Genetic variation and neuroimaging measures in Alzheimer disease.
OBJECTIVE
To investigate whether genome-wide association study (GWAS)-validated and GWAS-promising candidate loci influence magnetic resonance imaging measures and clinical Alzheimer's disease (AD) status.


METHODS
Multicenter case-control study of genetic and neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative.


METHODS
Multicenter GWAS. Patients A total of 168 individuals with probable AD, 357 with mild cognitive impairment, and 215 cognitively normal control individuals recruited from more than 50 Alzheimer's Disease Neuroimaging Initiative centers in the United States and Canada. All study participants had APOE and genome-wide genetic data available.


METHODS
We investigated the influence of GWAS-validated and GWAS-promising novel AD loci on hippocampal volume, amygdala volume, white matter lesion volume, entorhinal cortex thickness, parahippocampal gyrus thickness, and temporal pole cortex thickness.


RESULTS
Markers at the APOE locus were associated with all phenotypes except white matter lesion volume (all false discovery rate-corrected P values < .001). Novel and established AD loci identified by prior GWASs showed a significant cumulative score-based effect (false discovery rate P = .04) on all analyzed neuroimaging measures. The GWAS-validated variants at the CR1 and PICALM loci and markers at 2 novel loci (BIN1 and CNTN5) showed association with multiple magnetic resonance imaging characteristics (false discovery rate P < .05).


CONCLUSIONS
Loci associated with AD also influence neuroimaging correlates of this disease. Furthermore, neuroimaging analysis identified 2 additional loci of high interest for further study.
Biffi
Alessandro
A
Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Anderson
Christopher D
CD
Desikan
Rahul S
RS
Sabuncu
Mert
M
Cortellini
Lynelle
L
Schmansky
Nick
N
Salat
David
D
Rosand
Jonathan
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D002170:Canada; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D016015:Logistic Models; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States
D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; C101410:BIN1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins