Harnessing expression data to identify novel candidate genes in polycystic ovary syndrome

Michelle R. Jones, Angela Chua, Yii Der I. Chen, Xiaohui Li, Ronald M. Krauss, Jerome I. Rotter, Richard S. Legro, Ricardo Azziz, Mark O. Goodarzi

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed.

Original languageEnglish (US)
Article numbere20120
JournalPloS one
Volume6
Issue number5
DOIs
StatePublished - May 23 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Jones, M. R., Chua, A., Chen, Y. D. I., Li, X., Krauss, R. M., Rotter, J. I., Legro, R. S., Azziz, R., & Goodarzi, M. O. (2011). Harnessing expression data to identify novel candidate genes in polycystic ovary syndrome. PloS one, 6(5), [e20120]. https://doi.org/10.1371/journal.pone.0020120