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. Members will see their genotype report below, plus additional solutions in the Lifehacks section. Consider joining today.
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 quick 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…
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 a 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 we age:
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.
Fertility Genotype Report:
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s only information in the Lifehacks sections.
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]
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 rs1799963 is — or for i3002432 is —.
PCOS and infertility:
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.
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 —.
Too much DENND1A increases androgen hormone synthesis in the cells in the ovaries.
Check your genetic data for rs10818854 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs10818854 is —.
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 —.
The FSHR gene codes for the follicle-stimulating hormone receptor.
Check your genetic data for rs6166 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs6166 is —.
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: (most common genotype) higher (1.9x) risk of PCOS[ref]
- G/T: lower risk of PCOS compared to T/T (good)
- G/G: lower risk of PCOS compared to T/T (good)
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 —.
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.
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.
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 —.
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: Natural solutions 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.
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.
The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.
Related Articles 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.
Al-Achkar, Walid, et al. “Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women.” Reproductive Sciences (Thousand Oaks, Calif.), vol. 24, no. 9, Sept. 2017, pp. 1275–79. PubMed, https://doi.org/10.1177/1933719116682874.
Capalbo, A., et al. “The 312N Variant of the Luteinizing Hormone/Choriogonadotropin Receptor Gene (LHCGR) Confers up to 2·7-Fold Increased Risk of Polycystic Ovary Syndrome in a Sardinian Population.” Clinical Endocrinology, vol. 77, no. 1, July 2012, pp. 113–19. PubMed, https://doi.org/10.1111/j.1365-2265.2012.04372.x.
Carlomagno, Gianfranco, et al. “From Implantation to Birth: Insight into Molecular Melatonin Functions.” International Journal of Molecular Sciences, vol. 19, no. 9, Sept. 2018, p. 2802. PubMed Central, https://doi.org/10.3390/ijms19092802.
Choi, Youngsok, et al. “Genetic Variation of Methylenetetrahydrofolate Reductase (MTHFR) and Thymidylate Synthase (TS) Genes Is Associated with Idiopathic Recurrent Implantation Failure.” PloS One, vol. 11, no. 8, 2016, p. e0160884. PubMed, https://doi.org/10.1371/journal.pone.0160884.
England, Fertility Centers of New. “Can Infertility Be Treated? | About Infertility.” Fertility Centers of New England, https://www.fertilitycenter.com/our-services/about-infertility/. Accessed 17 May 2022.
FastStats. 20 Dec. 2021, https://www.cdc.gov/nchs/fastats/infertility.htm.
Gao, Hui, and Fang-biao Tao. “Prothrombin G20210A Mutation Is Associated with Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis Update.” Thrombosis Research, vol. 135, no. 2, Feb. 2015, pp. 339–46. PubMed, https://doi.org/10.1016/j.thromres.2014.12.001.
Goodarzi, Mark O., et al. “Replication of Association of DENND1A and THADA Variants with Polycystic Ovary Syndrome in European Cohorts.” Journal of Medical Genetics, vol. 49, no. 2, Feb. 2012, pp. 90–95. PubMed Central, https://doi.org/10.1136/jmedgenet-2011-100427.
Gu, Bon-Hee, et al. “Genetic Variations of Follicle Stimulating Hormone Receptor Are Associated with Polycystic Ovary Syndrome.” International Journal of Molecular Medicine, vol. 26, no. 1, July 2010, pp. 107–12. www.spandidos-publications.com, https://doi.org/10.3892/ijmm_00000441.
Hubacek, Jaroslav A., et al. “Association of MTHFR Genetic Variants C677T and A1298C on Predisposition to Spontaneous Abortion in Slavonic Population.” Clinica Chimica Acta; International Journal of Clinical Chemistry, vol. 440, Feb. 2015, pp. 104–07. PubMed, https://doi.org/10.1016/j.cca.2014.11.018.
Joham, Anju E., et al. “Prevalence of Infertility and Use of Fertility Treatment in Women with Polycystic Ovary Syndrome: Data from a Large Community-Based Cohort Study.” Journal of Women’s Health (2002), vol. 24, no. 4, Apr. 2015, pp. 299–307. PubMed, https://doi.org/10.1089/jwh.2014.5000.
Jusić, Amela, et al. “The Association of Factor V G1961A (Factor V Leiden), Prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G Polymorphisms with Recurrent Pregnancy Loss in Bosnian Women.” Medicinski Glasnik: Official Publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina, vol. 15, no. 2, Aug. 2018, pp. 158–63. PubMed, https://doi.org/10.17392/948-18.
Keefe, David, et al. “Oocyte Competency Is the Key to Embryo Potential.” Fertility and Sterility, vol. 103, no. 2, Feb. 2015, pp. 317–22. PubMed, https://doi.org/10.1016/j.fertnstert.2014.12.115.
Lerchbaum, E., et al. “Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women.” Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme, vol. 43, no. 11, Oct. 2011, pp. 743–47. PubMed, https://doi.org/10.1055/s-0031-1286279.
Li, Chao, et al. “Association of Rs10830963 and Rs10830962 SNPs in the Melatonin Receptor (MTNR1B) Gene among Han Chinese Women with Polycystic Ovary Syndrome.” Molecular Human Reproduction, vol. 17, no. 3, Mar. 2011, pp. 193–98. PubMed, https://doi.org/10.1093/molehr/gaq087.
