Supplementary Figure 1: Statistical power in the noncoding genome by cohort size, related to Figure 1 in the main manuscript.

We estimated the power at a significance threshold (alpha) of 5 × 10⁻⁵, accounting for 1,000 categories of noncoding variants, to detect an excess of noncoding variants at 122,500 risk loci in cases vs. controls as we varied the sample size and risk:non-risk ratio, which represents annotation quality (Supplementary Tables 1 and 3). In a) we assessed the power for detecting an excess of de novo mutations at a relative risk of 5 as sample size increases. With a risk:non-risk ratio of 1:20, approximately equivalent to assessing protein truncating variants in the coding genome, we achieve >80% power with a sample size of 5,000. In b) the power to detect an excess burden of rare variants (allele frequency ≤0.1%) is assessed at a relative risk of 1.2. In c) we assessed the power to identify an excess of de novo mutations at a specific genomic locus, e.g. the noncoding region regulating a single gene. Consequently, we set the significance threshold (alpha) at 2.5 × 10⁻⁶ to account for 20,000 genes. In d) we assessed the power to identify an excess of rare variants (allele frequency ≤0.1%) at a specific nucleotide (alpha = 1.7 × 10⁻¹¹), since this yielded better power than testing for burden at a locus (alpha = 2.5 × 10⁻⁶).