Fine Mapping of Genetic Susceptibility to Polycystic Ovary Syndrome on Chromosome 19p13.2 and Tests for Regulatory Activity
D. R. Stewart,
B. A. Dombroski,
M. Urbanek,
W. Ankener,
K. G. Ewens,
J. R. Wood,
R. S. Legro,
J. F. Strauss, III,
A. Dunaif and
R. S. Spielman
Department of Genetics (D.R.S., B.A.D., W.A., K.G.E., R.S.S.), Center for Research on Reproduction and Women’s Health, and Department of Obstetrics and Gynecology (J.F.S., J.R.W.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Division of Endocrinology, Metabolism, and Molecular Medicine (M.U., A.D.), Northwestern University Medical School, Chicago, Illinois 60611; and Department of Obstetrics and Gynecology (R.S.L.), Pennsylvania State University, Hershey, Pennsylvania 17033
Address all correspondence and requests for reprints to: Dr. Richard Spielman, Department of Genetics, University of Pennsylvania. School of Medicine, Philadelphia, Pennsylvania 19104-6145. E-mail: spielman{at}pobox.upenn.edu.
Context: Little is known about genes that contribute to polycysticovary syndrome (PCOS). We previously found linkage and associationof PCOS with the dinucleotide marker D19S884 in two independentsets of families; allele 8 of D19S884 confers increased risk.
Objective/Design: The objectives of the study were: 1) use thetransmission/disequilibrium test (TDT) to assess linkage andassociation between PCOS and D19S884 (and nearby markers) ina third set of families; and 2) test D19S884 and surroundingDNA sequence for in vitro regulatory activity in lymphoblastoidcell lines (LCLs) and granulosa cells.
Setting/Subjects: We studied 98 new families with a PCOS proband,father, mother, and other available offspring. We analyzed datafrom these families separately and in combination with dataobtained previously.
Interventions: Interventions were venipuncture.
Main Outcome Measures: Measures were transmission frequenciesand in vitro functional studies.
Results: The first result we found was that in the 98 new families,the TDT was significant for allele 8 of D19S884 (P = 0.043).In the total collection of 465 families, the TDT evidence isvery strong (nominal P < 7 x 10–5). Results for allother genetic markers near D19S884 were nonsignificant aftercorrection for multiple testing. The second result was thatan approximately 800-bp fragment containing various allelesof D19S884 showed modest but reproducible promoter activityin LCLs. However, no allelic differences were detected. No activityof this fragment was detected in granulosa cells.
Conclusions: This is the second independent confirmation oflinkage and association of D19S884 with PCOS. We found in additionthat some sequence in the region of D19S884 confers in vitropromoter activity in LCLs.
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