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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 of  KTN1  variants,  KTN1  mRNA 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 imputed  KTN1  single 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 the  KTN1  mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of  KTN1  mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts.    Results  Six replicable and two non-replicable  KTN1 -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 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10 –51  ≤  p  ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the  KTN1  mRNA expression in the putamen or SNc (0.021 ≤  p  ≤ 0.046). The  KTN1  mRNA 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 the  KTN1  variants, PD risk,  KTN1  mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and  KTN1  mRNA expression in SNc, suggesting that  KTN1  may play a functional role in the development of PD.

KTN1 Variants Underlying Putamen Gray Matter Volumes and Parkinson’s Disease