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

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

doi:10.3389/fnins.2020.00651

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

Front Neurosci. 2020 Jun 23:14:651. doi: 10.3389/fnins.2020.00651. eCollection 2020.

Authors

Qiao Mao¹, Xiaoping Wang², Bin Chen³, Longhua Fan⁴, Shuhong Wang², Yong Zhang⁵, Xiandong Lin⁶, Yuping Cao⁷, Yun-Cheng Wu⁸, Jiawu Ji⁹, Jianying Xu¹⁰, Jianming Zheng¹¹, Huihao Zhang¹², Chengchou Zheng¹³, Wenzhong Chen¹⁴, Wenhong Cheng¹⁴, Xingqun Luo¹⁵, Kesheng Wang¹⁶, Lingjun Zuo¹⁷, Longli Kang¹⁸, Chiang-Shan R Li¹⁷, Xingguang Luo¹⁹

Affiliations

¹ Department of Psychosomatic Medicine, People's Hospital of Deyang, Deyang, China.
² Department of Neurology, Shanghai Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Cardiovascular Medicine, Fujian Provincial Hospital, Fuzhou, China.
⁴ Qingpu Branch, Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Tianjin Mental Health Center, Tianjin, China.
⁶ Laboratory of Radiation Oncology and Radiobiology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou, China.
⁷ Department of Psychiatry, Second Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁹ Department of Psychiatry, Fuzhou Neuropsychiatric Hospital, Fujian Medical University, Fuzhou, China.
¹⁰ Zhuhai Municipal Maternal and Children's Health Hospital, Zhuhai, China.
¹¹ Huashan Hospital, Fudan University School of Medicine, Shanghai, China.
¹² The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
¹³ Minqing Psychiatric Hospital, Minqing, China.
¹⁴ Department of Psychiatry, Shanghai Mental Health Center, Shanghai, China.
¹⁵ Department of Clinical Medicine, College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
¹⁶ Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV, United States.
¹⁷ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
¹⁸ Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xiangyang, China.
¹⁹ Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China.

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; 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.

Keywords: KTN1; Parkinson’s disease; gray matter volume; mRNA expression; putamen; substantia nigra.

Abstract

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