Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci
Reza Hammond, Matthew C. Pahl, Chun Su, Diana L. Cousminer, Michelle E. Leonard, Sumei Lu, Claudia A. Doege, Yadav Wagley, Kenyaita M. Hodge, Chiara Lasconi, Matthew E. Johnson, James A. Pippin, Kurt D. Hankenson, Rudolph L. Leibel, Alessandra Chesi, Andrew D. Wells, Struan F.A. Grant
Abstract
To uncover novel significant association signals (p<5×10 −8 ), 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 × 10 −8 ≤p<5×10 −4 ) 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<5×10 −5 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.