The above analyses account for a possible confounding relationship between LoF intolerance and BGS. To illustrate this more clearly, we binned the BGS intensities into four categories of increasing score and classified SNPs in these bins according to whether they were in LoF-intolerant genes, ‘all other’ gene sets or a non-genic set (Supplementary Fig. 6). Note that the lower boundary of the top bin (BGS intensity > 0.75) corresponds approximately to the top 2% BGS threshold in Table 1 and is equivalent to a reduction in effective population size estimated at each SNP of 75% or more29. We found significant heritability enrichment across all BGS intensity intervals in LoF-intolerant genes that increased progressively with higher intensity scores. Notably, we also found heritability enrichment for SNPs under BGS pressure in genes that were not LoF intolerant, restricted to the highest BGS intensity bin. Indeed, the highest BGS intensity bin in non-LoF-intolerant genes was enriched for heritability at a level roughly equivalent to that for all LoF-intolerant genes. These findings point to BGS and LoF intolerance as making at least partially independent
