In this study, we investigated rare sequence variants of CHRNA4 in nearly 1200 ND cases and 1200 comparison subjects. The effect of some of the rare variants identified on availability of α4β2 nAChRs was assessed by means of iodide 123-labeled 5-iodo-A-85380 ([123I]5-IA) single-photon emission computed tomography (SPECT) imaging. [123I]5-IA binds with relative selectivity to α4β2 nAChRs (24) and thus can be used to measure the availability of α4β2 nAChRs (25). Here, we report that nonsynonymous rare variants in the exon 5 region encoding the cytoplasmic loop are protective for ND, with the strongest evidence for the African American (AA) population. We also found that at least a subset of these rare variants in CHRNA4 alters availability of high affinity nAChRs in human brain.
