KTN1 Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease.

Background Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson's disease (PD). Recent studies have reported specific effects of kinectin 1 gene (KTN1) variants on the putamen GMV. Objective To examine the relationship ofKTN1variants,KTN1mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD. Methods We examined the associations between PD and a total of 1847 imputedKTN1single nucleotide polymorphisms (SNPs) in one discovery sample [2,000 subjects with PD vs. 1,986 healthy controls (HC)], and confirmed the nominally significant associations (p< 0.05) in two replication samples (900 PD vs. 867 HC, and 940 PD vs. 801 HC, respectively). The regulatory effects of risk variants on theKTN1mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels ofKTN1mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts. Results Six replicable and two non-replicableKTN1-PD associations were identified (0.009 <= p <= 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 <= p <= 0.049) and putamen GMVs (19.08 <= beta <= 60.38; 2.82 <= Z <= 15.03; 5.0 x 10(-51)<= p <= 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased theKTN1mRNA expression in the putamen or SNc (0.021 <= p <= 0.046). TheKTN1mRNA was abundant in the putamen and/or SNc across five independent cohorts and differentially expressed in the SNc between PD and HC in one cohort (p= 0.047). Conclusion There was a consistent, significant, replicable, and robust positive relationship among theKTN1variants, PD risk,KTN1mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk andKTN1mRNA expression in SNc, suggesting thatKTN1may play a functional role in the development of PD.