Sparse reduced-rank regression detects genetic associations with voxel-wise longitudinal phenotypes in Alzheimer's disease

Abstract

Scanning the entire genome in search of variants related to imaging phenotypes holds great promise in elucidating the genetic etiology of neurodegenerative disorders. Here we discuss the application of a penalized multivariate model, sparse reduced-rank regression (sRRR), for the genome-wide detection of markers associated with voxel-wise longitudinal changes in the brain caused by Alzheimer’s disease (AD). Using a sample from the Alzheimer’s Disease Neuroimaging Initiative database, we performed three separate studies that each compared two groups of individuals to identify genes associated with disease development and progression. For each comparison we took a two-step approach: initially, using penalized linear discriminant analysis, we identified voxels that provide an imaging signature of the disease with high classification accuracy; then we used this multivariate biomarker as a phenotype in a genome-wide association study, carried out using sRRR. The genetic markers were ranked in order of importance of association to the phenotypes using a data re-sampling approach. Our findings confirmed the key role of the APOE and TOMM40 genes but also highlighted some novel potential associations with AD.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in AD [31][32][33][34][35][36][37][38][39][40][41][42][43][44], and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms [32][33][34][35][36][37]45], although the latter assumption needs replication due to contradictory results [36,[46][47][48][49]. A fixed-effect meta-analysis approach showed that rs4420638 at the TOMM40/APOE/APOC1 gene locus is associated with longevity [50,51].…”

Brain Image Classification Based on Automated Morphometry and Penalised Linear Discriminant Analysis with Resampling

“…To our knowledge, this is for the first time when pLDA is used for selecting highly discriminative brain imaging features in schizophrenia. In our previous study, pLDA was successfully applied for selecting image phenotypes that were used in searching for genotypes most associated with Alzheimer's disease [20]. Here, pLDA is used in combination with DBM in the pipeline for the classification of MRI data of patients with first episode schizophrenia (FES) and healthy controls.…”

“…The pLDA has been successfully employed in our previous imaging-genetics study [20] in which image phenotypes, using pre-selected pLDA, were used for searching the genotypes most associated with Alzheimer's disease. To our knowledge, this is the first study that uses pLDA for selecting brain imaging features for the purposes of distinguishing diseased individuals from healthy controls in schizophrenia research.…”

The Pathogenic Component of the APOE-TOMM40 Region in Alzheimer’s disease: Its Implications in Metabolomics and Pharmacogenomics

“…A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in AD [20][21][22][23][24][25][26][27][28][29][30][31][32][33], and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms [21][22][23][24][25][26]34]. A fixed-effect meta-analysis approach showed that rs4420638 at the TOMM40/APOE/APOC1 gene locus is associated with longevity [35,36].…”