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To uncover novel significant association signals (p&lt;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&lt;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&lt;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.

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci