Identification of Novel Genes Associated with Cortical Thickness in Alzheimer’s Disease: Systems Biology Approach to Neuroimaging Endophenotype

Article type: Research Article

Authors: Kim, Bo-Hyun^a | Choi, Yong-Ho^a | Yang, Jin-Ju^a | Kim, SangYun^b | Nho, Kwangsik^{c; *} | Lee, Jong-Min^{a; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Biomedical Engineering, Hanyang University, Seoul, Korea | [b] Department of Neurology, Seoul National University College of Medicine and Clinical Neuroscience Center of Seoul National University Bundang Hospital, Seongnam, Korea | [c] Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: [*] Correspondence to: Jong-Min Lee, PhD, Department of Biomedical Engineering, Hanyang University, Sanhakgisulkwan #319, Wangsimni-ro Seongdong-gu, Seoul, 04763, Korea. Tel.: +82 2 2220 0685; E-mail: ljm@hanyang.ac.kr. and Kwangsik Nho, PhD, Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel.: +1 317 963 7503; E-mail: knho@iupui.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by a heterogeneous distribution of pathological changes in the brain. Cortical thickness is one of the most sensitive imaging biomarkers for AD representing structural atrophy. The purpose of this study is to identify novel genes associated with cortical thickness. We measured the whole-brain mean cortical thickness from magnetic resonance imaging (MRI) scans in 919 subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort, including 163 AD patients, 488 mild cognitive impairment patients, and 268 cognitively normal participants. Based on the single-nucleotide polymorphism (SNP)-based genome-wide association study, we performed gene-based association analysis for mean cortical thickness. Furthermore, we performed expression quantitative trait loci, protein-protein interaction network, and pathway analysis to identify biologically functional information. We identified four genes (B4GALNT1, RAB44, LOC101927583, and SLC26A10), two pathways (cyclin-dependent protein kinase holoenzyme complex and nuclear cyclin-dependent protein kinase holoenzyme complex), and one protein-protein interaction (B4GALNT1 and GALNT8 pair). These genes are involved in protein degradation, GTPase activity, neuronal loss, and apoptosis. The identified pathways are involved in the cellular processes and neuronal differentiation, which contribute to neuronal loss that is responsible for AD. Furthermore, the most significant SNP (rs12320537) in B4GALNT1 is associated with expression levels of B4GALNT1 in several brain regions. Thus, the identified genes and pathways provide deeper mechanistic insight into the molecular basis of brain atrophy in AD.

Keywords: Alzheimer’s disease, brain, cortical thickness, gene-based association analysis, genome-wide association study, imaging genetics

DOI: 10.3233/JAD-191175

Journal: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 531-545, 2020