A Swedish genome-wide haplotype association analysis identifies novel candidate loci associated with endometrial cancer risk
Genome-wide association studies [GWAS] have identified a limited number of endometrial cancer risk loci by analyzing single nucleotide polymorphisms [SNPs]. We hypothesized that analyzing haplotypes rather than SNPs could provide novel and more detailed information on genetic cancer susceptibility loci. To examine the association of a SNP or haplotype with endometrial cancer risk we performed a two-stage haplotype GWAS. The discovery GWAS included a sub-cohort of 1,116 Swedish endometrial cancer cases and 5,021 controls from previously published GWAS data. A sliding window analysis was employed with window sizes of 1-25 SNPs using a logistic regression model. The Swedish haplotype analysis identified 15 novel candidate risk loci (2q31.1, 4p16.1, 4p15.31, 6q13, 7p21.1, 9p13.3, 10q26.3, 11q21, 12q13.11, 13q12.11, 15q13.3, 16q24.3, 19q13.32, 20p12.3 and 22q13.2) with OR ranging from 1.6 to 3.3 and p-values from 4.25 × 10-8 to 9.86 × 10-15. A second replication haplotype analysis of the Swedish novel loci was performed using two cohorts from Belgium and Germany. In spite of small sample sizes in the replication cohorts, there was still support for most loci with positive ORs. In addition, the findings in the two European cohorts motivates further studies to search for founder haplotypes. These novel findings suggested that endometrial cancer loci, identified through haplotype analysis, conferred a higher risk compared to previous single-variant GWAS.
Authors
- Emma Tham (ORCID: https://orcid.org/0000-0001-6079-164X)
- Annika Lindblom (ORCID: https://orcid.org/0000-0001-7675-7569)
- Serena Barilla (ORCID: https://orcid.org/0000-0003-2802-4592)
- Frédéric Amant (ORCID: https://orcid.org/0000-0002-5452-4905)
- Litika Vermani (ORCID: https://orcid.org/0000-0002-3086-5633)
- Jessada Thutkawkorapin (ORCID: https://orcid.org/0000-0001-9306-844X)
- Elin Barnekow (ORCID: https://orcid.org/0000-0002-4960-664X)
- Xue Min Wang (ORCID: https://orcid.org/0000-0002-2038-8829)
- Tracy A. O’Mara (ORCID: https://orcid.org/0000-0002-5436-3232)
- Hafdís T. Helgadóttir (ORCID: https://orcid.org/0000-0003-4352-152X)
- Emil Andersson (ORCID: https://orcid.org/0000-0001-6523-4973)
- Wen Liu (ORCID: https://orcid.org/0000-0002-7418-2543)
- Diether Lambrechts
- Peter A. Fasching
- Amanda B. Spurdle (ORCID: https://orcid.org/0000-0003-1337-7897)
- Miriam Mints
- Per Hall
- Sara Margolin (ORCID: https://orcid.org/0000-0002-5526-5570)
Institutions
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Chulalongkorn University (TH)
- QIMR Berghofer Medical Research Institute (AU)
- Universitair Ziekenhuis Leuven (BE)
- Karolinska Institutet (SE)
- Universitätsklinikum Erlangen (DE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Stockholm South General Hospital (SE)
- Comprehensive Cancer Center Erlangen (DE)
- KU Leuven (BE)
Publication Details
- Journal
- PLoS ONE
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1371/journal.pone.0316086
- Citations
- 2
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Foundation for the National Institutes of Health
- Ovarian Cancer Research Fund
- Genome Canada
- Cancerfonden
- Stockholms Läns Landsting
- Vetenskapsrådet
- Radiumhemmets Forskningsfonder
- National Institutes of Health
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council
- FP7 Health