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- Title
Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci.
- Authors
Hammond, Reza K.; Pahl, Matthew C.; Chun Su; Cousminer, Diana L.; Leonard, Michelle E.; Sumei Lu; Doege, Claudia A.; Wagley, Yadav; Hodge, Kenyaita M.; Lasconi, Chiara; Johnson, Matthew E.; Pippin, James A.; Hankenson, Kurt D.; Leibel, Rudolph L.; Chesi, Alessandra; Wells, Andrew D.; Grant, Struan F. A.
- Abstract
To uncover novel significant association signals (p<5-108), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 - 108-p<5-104) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5-105 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at NAV1, MTIF3, and ADCY3. Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.
- Subjects
GENOME-wide association studies; HUMAN embryonic stem cells; WAIST-hip ratio; SAMPLE size (Statistics)
- Publication
eLife, 2021, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.62206