What is the cause of PCOS?

According to the 2020 study on Distinct Subtypes of PCOS with Novel Genetic Associations, there are specific genetic variations associated with each of the PCOS sub-types.

PCOS often runs in families with a 5x increased risk of having the condition if your biological mother has it.[1] You have a 60-70% chance of having PCOS if your biological mother has PCOS[2] and a 50% chance if your biological sister has PCOS.[3]  In this article we explore the link between PCOS and genetics.

The underlying cause of PCOS is a result of a complex interaction of genetic, epigenetic and environmental factors.[4]

Genetic factors relate to how individual or groups of genes are implicated in health and disease.[5]  The genetic link underlying PCOS is far more complex than a single inherited gene and genetic factors explain less than 10% of PCOS heritability.[6] 

Epigenetic factors relate to how genes are expressed or function, in response to the environmental factors within the womb or later in life.[7]

Environmental factors include lifestyle, diet, stress / trauma and exposure to endocrine-disruptors,[8] natural or man-made chemicals that may mimic, block or interfere with the body’s hormones.[9]

There are more than 240 genetic variations and 29 genetic loci (specific regions of DNA) associated with PCOS.[10],[11],[12],[13]  Certain groups of genes have been identified that influence some of the primary characteristics associated with PCOS, including:

• Androgen excess: DENND1A, CYP17A1 and SHBG contribute to elevated androgens and therefore lead to changes in appearance such as acne and hirsutism; [14],[15]

• Hormonal regulation: FSHB, FSHR and LHCGR affect signaling of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and therefore influence ovulation and menstrual cycles;[16],[17]

• Ovarian function: AMH, ERBB4 and GATA4 regulate follicle maturation and ovarian reserve and therefore influence ovulation and fertility; [18],[19]

• Ovarian aging: CHEK2 and RAD50 are believed to play a role in reproductive aging and egg quality and therefore influence fertility;[20]

• Metabolic dysfunction: THADA, FTO, INSR and HMGA2 are associated with insulin resistance, obesity and Type 2 diabetes;[21],[22] and

• Inflammation: TOX3, YAP1 and MAPRE1 are linked to chronic inflammation.[23]

Reviewed by Malav Trivedi PhD. FRSB, expert on epigenetics.

Sources

[1] https://www.nature.com/articles/s41591-019-0666-1

[2] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883751/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883751/

[5] https://www.cdc.gov/genomics/about/basics.htm

[6] https://academic.oup.com/jcem/article/98/12/4565/2833703

[7] https://www.cdc.gov/genomics/disease/epigenetics.htm

[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864804/

[9] https://www.niehs.nih.gov/health/topics/agents/endocrine

[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310679/

[11] https://www.sciencedirect.com/science/article/pii/S2590161319300948#bib0065

[12] https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007813

[13] https://www.nature.com/articles/ncomms9464

[14] https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007813

[15] https://pmc.ncbi.nlm.nih.gov/articles/PMC8775814/

[16] https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007813

[17] https://academic.oup.com/humupd/article-abstract/20/5/688/2952639?redirectedFrom=fulltext#google_vignette

[18] https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007813

[19] https://www.nature.com/articles/ncomms9464

[20] https://www.fertstert.org/article/S0015-0282(17)30535-6/fulltext

[21] https://www.nature.com/articles/ncomms9464

[22] https://pubmed.ncbi.nlm.nih.gov/21151128/

[23] https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1556568