The third association signal (chromosome 6p22) features a cluster of highly associated SNPs (including rs9465871) with risk-allele frequencies between 18 and 35%, mapping to intron 5 of the CDKAL1 (CDK5 regulatory subunit associated protein 1-like 1) gene. Although the function of CDKAL1 is not known, it shares homology at the protein domain level with CDK5 regulatory subunit associated protein 1 (CDK5RAP1). CDK5RAP1 is known to inhibit the activation of CDK5, a cyclin-dependent kinase which has been implicated in the maintenance of normal beta-cell function108. Our own follow-up studies, and scans by other groups have shown strong replication of this finding19-22. The effect of this variant on T2D-risk shows significant departures from additivity (Supplemantary Table 8).
