To uncover novel significant association signals (P<5x10-8), GWAS requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5x10-8 ≤ P < 5x10-4) 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 ESC-derived hypothalamic-like neurons. This approach, with its extremely low false positive rate, identified 15 loci at P<5x10-5 in the 2010 GWAS, 13 of which achieved genome-wide significance by 2018, including at NAV1, MTIF3 and ADCY3. 80% 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 datasets without increasing sample size.

中文翻译：

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GWAS SNP 在暗示性阈值下的生物学限制揭示了额外的 BMI 位点

为了发现新的显着关联信号 (P<5x10-8)，GWAS 需要越来越大的样本量来克服多重测试的统计校正。作为替代方案，我们的目标是使用染色质可及性和与基因启动子的直接接触作为生物学限制，在日益强大的 GWAS 工作中确定暗示信号 (5x10-8 ≤ P < 5x10-4) 之间的关联。我们使用来自人类脂肪细胞和 ESC 衍生的下丘脑样神经元的 ATAC-seq 和以启动子为中心的 Capture C 数据，对三项 GIANT BMI GWAS 工作进行了回顾性分析。该方法以其极低的假阳性率，在 2010 年 GWAS 中鉴定出 15 个 P<5x10-5 的位点，其中 13 个位点到 2018 年实现了全基因组显着性，包括 NAV1、MTIF3 和 ADCY3。80% 的 2015 年受限基因座在 2018 年实现了全基因组显着性。我们在腰臀比分析中观察到类似的结果。总之，对次显着 GWAS 信号的生物学限制可以揭示潜在的真阳性位点，以便在现有数据集中进一步研究，而无需增加样本量。