Allelic variant in SLC6A3 rs393795 affects cerebral regional homogeneity and gait dysfunction in patients with Parkinson's disease

Lina Wang; Yongsheng Yuan; Jianwei Wang; Yuting Shen; Yan Zhi; Junyi Li; Min Wang; Kezhong Zhang

doi:10.7717/peerj.7957

Allelic variant in SLC6A3 rs393795 affects cerebral regional homogeneity and gait dysfunction in patients with Parkinson's disease

PeerJ. 2019 Nov 4:7:e7957. doi: 10.7717/peerj.7957. eCollection 2019.

Authors

Lina Wang^#¹, Yongsheng Yuan^#¹, Jianwei Wang², Yuting Shen¹, Yan Zhi¹, Junyi Li¹, Min Wang², Kezhong Zhang¹

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

^# Contributed equally.

Abstract

Aims: We sought to explore the role of the SLC6A3 rs393795 allelic variant in cerebral spontaneous activity and clinical features in Parkinson's disease (PD) via imaging genetic approach.

Methods: Our study recruited 50 PD and 45 healthy control (HC) participants to provide clinical, genetic, and resting state functional magnetic resonance imaging (rs-fMRI) data. All subjects were separated into 16 PD-AA, 34 PD-CA/CC, 14 HC-AA, and 31 HC-CA/CC four subgroups according to SLC6A3 rs393795 genotyping. Afterwards, main effects and interactions of groups (PD versus HC) and genotypes (AA versus CA/CC) on cerebral function reflected by regional homogeneity (ReHo) were explored using two-way analysis of covariance (ANCOVA) after controlling age and gender. Finally, Spearman' s correlations were employed to investigate the relationships between significantly interactive brain regions and clinical manifestations in PD subgroups.

Results: Compared with HC subjects, PD patients exhibited increased ReHo signals in left middle temporal gyrus and decreased ReHo signals in left pallidum. Compared with CA/CC carriers, AA genotype individuals showed abnormal increased ReHo signals in right inferior frontal gyrus (IFG) and supplementary motor area (SMA). Moreover, significant interactions (affected by both disease factor and allelic variation) were detected in right inferior temporal gyrus (ITG). Furthermore, aberrant increased ReHo signals in right ITG were observed in PD-AA in comparison with PD-CA/CC. Notably, ReHo values in right ITG were negatively associated with Tinetti Mobility Test (TMT) gait subscale scores and positively related to Freezing of Gait Questionnaire (FOG-Q) scores in PD-AA subgroup.

Conclusions: Our findings suggested that SLC6A3 rs393795 allelic variation might have a trend to aggravate the severity of gait disorders in PD patients by altering right SMA and IFG function, and ultimately result in compensatory activation of right ITG. It could provide us with a new perspective for exploring deeply genetic mechanisms of gait disturbances in PD.

Keywords: Gait dysfunction; Imaging genetics; Parkinson’s disease; Regional homogeneity; SLC6A3; rs393795.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No.81671258 & No. 81901297), the Science and Technology Project of Jiangsu Provincial Commission of Health and Family Planning (No. H201602), the Natural science foundation of Jiangsu Province (No. BK20141494), the Jiangsu Provincial Personnel Department “the Great of Six Talented Man Peak” Project (No. 2014-WSN-013), the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Science and Technology Project of Jiangsu Bureau of Traditional Chinese Medicine (No. YB2015163). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.