Genetics of Ovarian Failure

By: Maire Peters

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PRESENTS

Age at natural menopause

• Menopause is the cessation of reproductive function of the human ovaries.

• The median age at menopause– in Europe from 50.1 to 52.8 years,– in North America from 50.5 to 51.4 years, – in Latin America from 43.8 to 53 years, – in Asia from 42.1 to 49.5 years.

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Premature menopause

• Premature ovarian failure/primary ovarian insufficiency (POF/POI) is a cause of female infertility due to the loss of normal ovarian function in women before the age of 40 years.

• POI affects approximately 1 in 10,000 women by age 20; 1 in 1,000 women by age 30; 1 in 100 women by age 40.

• Early menopause (EM) is defined as menopause occurring at 40-45 years of age. EM occurs in 5-10% of women.

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Mechanisms leading to POI

Persani L et al. J Mol Endocrinol 2010;45:257-279

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Causes of POI

Figure adapted from Shelling 2010

POI

Familial genetic causes

Autoimmune conditions

IdiopathicX

chromosome abnormalities

Iatrogenic agents

≈ 10%

≈5%

≈ 20%

≈ 65%

FOXL2 FSHR

≈ 25%

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X chromosome defects

X chromosome defects Frequency of POI Frequency in POI

Turner’s syndrome 100% 4-5%

FMR1 premutation 13-26% 15% (familial)3% (sporadic)

Translocations, deletions 80-100% Unknown

BMP15 variants 0-10% 1.5%

7-54 CGG repeats

55-200 CGG repeats

more than 200 repeats

Normal

Premutation

Full mutation

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Autosomal defectsAutosomal defects Frequency in POIComplex diseases: galactosemia (GALT), BPES (FOXL2), mitochondrial (POLG), ovarian leukodystrophy (EIF2B)

Rare

FSH/LH resistance (FSHR and LHR) <1%INHA variants unknownGDF9 variants ≈1%NOBOX, FIGLA unknown

Each single gene is responsible for less than 1-6% of POI.

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Genes involved in POI pathogenesis

Persani L et al. J Mol Endocrinol 2010;45:257-279

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GWASs in POI

Ethnicity Sample size (cases/controls)

Replication Region SNP Reference

Korean 24/24 98/218 - - Pyun et al., 2012

Chinese 391/895 400/800 8q22.3 8 SNPs Qin et al., 2012

European 99/235 60/90 - - Knauff et al., 2009

GWAS – Genome-wide association study

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Genes associated with age at natural menopause

Function Genes Related genes

DNA repair EXO1, HELQ, UIMC1, TLK1, POLG, PRIM1

FAM175A, FANCI

Immune function NLRP11, BAT2 IL11

X-chromosome inactivation

ASH2L EIF4EBP1

Hormonal regulation - FSHB

Known binding partner for FMR1

TDRD3

Various functions RHBDL2, FNDC4, MCM8, SYCP2L, TMEM150B

EIF2B4

These 17 variants explain 2.5–4.1% of the population variation in menopausal age (Stolk et al., 2012). 10

Genetics of early menopause

• EM has a substantial genetic component. • A woman whose mother had an EM has a 6-fold

increased risk of having EM.• Large GWAS with sample size of 3,500 cases

(women with menopause before 45 years of age) and 13,500 controls (Perry et al., 2013).

• For all 17 variants associated with age at natural menopause, the allele that was associated with younger menopause age was also associated with increased risk of EM and POI (Perry et al., 2013).

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Genetics of early menopause

• Combining the effect of the 17 variants shows a larger effect on EM risk than smoking.

• It is hypothesized that EM and POI represent the tail of the menopause distribution, with individuals carrying more age at menopause-lowering variants having increased risk of EM and POI (Perry et al., 2013).

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Future perspectives

The discovery of additional genetic components involved in the determination of menopause age should make it possible to predict the onset of menopause, enabling women to make informed reproductive choices.

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Thank you for your attention

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