Oral Presentation ESA-SRB-APEG-NZSE 2022

Genome wide association study meta-analysis finds DENND1A, C8orf49 and XBP1 associated with lean PCOS. (#141)

Kharis Burns 1 2 , Benjamin Mullin 3 4 , Loes Moolhuijsen 5 , Ky’Era Actkins 6 , Jaakko Tyrmi 7 8 , Cecilia Lindgren 9 10 11 , Mark Daly 9 12 13 , Hannele Laivuori 7 12 14 , Jinrui Cui 15 , Mark Goodarzi 15 , Triin Laisk 16 , Jenny Visser 5 , Corrine K Welt 17 , Scott G Wilson 3 4 18 , Bronwyn GA Stuckey 2 3 19
  1. Department of Endocrinology and Diabetes, Royal Perth Hospital, Perth, WA, Australia
  2. Medical School, The University of Western Australia, Crawley, WA, Australia
  3. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
  4. School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
  5. Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  6. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  7. Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  8. Systems Epidemiology, Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
  9. Broad Institute of MIT and Harvard, ,, Cambridge, MA, USA
  10. Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
  11. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  12. Institute for Molecular Medicine Finland, FIMM, hiLIFE, University of Helsinki, Helsinki, Finland
  13. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
  14. Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland
  15. Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  16. Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
  17. Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA
  18. Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
  19. The Keogh Institute for Medical Research, Nedlands, WA, Australia

 

Lean and obese women with Polycystic Ovary Syndrome (PCOS) display different clinical characteristics, implying a different pathophysiology depending on body mass index (BMI). PCOS phenotypes, stratified by BMI, are potentially genetically distinct.

This study aimed to detect genotype differences between lean and overweight/obese PCOS-affected women and explore distinctions in genetic architecture based on BMI.

Case-control genome-wide association study (GWAS) data from Caucasian PCOS-affected women and controls were pooled from six international PCOS research groups, and separated according to three BMI stratifications (lean BMI<25kg/m2, overweight BMI >25-<30kg/m2 and obese BMI >30kg/m2). A meta-analysis of GWAS data (Meta-GWAS) from each BMI tier was performed.

The population comprised 257,155 women (6,273 cases and 250,822 controls) from Australian, American, Netherlands, Estonian and Finnish cohorts. Almost half of the population (47.1%, n=120,983) were of lean BMI. Two genetic loci meeting genome-wide significance (p<5x10-8) for lean PCOS were identified - rs12000707, within DENND1A (9q33.3;  p=1.55x10-12) and rs2228260 within XBP1 (22q12.1; p=3.68x10-8). DENND1A is a well-recognised genetic risk locus for PCOS and is associated with hyperandrogenism and ovulatory dysfunction. XBP1 is involved in glucose and lipid metabolism, suggesting a plausible biological link with PCOS. The signal at XBP1 is part of a large linkage disequilibrium (LD) block containing other genes, including CHEK2, with putative PCOS involvement.

Gene-based association testing identified C8orf49 as significantly associated with lean PCOS. C8orf49 is located in close proximity to two other genes previously implicated in PCOS, GATA4 and NEIL2, and may be part of a PCOS-susceptibility gene cluster on chromosome 8. The association between these genetic loci and lean PCOS is a novel finding.

The SNPs and genes identified in this study provide further evidence of distinct genetic architecture underlying lean and overweight/obese PCOS. The identification of loci associated specifically with lean PCOS is of significant interest.