genetics of pcos: the insulin receptor pathway

Genetics of PCOS: The insulin receptor pathwayYvonne Louwers, Lisette Stolk, Andre Uitterlinden, Mark Goodarzi, Ricardo Azziz,

Mark McCarty, Steven Franks, Joop Laven

PCOS consensus meeting. Women’s health aspects of PCOS. November 18th

PCOS is a complex genetic trait

Oligo- or Amenorrhea (cycle length > 35 days)Hyperandrogenism (hirsutism and / or FAI > 4.5)PCO ( > 12 follicles, 2 – 9 mm, in one or both ovaries

d/ i l 10 L)

2 out of 3: PCOS

and/or ovarian volume > 10 mL)

Rule out:Hyperprolactinemia,NCAH, Cushing’s syndrome,

Androgen Secreting Neoplasm, Acromegaly

ESHRE / ASRM sponsored PCOS consensus meeting 2003, Rotterdam, The Netherlands

PCOS is a heterogeneous phenotype indicating a complex genetic background, which might be altered by the environment

Genetics of population variation of traits

RareRare Common

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ecy

of T

rait

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SNP’s with moderate effects

n Fr

eque

nc moderate effects

Mutations with severe effects

Mutations with severe effects

Popu

latio

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DiPCOS BMD H t i Gl l l H i ht M DiseasePCOS; BMD; Hypertension; Glucose levels; Height; MenopauseUitterlinden et al, 2004

Genetics of PCOS

Two candidate gene studies:

The insulin receptor pathway: replication of associationIn collaboration with: professor Goodarzi and professor Azziz, Cedars-Sinai Medical Center

BMI susceptibility genes: genetic risk scoreBMI susceptibility genes: genetic risk scoreIn collaboration with: professor McCarthy and professor Franks, Oxford University

Insulin signaling pathway

Discovery stage295 variants in 39 genes

Insulin receptor (INSR)4 SNPs associated with PCOS

Replication

In collaboration with Goodarzi and Azziz et al, unpublished data

Insulin receptor polymorphisms and PCOS

chromosome 19

Insulin receptor (INSR)

In collaboration with Goodarzi and Azziz et al, unpublished data

Genetics of PCOS



A tagging SNP approach identified novel INSR SNPs associated with PCOS, one of which confirmed association with PCOS in a replication cohort

BMI susceptibility genes: genetic risk scoreIn collaboration with: professor McCarthy and professor Franks, Oxford University

BMI susceptibility genes and PCOS (1)

nearest gene SNP chromosome ndiv

idua

ls

UK cohortGenetic Risk Score (GRS)

nearest gene SNP chromosomeBDNFOS rs4074134 11FAIM2 rs7138803 12ETV5 rs7647305 3

erce

ntag

e of

in

FTO rs9939609 16GNPDA2 rs10938397 4KCTD15 rs11084753 19MC4R rs17782313 18

pe

number of BMI increasing alleles

s Dutch cohortMC4R rs17782313 18MTCH2 rs10838738 11NEGR1 rs2815752 1SEC16B rs10913469 1

e of

indi

vidu

als utc co o t

SH2B1 rs7498665 16TMEM18 rs6548238 2

perc

enta

ge

number of BMI increasing allelesIn collaboration with McCarthy et al, unpublished data


GRS for BMI increasing alleles and risk for PCOS4 Combined Dutch and UK cohort

2

3

o (9

5% C

I)

1

2

Odd

s ra

tio

0< 8 8 to 9 10 to 11 12 to 13 14 to 15 16 to 17 > 18

Genetic risk score

Number of BMI risk alleles carried is not associated with an increased risk of PCOS

In collaboration with McCarthy et al, unpublished data


Incidence of PCOS

10

12

4

6

8

0

2

4

Underweight Normal Overweight Obesity

Yildiz et al. JCEM 2007

Genetics of PCOS

Th i li t th li ti f i ti



A tagging SNP approach identified novel INSR SNPs associated with PCOS, one gg g ppof which confirmed association in a replication cohort

BMI susceptibility genes: genetic risk scoreIn collaboration with: professor McCarthy and professor Franks, Oxford University

Number of BMI risk alleles carried is not associated with an increased riskNumber of BMI risk alleles carried is not associated with an increased risk of PCOS

Acknowledgements

ErasmusMC Medical CenterThe Netherlands

Joop Laven

University of Oxford, UKMark McCarthy

Steven Franks

Cedars-Sinai Medical Center USA

Mark Goodarzi

Andre Uitterlinden

Lisette Stolk

Mila Jhamai

Blanca HerreraRicardo Azziz

genetics of pcos: the insulin receptor pathway

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