Lissalde-Lavigne, G., et al. “Factor V Leiden and Prothrombin G20210A Polymorphisms as Risk Factors for Miscarriage during a First Intended Pregnancy: The Matched Case-Control ‘NOHA First’ Study.” Journal of Thrombosis and Haemostasis: JTH, vol. 3, no. 10, Oct. 2005, pp. 2178–84. PubMed, https://doi.org/10.1111/j.1538-7836.2005.01581.x.
Nishihara, Takuji, et al. “Oral Melatonin Supplementation Improves Oocyte and Embryo Quality in Women Undergoing in Vitro Fertilization-Embryo Transfer.” Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, vol. 30, no. 5, May 2014, pp. 359–62. PubMed, https://doi.org/10.3109/09513590.2013.879856.
Pacchiarotti, Alessandro, et al. “Effect of Myo-Inositol and Melatonin versus Myo-Inositol, in a Randomized Controlled Trial, for Improving in Vitro Fertilization of Patients with Polycystic Ovarian Syndrome.” Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, vol. 32, no. 1, 2016, pp. 69–73. PubMed, https://doi.org/10.3109/09513590.2015.1101444.
Pau, Cindy T., et al. “Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome.” PLoS ONE, vol. 12, no. 1, Jan. 2017, p. e0168870. PubMed Central, https://doi.org/10.1371/journal.pone.0168870.
Pietropolli, A., et al. “Plasminogen Activator Inhibitor-1, Factor V, Factor II and Methylenetetrahydrofolate Reductase Polymorphisms in Women with Recurrent Miscarriage.” Journal of Obstetrics and Gynaecology: The Journal of the Institute of Obstetrics and Gynaecology, vol. 34, no. 3, Apr. 2014, pp. 229–34. PubMed, https://doi.org/10.3109/01443615.2013.836476.
Reznikoff-Etiévan, M. F., et al. “Factor V Leiden and G20210A Prothrombin Mutations Are Risk Factors for Very Early Recurrent Miscarriage.” BJOG: An International Journal of Obstetrics and Gynaecology, vol. 108, no. 12, Dec. 2001, pp. 1251–54. PubMed, https://doi.org/10.1111/j.1471-0528.2001.00298.x.
Ridker, P. M., et al. “Factor V Leiden Mutation as a Risk Factor for Recurrent Pregnancy Loss.” Annals of Internal Medicine, vol. 128, no. 12 Pt 1, June 1998, pp. 1000–03. PubMed, https://doi.org/10.7326/0003-4819-128-12_part_1-199806150-00007.
Shahrokhi, Seyedeh Z., et al. “The Relationship Between the MTHFR C677T Genotypes to Serum Anti-Müllerian Hormone Concentrations and In Vitro Fertilization/Intracytoplasmic Sperm Injection Outcome.” Clinical Laboratory, vol. 63, no. 5, May 2017, pp. 927–34. PubMed, https://doi.org/10.7754/Clin.Lab.2016.161104.
Shi, X., et al. “Maternal Genetic Polymorphisms and Unexplained Recurrent Miscarriage: A Systematic Review and Meta-Analysis.” Clinical Genetics, vol. 91, no. 2, Feb. 2017, pp. 265–84. PubMed, https://doi.org/10.1111/cge.12910.
Spinedi, Eduardo, and Daniel P. Cardinali. “The Polycystic Ovary Syndrome and the Metabolic Syndrome: A Possible Chronobiotic-Cytoprotective Adjuvant Therapy.” International Journal of Endocrinology, vol. 2018, July 2018, p. e1349868. www.hindawi.com, https://doi.org/10.1155/2018/1349868.
Tagliaferri, Valeria, et al. “Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study.” Reproductive Sciences (Thousand Oaks, Calif.), vol. 25, no. 2, Feb. 2018, pp. 269–75. PubMed, https://doi.org/10.1177/1933719117711262.
Tannus, Samer, et al. “Treatment Strategies for the Infertile Polycystic Ovary Syndrome Patient.” Women’s Health (London, England), vol. 11, no. 6, Nov. 2015, pp. 901–12. PubMed, https://doi.org/10.2217/whe.15.40.
Thaler, C. J. “Folate Metabolism and Human Reproduction.” Geburtshilfe Und Frauenheilkunde, vol. 74, no. 9, Sept. 2014, pp. 845–51. PubMed Central, https://doi.org/10.1055/s-0034-1383058.
Zeng, Shuangshuang, et al. “MTHFR C677T Polymorphism Is Associated with Follicle-Stimulating Hormone Levels and Controlled Ovarian Hyperstimulation Response: A Retrospective Study from the Clinical Database.” Fertility and Sterility, vol. 111, no. 5, May 2019, pp. 982-990.e2. ScienceDirect, https://doi.org/10.1016/j.fertnstert.2019.01.016.
Zou, Ju, et al. “Association of Luteinizing Hormone/Choriogonadotropin Receptor Gene Polymorphisms with Polycystic Ovary Syndrome Risk: A Meta-Analysis.” Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, vol. 35, no. 1, Jan. 2019, pp. 81–85. PubMed, https://doi.org/10.1080/09513590.2018.1498834.
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 also 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.