ALPHA PSYCHIATRY
Original Articles

The Role of 3’ Regulatory Region Flanking Kinectin 1 Gene in Schizophrenia

1.

Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

2.

Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China

3.

Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China

4.

Department of Psychiatry, Fujian Medical University Affiliated Fuzhou Neuropsychiatric Hospital, Fuzhou, Fujian, China

5.

Department of Neurology, Jiading Branch of Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

6.

Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV, USA

7.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China

8.

Department of Cardiovascular Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China

9.

Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing, China

10.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Alpha Psychiatry 2024; 25: 413-420
DOI: 10.5152/alphapsychiatry.2024.241616
Read: 534 Downloads: 139 Published: 26 July 2024

Objective: Schizophrenia is often associated with volumetric reductions in cortices and expansions in basal ganglia, particularly the putamen. Recent genome-wide association studies have highlighted the significance of variants in the 3’ regulatory region adjacent to the kinectin 1 gene (KTN1) in regulating gray matter volume (GMV) of the putamen. This study aimed to comprehensively investigate the involvement of this region in schizophrenia.

Methods: We analyzed 1136 single-nucleotide polymorphisms (SNPs) covering the entire 3’ regulatory region in 4 independent dbGaP samples (4604 schizophrenia patients vs. 4884 healthy subjects) and 3 independent Psychiatric Genomics Consortium samples (107240 cases vs. 210203 controls) to identify consistent associations. Additionally, we examined the regulatory effects of schizophrenia-associated alleles on KTN1 mRNA expression in 16 brain areas among 348 subjects, as well as GMVs of 7 subcortical nuclei in 38258 subjects, and surface areas (SA) and thickness (TH) of the entire cortex and 34 cortical areas in 36936 subjects.

Results: The major alleles (f > 0.5) of 25 variants increased (β > 0) the risk of schizophrenia across 2 to 5 independent samples (8.4 × 10−4 ≤ P ≤ .049). These schizophrenia-associated alleles significantly elevated (β > 0) GMVs of basal ganglia, including the putamen (6.0 × 10−11 ≤ P ≤ 1.1 × 10−4 ), caudate (8.7 × 10−4 ≤ P ≤ 9.4 × 10−3 ), pallidum (P = 6.0 × 10−4 ), and nucleus accumbens (P=2.7 × 10−5 ). Moreover, they potentially augmented (β > 0) the SA of posterior cingulate and insular cortices, as well as the TH of frontal (pars triangularis and medial orbitofrontal), parietal (superior, precuneus, and inferior), and temporal (transverse) cortices, but potentially reduced (β < 0) the SA of the whole, frontal (medial orbitofrontal), and temporal (pole, superior, middle, and entorhinal) cortices, as well as the TH of rostral middle frontal and superior frontal cortices (8.9 × 10−4 ≤ P ≤ .050).

Conclusion: Our findings identify significant and functionally relevant risk alleles in the 3’ regulatory region adjacent to KTN1, implicating their crucial roles in the development of schizophrenia.

Cite this article as: Guo X, Luo X, Huang X, et al. The role of 3’ regulatory region flanking kinectin 1 in schizophrenia. Alpha Psychiatry. 2024;25(3):413-420.

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