We also evaluated the utility of known regulatory annotations in predicting eQTLs for rare variants. Comparing annotated rare variants with all rare variants, we observed strong enrichment (up to a 2-fold increase near the TSS) of annotated variants, indicating that annotation is highly informative in predicting eQTLs (Figure S22). Furthermore, we observed that the enrichment was higher in family-based eQTLs than in population eQTLs as a function of effect size (Figure S24). To test the contribution of different annotations to a large effect in the family, we further stratified by MAF and strength of evolutionary constraint. We observed that variants with lower MAF and with increasing degree of evolutionary constraint were the most informative factors indicative of large cis-eQTL effects in the family (Figure 2C).