Family-based analysis of candidate genes for polycystic ovary syndrome.
BACKGROUND
Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.


OBJECTIVE
The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations.


METHODS
The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS.


METHODS
The study was conducted at academic medical centers.


METHODS
A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS.


METHODS
There were no interventions.


METHODS
The outcome measure was transmission frequency of SNP alleles.


RESULTS
We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT chi(2) = 10.0 (P = 0.0016) and haplotype-C/A8 TDT chi(2) = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, chi(2) = 9.1; P(corrected) = 0.042) is significant after correction for multiple testing.


CONCLUSIONS
A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.
Ewens
Kathryn G
KG
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Stewart
Douglas R
DR
Ankener
Wendy
W
Urbanek
Margrit
M
McAllister
Jan M
JM
Chen
Chen
C
Baig
K Maravet
KM
Parker
Stephen C J
SC
Margulies
Elliot H
EH
Legro
Richard S
RS
Dunaif
Andrea
A
Strauss
Jerome F
JF
Spielman
Richard S
RS
D005190:Family; D005260:Female; D000071837:Fibrillins; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D009679:Nuclear Family; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D012307:Risk Factors
C493782:FBN3 protein, human; D000071837:Fibrillins; D008840:Microfilament Proteins; D011333:Pro-Opiomelanocortin