Voxelwise genome-wide association study (vGWAS).
The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age+/-s.d.: 75.52+/-6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.
Stein
Jason L
JL
Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles School of Medicine, Neuroscience Research Building 225E, 635 Charles Young Drive, Los Angeles, CA 90095-1769, USA.
Hua
Xue
X
Lee
Suh
S
Ho
April J
AJ
Leow
Alex D
AD
Toga
Arthur W
AW
Saykin
Andrew J
AJ
Shen
Li
L
Foroud
Tatiana
T
Pankratz
Nathan
N
Huentelman
Matthew J
MJ
Craig
David W
DW
Gerber
Jill D
JD
Allen
April N
AN
Corneveaux
Jason J
JJ
Dechairo
Bryan M
BM
Potkin
Steven G
SG
Weiner
Michael W
MW
Thompson
Paul
P
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D001921:Brain; D003072:Cognition Disorders / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable