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

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 genomewide 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 cyclindependent 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 4 identified genes and pathways provide deeper mechanistic insight into the molecular basis of brain atrophy in AD.

1-L Transcription in Alzheimer’s Disease

“…Olfactory dysfunction is known in AD [ 53 ]. One study identified OR7A10 among genes associated with cortical thickness in AD [ 54 ].…”

Cardiac copper content and its relationship with heart physiology: Insights based on quantitative genetic and functional analyses using BXD family mice

“…SLC35A1 protein transports activated sugars into the endoplasmic reticulum (ER) and/or Golgi apparatus and SLC35A1 mutations have been associated with congenital disorder of glycosylation II and platelet life span ( 47 , 48 ). SLC26A10 is an anion transporter and has been found to be related to cortical thickness in Alzheimer’s disease ( 49 ). Two genes, Usb1 and Lrig3 , have recently been studied as therapeutic targets in poikiloderma with neutropenia and prostate cancer, respectively ( 50 , 51 ), while Ica1 encodes an autoantigen involved in autoimmune insulin-dependent diabetes mellitus and primary Sjogren’s syndrome ( 52 ).…”

Development of quantitative and continuous measure for severity degree of Alzheimer’s disease evaluated from MRI images of 761 human brains

“…The diagnosis of AD requires not only the identification of cohort that classify different tripartite stages of AD but also the estimation of the severity degree of AD for a given individual [1][2][3][4][5]. The symptoms of AD appear in various forms in the human body, behavior, and cognition, yet the direct anatomical evidences appear in the structural change within the brain [6][7][8][9][10][11]. Among these evidences is the degradation of the cortical thickness of human brain, which is one of the imprints of AD.…”