Ventricular enlargement occurs in several neurodegenerative and psychiatric diseases. A large genome-wide association study (GWAS) has identified seven loci associated with ventricular volume. The rate of ventricular enlargement increased in the progression of disease from normal cognition to dementia. Here, we aimed to use the rate of ventricular enlargement as an endophenotype for the development and progression of neurodegenerative diseases to discover more common genetic variants. We performed a GWAS of the rate of ventricular enlargement using 507 nondemented non-Hispanic white participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Linear regression model was used to identify the association of the rate of ventricular enlargement with single nucleotide polymorphisms (SNPs) in PLINK software. The associations of genome-wide significant SNPs with other four phenotypes were further discussed. Two SNPs (rs11620312, P = 4.04×10−8; rs79174114, P = 4.28×10−8) within SIAH3 gene in linkage disequilibrium (LD) reached genome-wide significance for association with increased rate of ventricular enlargement. Some intergenic SNPs and SNPs within NKAIN2, TBC1D2, GALNT18, ABCC1 and SRCIN1 genes were identified as potential candidates. SIAH3 rs11620312-C carriers were associated with poor cognition and brain hypometabolism longitudinally. Our findings indicated that SIAH3 gene may have potential influence on the pathogenesis of neurodegenerative diseases.