/T: decreased risk of PCOS[ref]
  • G/T: typical risk of PCOS
  • G/G: typical risk of PCOS

Members: Your genotype for rs1501299 is .

MTNR1B gene:

The melatonin receptor 1B is a part of the regulation of your body’s circadian rhythm. Melatonin is important in the regulation of insulin release at night and can play a big role in fasting glucose levels.

Check your genetic data for rs10830963 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/G: increased risk of higher insulin levels, PCOS
  • G/G: increased risk of higher insulin levels, PCOS[ref][ref]

Members: Your genotype for rs10830963 is .

 


Optimizing fertility:

Your overall health impacts your ability to reproduce. This makes sense for all animals and especially for humans.

There are quite a few genetic variants affecting the very basic aspects of health that also affect fertility. You need healthy egg cells in order to get pregnant. This list is a bit of a hodge-podge of some of those variants that affect the quality of the oocyte.[ref]

Melatonin genes that impact fertility:

Whether you carry the melatonin receptor variant (above) or not, melatonin is important for everyone when it comes to fertility. This is especially true for older women who are TTC – melatonin levels drop as we get older.

The ‘sleep hormone’ does a lot in the body. Within cells, it acts as a natural antioxidant, reducing reactive oxygen species. Melatonin receptors are found in high levels in the ovaries and in the follicle cells. Melatonin turns out to be fairly important in egg quality for IVF.[ref][ref][ref][ref] Melatonin also may play a role in keeping the mother’s body from rejecting the fetus.[ref]

How can you increase melatonin? Two free things you can do that will greatly impact melatonin levels: Block 100% of blue light at night and get out in the sunshine during the day.

Read more about other melatonin genetic variants here.

Vitamin A:

Active forms of vitamin A in the body are essential for both male and female reproduction.[ref]

Vitamin A can be obtained in the diet in retinol forms from animal sources or in beta-carotene in plants. The beta-carotene form has to be converted by the body into the retinol form — which is where genetics comes into play.

Note that while essential in the right amount, too much vitamin A, through drugs like Accutane (isotretinoin, acne medicine) or through really high levels of vitamin A supplements, can cause birth defects.

The BCMO1 enzyme converts beta-carotene into the retinal form the body uses. There are two gene variations in the BCMO1 gene that help determine a person’s ability to convert beta-carotene into the retinol a body uses.[ref]

People with a T allele on both rs12934922 and rs7501331 have a 69% decreased conversion of beta-carotene to retinol.

Check your genetic data for rs7501331 (23andMe v4 and v5, AncestryDNA):

  • C/C: typical
  • C/T: decreased beta-carotene conversion by 32%
  • T/T: decreased beta-carotene conversion by 32% or more

Members: Your genotype for rs7501331 is .

Check your genetic data for rs12934922 (23andMe v4 and v5):

  • A/A: typical
  • A/T: decreased beta-carotene conversion
  • T/T: decreased beta-carotene conversion

Members: Your genotype for rs12934922 is .


Detoxification pathways:

BPA and phthalates are two well-known endocrine disruptors that are extremely prevalent in our environment today. BPA is well known as a component of plastics, but it is also found in food can linings, processed foods, thermal receipt paper, and more. Phthalates are found in fragrances (laundry detergent, air fresheners), lotions, plastics, pharmaceuticals, nail polish, and more.[ref][ref]

Both BPA and phthalates have been clearly shown in animal studies to disrupt reproduction in multiple ways. They also may be affecting the reproduction of offspring.[ref]

In women undergoing IVF, increasing concentrations of BPA in their blood correlate linearly with a decreasing number of oocytes and pregnancy.[ref] And yes, nearly everyone has BPA and phthalate metabolites in their body.

Some people can detoxify and clear out the BPA and phthalates better than other people.


Lifehacks when TTC:

I’ve thrown a lot of information into this article, but it is just a portion of what goes into the mix for fertility.

If you are dealing with infertility, genetic variants are probably playing a role — whether through PCOS, altering your vitamin or hormone levels, or increasing risk of problems from toxins.  But this is just a part of the picture… stress, sleep, and diet are all important also.

Getting help:

Obviously, the first place to go for help when trying to conceive is your OB/GYN for testing. Your OB can do ultrasounds and other tests to rule out a physical cause. Hormone testing is also available to make sure everything is normal there.

There are also fertility experts that offer online coaching and help as you go through this process. Dr. Ibby Omole is one that I can recommend if you are looking for information online.  Alternatively, ask around for recommendations in your local area. When coping with infertility issues, talking to people, gathering a lot of useful information, and getting emotional support are all helpful.

The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.

Diet:

There have been quite a few studies on the effects of eating more fruits and vegetables on IVF outcomes.

Some studies show that increasing amounts of fruit and veggies don’t make much difference. What does make a difference for oocyte quality and IVF outcome is avoiding pesticide residue. This could mean eating organic fruits and vegetables (or just avoiding conventional produce).[ref]

Personally, I was surprised that more fruits and vegetables didn’t make a difference in getting pregnant, but this may be due to women taking prenatal vitamins having the micronutrients covered fairly well.[ref][ref]

MTHFR and fertility:

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Related Genes and Topics:

BPA: How Your Genes Influence BPA Detoxification
BPA, a chemical found in some plastics, has been linked to a variety of effects on people including obesity, insulin resistance, and epigenetic effects on the fetus. It is everywhere in our food supply. In fact, a CDC report showed that 92% of people have BPA in their urine.

Detoxifying Phthalates: Genes and Diet
Plastics are everywhere – and a source of the chemicals that we are exposed to on a daily basis. One component of plastics is a class of compounds referred to as phthalates, which can act as an endocrine disruptor and mimic estrogen.

PCOS: Genetics and Root Causes
Polycystic ovarian syndrome (PCOS) is an endocrine disorder causing an increase in androgen hormone production in women. It also increases the risk of infertility. PCOS affects 5 -10% of premenopausal women, and genetics plays a large role in whether you have PCOS.

BCO1 Gene: Converting Beta-Carotene to Vitamin A
Genetics plays a huge role in how well you convert beta-carotene into vitamin A! Discover how well you convert beta-carotene into retinol.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.