机构：[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
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.
基金：
This work was supported in part by NIH grants R21AA021380,
R21AA020319, and R21AA023237 to XGL, and R01DA023248
to C-SL. We thank NIH GWAS Data Repository, the
Contributing Investigator(s) who contributed the phenotype
and genotype data from his/her original study (e.g., Drs.
Payami, Foroud, Singleton, Hardy, Gasser, Hamza, Factor,
Nutt, Zabetian, Molho, Higgins, and Nichols, etc.), and the
primary funding organization that supported the contributing
study. Funding and other supports for phenotype and
genotype data were provided through the NIH Grants
R01NS36960 to Haydeh Payami, R01NS037167 to Tatiana
Foroud, and R01NS036711 to Myers. The dbGaP datasets
used for the analyses described in this manuscript were
obtained from http://www.ncbi.nlm.nih.gov/sites/entrez?Db=
gap. dbGaP Study Accession phs000196.v3.p1, phs000126.v2.p1,
and phs001172.v1.p2. The Genotype-Tissue Expression (GTEx)
Project was supported by the Common Fund of the Office
of the Director of the National Institutes of Health, and by
NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The GTEx
data used for the analyses described in this manuscript were
obtained from the GTEx Portal and dbGaP accession number
phs000424.v2.p1.
第一作者机构：[1]Department of Psychosomatic Medicine, People’s Hospital of Deyang, Deyang, China,
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Mao Qiao,Wang Xiaoping,Chen Bin,et al.KTN1Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease[J].FRONTIERS IN NEUROSCIENCE.2020,14:doi:10.3389/fnins.2020.00651.
APA：
Mao, Qiao,Wang, Xiaoping,Chen, Bin,Fan, Longhua,Wang, Shuhong...&Luo, Xingguang.(2020).KTN1Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease.FRONTIERS IN NEUROSCIENCE,14,
MLA：
Mao, Qiao,et al."KTN1Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease".FRONTIERS IN NEUROSCIENCE 14.(2020)
