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

Abstract

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;

Sex-different interrelationships of rs945270, cerebral gray matter volumes, and attention deficit hyperactivity disorder: a region-wide study across brain

“…However, in females, the rs945270-ADHD association was not significant, even after adjusting for GMVs. Furthermore, this allele also significantly increased putamen GMV only in males, confirming previous findings [ 15 , 17 , 18 ]. The regulatory effect of the major allele C of rs945270 on GMVs was not influenced by ADHD symptom scores.…”

“…A previous genome-wide association study (GWAS) reported that the major allele C of rs945270 at 3’ flanking to the kinectin 1 gene ( KTN1 ) showed the most significant positive effect on putamen GMV ( p = 1.1 × 10 −33 ) [ 15 ], a finding confirmed by follow-up meta GWAS ( p = 1.0 × 10 −43 ) [ 16 ] and candidate gene association studies (5.0 × 10 −51 ≤ p ≤ 1.3 × 10 −5 ) [ 17 , 18 ]. This allele had also a significant positive effect on the pallium GMV ( p = 3.0 × 10 −7 ) [ 15 ].…”

“…However, the alleles of nine other variants at the 5′- and 3′-UTRs of KTN1 were reported to reliably increase both risks for ADHD and putamen GMV [ 23 ], which seemed to contradict the preceding negative “ADHD–GMV” associations. Further, it has been reported that the major allele C of rs945270 increased the risk for alcohol and nicotine co-dependence [ 24 ], a comorbid condition frequently observed in individuals with ADHD, and Parkinson’s disease [ 18 , 25 ]. As the putamen GMV was significantly reduced in patients with alcoholism [ 26 ] and Parkinson’s disease [ 27 – 31 ], the latter seemed to contradict the afore-described finding of positive “allele C–GMV” associations, too.…”

Common protein-coding variants influence the racing phenotype in galloping racehorse breeds

“…In humans, KTN1 gene variants are strongly associated with KTN1 gene expression in the putamen and the volume of the putamen 113 , a region of the forebrain belonging to the basal ganglion that influences motor behaviours including motor planning and execution, motor preparation, amplitudes of movement and sequences of movement [113][114][115][116][117][118][119][120] . Here, the KTN1 G-allele was <1% in Thoroughbreds but had an average frequency of 0.22 in the other racing breeds, was 0.34 in the ancestral breeds and 0.21 in the sport horse breeds.…”

A genetic and transcriptomic assessment of theKTN1gene in Parkinson’s disease risk

“…Recently, Mao and colleagues reported nominal associations between common intergenic variants downstream and upstream of the KTN1 gene and PD risk, as well as an increased KTN1 mRNA expression in the putamen and SNpc, which resulted in a compensatory increase in the gray matter volumes (GMV) of these two brain regions in PD patients, suggesting that KTN1 may play a functional role in the development of PD 6 . KTN1 encodes the integral membrane protein kinectin 1, a receptor that is involved in organelle transport within the cell by allowing vesicle binding to kinesin 7 .…”