The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Genome Wide Association Study Identifies 5 Novel Loci Associated with Polycystic Ovary Syndrome (PCOS) in Caucasian Women (#153)

Kharis Burns 1 2 3 , Benjamin H Mullin 2 4 , Purdey Campbell 2 , Suzanne J Brown 2 , Ee Mun Lim 2 3 5 , Narelle Hadlow 3 5 , John Joseph 5 , Timothy Spector 6 , Gerald F Watts 3 7 , Scott G Wilson 2 4 6 , Bronwyn GA Stuckey 1 2 3
  1. The Keogh Institute for Medical Research, Nedlands, WA, Australia
  2. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
  3. School of Medicine, Faculty of Health and Biomedical Sciences , University of Western Australia, Perth, WA, Australia
  4. School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
  5. Pathwest Laboratory Medicine WA, Nedlands, WA, Australia
  6. Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
  7. Cardiometabolic Service, Department of Cardiology, Royal Perth Hospital, Perth, WA, Australia

PCOS is the most common reproductive endocrinopathy, affecting 5-10% of women. Familial inheritance patterns suggest a genetic basis, however polymorphisms identified through GWAS do not explain the entirety of PCOS aetiology. Additionally these investigations have been conducted in ethnically diverse women and do not differentiate between lean and obese phenotypes.

PCOS-affected Caucasian subjects, defined using NIH criteria, were recruited through clinics and study advertisement. Relative to local population phenotypes, a higher proportion of lean subjects was included. Blood was collected for DNA extraction, genetic analysis and hormonal profiling, including gonadotrophins, androgens, fasting glucose and insulin.

Genotyping was performed using the Illumina HumanOmniExpress array. Imputation was performed using the Haplotype Reference Consortium panel. Control subjects were sourced from the TwinsUK cohort. A case-control GWAS was performed in 305 PCOS-affected women and 4986 controls. Analysis was performed using GEMMA software (MAF threshold 0.05).

Approximately one third (30.2%) of the affected population was of lean/normal BMI (<25kg/m2). An elevated LH:FSH ratio was seen in 30.4% and 68.5% were insulin resistant (HOMA-IR>1.8). Five novel loci were identified for association with PCOS at genome-wide significance level (p<5x10-8). These loci have not previously been linked with PCOS, though some have been implicated in gonadotrophin release, infertility, insulin and glucagon metabolism, features which may be abnormal in PCOS. All SNPs are intronic, hence may be involved in the regulation of genes implicated in PCOS. Directionally consistent significant (p<0.05) associations were noted for two signals previously identified in Caucasian women, rs7563201 within the gene THADA, and rs1351592, within ERBB4/HER4.

Identification of these novel SNPs provides further evidence for a genetic aetiology in PCOS. The function of these newly elucidated loci may be complex, varying from direct effects on the aetiology of PCOS-associated traits, including metabolic derangement and infertility, to the involvement in regulation of other potential contributory genes.