Harnessing Expression Data to Identify Novel Candidate Genes in Polycystic Ovary Syndrome

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.

Four polymorphisms of the CAPN 10 gene and their relationship to polycystic ovary syndrome susceptibility: a meta‐analysis

“…Polycystic ovary syndrome (PCOS) characterized by chronic ovulatory dysfunction, hyperandrogenism, polycystic ovary morphology, obesity and insulin resistance is a common endocrine disorder affecting 5–10% of women of reproductive age 1 . Many studies suggest that the genetic factors play an important role in the aetiology of PCOS 2 . Those have been analysed in searching for the molecular basis of PCOS, such as genes involved in steroid hormone biosynthesis (CYP11a, CYP17 and CYP19), 3,4 genes involved in gonadotropin action (LHR and FSHR), 5 genes involved in the insulin signalling pathway (TRB3 and IRS‐1/2) 6,7 and genes involved in insulin receptor (INSR) gene 8…”

“…1 Many studies suggest that the genetic factors play an important role in the aetiology of PCOS. 2 Those have been analysed in searching for the molecular basis of PCOS, such as genes involved in steroid hormone biosynthesis (CYP11a, CYP17 and CYP19), 3,4 genes involved in gonadotropin action (LHR and FSHR), 5 genes involved in the insulin signalling pathway (TRB3 and IRS-1/2) 6,7 and genes involved in insulin receptor (INSR) gene. 8 As PCOS is associated with a 2-7-fold increased risk to develop impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM), genes related to T2DM may also play a role in PCOS pathogenesis.…”

Genomic Signatures of a Global Fitness Index in a Multi‐Ethnic Cohort of Women

“…DNAJB1, one of the genes they identified as over-expressed among high male responders following 6 weeks of aerobic training, was also significantly over-expressed in mRNA collected at baseline among high responders to the GEAR exercise protocol. DNAJB1 is an androgen protein co-chaperone in the glucocorticoid receptor signalling (Jones, 2011) that is under transcriptional regulation by insulin (Goodall et al, 2010). Two genes (CTTN, PRKAR2B) were also over-expressed (FDR < 0.10) in baseline mRNA levels among the women who were subsequently categorized as "high" versus "low" responders.…”

Polycystic Diseases in Visceral Organs

“…Recent studies have identified that DKK1 and DNAJB1 are differentially expressed in PCOS tissue [76]. Thus, DKK1 (encoding a dickkopf related protein) and DNAJB1 (encoding DnaJ or Hsp40 homolog) are potential genes of interest in the pathogenesis of PCOS.…”