Studies of mice with a large deletion of the ARPKD-associated <i>Pkhd1</i> locus likely explain its GWAS association with glaucoma in humans

<i>PKHD1</i>, the gene primarily mutated in human autosomal recessive polycystic kidney disease, is one of the top 20 genes associated with primary open angle glaucoma (POAG) and associated endophenotypes in Genome-Wide Association Studies. Here, we show that <i>Pkhd1</i> ^{<i>del3-67/del3-67</i>} mutant mice develop congenital glaucoma due to anterior segment dysgenesis. Using a combination of genetic, epigenetic, bioinformatics and mouse developmental biology approaches, we show that <i>Pkhd1</i> ^{<i>del3-67/del3-67</i>} mice lack <i>Tfap2b</i> and AP-2β expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest that the <i>Pkhd1</i> ^{<i>del3-67</i>} deletion disrupts features of the <i>Pkhd1-Tfap2b</i> genomic architecture essential for <i>Tfap2b</i> cell-specific activities. Consistent with this model, <i>Pkhd1</i> ^{<i>del3-67/+</i>} ;<i>Tfap2b</i> ^<i>ko</i>/+trans-heterozygotes lack <i>Tfap2b</i> and AP-2β in relevant cell-types and have similar eye abnormalities as neural crest cell-specific <i>Tfap2b</i> ^<i>ko</i> mutants. These findings provide a likely causal explanation for how SNPs associated with <i>PKHD1</i> are functionally linked to POAG and add insight into understanding the complexity of disease-causing SNP associations and gene regulatory mechanisms.