Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort

Abstract

A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10−7 and p<10−6). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.

Massively expedited genome-wide heritability analysis (MEGHA)

“…More than 3,500 native Englishspeaking adults with normal or corrected-to-normal vision were recruited from Harvard University, MGH, and the surrounding Boston communities. To avoid spurious effects resulting from population stratification, we restricted our analyses to 1,320 young adults (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) Imaging Data Processing. We used FreeSurfer (freesurfer.net) (49), version 4.5.0, a freely available, widely used, and extensively validated brain MRI analysis software package, to process the structural brain MRI scans and compute global and regional morphological measurements.…”

“…Brain imaging data are a prototype case where a vast array of potentially relevant phenotypes are routinely collected and phenotypic complexity has grown exponentially as new tools to analyze highresolution structure and point-to-point connectivity have emerged. A wide range of volume-, surface-, and connection-based measures are of potential interest in analyzing the relationship between genetic and brain data in the context of clinical conditions (17)(18)(19)(20)(21). Although, in principle, any measure computable from different brain imaging modalities can be used as phenotypes in genetic studies, ideal candidate imaging traits should be heritable intermediate (or endo-) phenotypes (22)(23)(24), to uncover the genetic underpinnings of various neuropsychiatric disorders or biological processes of interest (25).…”

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].…”

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].…”