Effect of the Minor C Allele of CNTN4 rs2619566 on Medial Hypothalamic Connectivity in Early-Stage Patients of Chinese Han Ancestry with Sporadic Amyotrophic Lateral Sclerosis

Yao Wang; Yujie He; Yanyan Zhu; Ting He; Jie Xu; Qinmei Kuang; Yuqi Ji; Renshi Xu; Fangjun Li; Fuqing Zhou

doi:10.2147/NDT.S339456

Effect of the Minor C Allele of CNTN4 rs2619566 on Medial Hypothalamic Connectivity in Early-Stage Patients of Chinese Han Ancestry with Sporadic Amyotrophic Lateral Sclerosis

Neuropsychiatr Dis Treat. 2022 Feb 25:18:437-448. doi: 10.2147/NDT.S339456. eCollection 2022.

Authors

Yao Wang^{1

2}, Yujie He^{1

2}, Yanyan Zhu^{1

2}, Ting He^{1

2}, Jie Xu^{1

2}, Qinmei Kuang^{1

2}, Yuqi Ji^{1

2}, Renshi Xu³, Fangjun Li⁴, Fuqing Zhou^{1

2}

Affiliations

¹ Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
² Neuroimaging Lab, Jiangxi Province Medical Imaging Research Institute, Nanchang, 330006, People's Republic of China.
³ Department of Neurology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, 330006, People's Republic of China.
⁴ Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.

Abstract

Objective: Clinical symptoms such as major defects in energy metabolism may involve the hypothalamus in amyotrophic lateral sclerosis (ALS) patients. Our recent study discovered that the single-nucleotide polymorphisms (SNPs) of rs2619566, rs79609816 and rs10260404 are associated with sporadic ALS (sALS). Thus, this study aims to investigate the hypothalamic functional reorganization and its association with the above polymorphisms risk alleles in sALS patients of Chinese Han ancestry.

Methods: Forty-four sALS patients (28 males/16 females) and 40 healthy subjects (HS; 28 males/12 females) underwent resting-state functional MRI, genotyping and clinical assessments. A two-sample t test (P < 0.01, GRF correction at P < 0.05) was performed to compare hypothalamic connectivity for group-level analysis in disease diagnosis and genotype, and then the genotype-diagnosis interaction effect was assessed. Finally, Spearman correlation analyses were performed to assess the relationship between the altered functional connectivity and their clinical characteristics.

Results: The sALS patients showed a short disease duration (median = 12 months). Regarding the diagnosis effect, the sALS patients showed widespread hypothalamic hyperconnectivity with the left superior temporal gyrus/middle temporal gyrus, right inferior frontal gyrus, and left precuneus/posterior cingulate gyrus. For the genotype effect of SNPs, hyperconnectivity was observed in only the medial hypothalamus when the sALS patients harboring the minor C allele of rs2619566 in contactin-4 (CNTN4), while the sALS patients with the TT allele showed a hyperconnectivity network in the right lateral hypothalamus. This connectivity pattern was not observed in other SNPs. No significant genotype-diagnosis interaction was found. Moreover, altered functional connectivity was not significantly correlated with clinical characteristics (P : 0.11-0.90).

Conclusion: These results demonstrated widespread hypothalamic hyperconnectivity in sALS. The risk allele C of the CNTN4 gene may therefore influence functional reorganization of the medial hypothalamus. The effects of the CNTN4 rs2619566 polymorphism may exist in the hypothalamic functional connectivity of patients with sALS.

Keywords: hypothalamus; lateral hypothalamus; medial hypothalamus; resting-state functional connectivity; sporadic amyotrophic lateral sclerosis.