Next, to explore the realistic scenario where the model used to estimate enrichment does not match the (unknown) causal model, we performed three sets of simulations where all causal SNPs were in a particular category, but the model used to estimate heritability did not include this causal category. The three sets of simulations were (1) all causal SNPs in coding regions, yielding a true 1.6x DHS enrichment due to coding/DHS overlap, (2) all causal SNPs in FANTOM5 enhancers, yielding a true 4.0x DHS enrichment due to FANTOM5 enhancer/DHS overlap, and (3) all causal SNPs in 200bp DHS flanking regions, yielding a true 0x DHS enrichment. For the coding and FANTOM5 enhancer causal simulations, we transformed the full baseline model into a misspecified model by removing the causal category and window around the causal category; the baseline model includes a 500bp window around DHS but not a 200bp window, and so is misspecified also in that case. Results from these simulations are displayed in Figure 2b. The two-category estimators were not robust to model misspecification and consistently over-estimated DHS enrichment by a wide margin. Stratified LD score regression with the full baseline model gave more accurate mean estimates of enrichment.
