Genome-Wide Association Study of Brain Connectivity Changes for Alzheimer\u2019s Disease

Samar S M Elsheikh,Alessandro Crimi,Nicola J Mulder,Emile R Chimusa

doi:10.1038/s41598-020-58291-1

Abstract

Variations in the human genome have been found to be an essential factor that affects susceptibility to Alzheimer’s disease. Genome-wide association studies (GWAS) have identified genetic loci that significantly contribute to the risk of Alzheimers. The availability of genetic data, coupled with brain imaging technologies have opened the door for further discoveries, by using data integration methodologies and new study designs. Although methods have been proposed for integrating image characteristics and genetic information for studying Alzheimers, the measurement of disease is often taken at a single time point, therefore, not allowing the disease progression to be taken into consideration. In longitudinal settings, we analyzed neuroimaging and single nucleotide polymorphism datasets obtained from the Alzheimer’s Disease Neuroimaging Initiative for three clinical stages of the disease, including healthy control, early mild cognitive impairment and Alzheimer’s disease subjects. We conducted a GWAS regressing the absolute change of global connectivity metrics on the genetic variants, and used the GWAS summary statistics to compute the gene and pathway scores. We observed significant associations between the change in structural brain connectivity defined by tractography and genes, which have previously been reported to biologically manipulate the risk and progression of certain neurodegenerative disorders, including Alzheimer’s disease.

Highlights

Variations in the human genome have been found to be an essential factor that affects susceptibility to Alzheimer’s disease
In another study Jahanshad et al.[22] conducted a Genome-wide association studies (GWAS) on dementia subjects using connectivity patterns as a phenotype, and identified the genetic variant rs2618516 located in the SPON1 gene; this study considered cross sectional phenotype, collected at one specific time point
Association studies of human genome variation and imaging features of the brain have led to new discoveries in Alzheimer’s disease (AD) disease susceptibility

Summary

Introduction

Variations in the human genome have been found to be an essential factor that affects susceptibility to Alzheimer’s disease. By merging brain imaging with genetics, previous studies proposed different ways of analyzing the data, to discover genetic factors that affect the structure and function of the human brain. Significant efforts in this area have been made by the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA)[10] project. Additional efforts in the literature include the development of multivariate methods that aim at identifying the imaging-genetics associations through applying sparse canonical correlations, to adjust for similarity patterns between and within different clinical stages of the disease - an assumption which is hardly met[15]

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