title: 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.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 950 West Walnut Street R2 E124, Indianapolis, IN 46202, USA. shenli@iupui.edu
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.forename: John D
authors.initials: JD
authors.lastname: West
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Chantel D
authors.initials: CD
authors.lastname: Sloan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Dechairo
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D016000:Cluster Analysis; D003072:Cognition Disorders / Q000235:genetics*; D016208:Databases, Factual; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D001057:Apolipoproteins E