AUTHOR=Mao Qiao , Wang Xiaoping , Chen Bin , Fan Longhua , Wang Shuhong , Zhang Yong , Lin Xiandong , Cao Yuping , Wu Yun-Cheng , Ji Jiawu , Xu Jianying , Zheng Jianming , Zhang Huihao , Zheng Chengchou , Chen Wenzhong , Cheng Wenhong , Luo Xingqun , Wang Kesheng , Zuo Lingjun , Kang Longli , Li Chiang-Shan R. , Luo Xingguang 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=14

YEAR=2020

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2020.00651

DOI=10.3389/fnins.2020.00651

ISSN=1662-453X

ABSTRACT=<sec><title>Background</title><p>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 (<italic>KTN1</italic>) variants on the putamen GMV.</p></sec><sec><title>Objective</title><p>To examine the relationship of <italic>KTN1</italic> variants, <italic>KTN1</italic> mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD.</p></sec><sec><title>Methods</title><p>We examined the associations between PD and a total of 1847 imputed <italic>KTN1</italic> 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 (<italic>p</italic> &lt; 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 <italic>KTN1</italic> mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of <italic>KTN1</italic> mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts.</p></sec><sec><title>Results</title><p>Six replicable and two non-replicable <italic>KTN1</italic>-PD associations were identified (0.009 ≤ <italic>p</italic> ≤ 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 ≤ <italic>p</italic> ≤ 0.049) and putamen GMVs (19.08 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10<sup>–51</sup> ≤ <italic>p</italic> ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the <italic>KTN1</italic> mRNA expression in the putamen or SNc (0.021 ≤ <italic>p</italic> ≤ 0.046). The <italic>KTN1</italic> 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 (<italic>p</italic> = 0.047).</p></sec><sec><title>Conclusion</title><p>There was a consistent, significant, replicable, and robust positive relationship among the <italic>KTN1</italic> variants, PD risk, <italic>KTN1</italic> mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and <italic>KTN1</italic> mRNA expression in SNc, suggesting that <italic>KTN1</italic> may play a functional role in the development of PD.</p></sec>