The NicW-associated SNPs mapped to the PCDH-α, -β, and -γ gene cluster. Genes expressed from this ~800-kilobase region on human chromosome 5 encode structurally similar transmembrane proteins that are enriched at the synapses of neurons.61 The expression of PCDH-α, -β, and -γ genes in the nervous system is tightly controlled.62, 63 The specific position of rs31746 within the gene cluster is noteworthy; it maps to HS5-1, a previously characterized long-range, neuron-specific enhancer element.47–49 The critical function of this regulatory element is supported by several studies, including data compiled by ENCODE on DNAse hypersensitivity and transcription factor binding. Rs31746 is within HS5-1a, a component of HS5-1 that interacts directly with CTCF.47 HS5-1 recruits CTCF and additional proteins that control the chromatin structure of the PCDH-α, -β, and -γ gene region. Through protein partners, HS5-1 and other cis-regulatory elements in the region direct long-range DNA looping and interactions that facilitate the expression of specific PCDH-α, -β, and -γ gene mRNAs via alternative promoter usage.47–49, 56, 64 Targeted deletion of HS5-1 in mice reduced the expression of PCDHβ8 mRNA, which we observed to
