Affiliations: [a] Center for Human Genetics and Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA | [b] Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA | [c] Olin Neuropsychiatry Research Center, Harford Hospital, Hartford, CT, USA
Correspondence:
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Correspondence to: Tricia A. Thornton-Wells, Center for Human Genetics and Research, 519 Light Hall, Nashville, TN 37232, USA. Tel.: +1 615 343 0396; Fax: +1 615 343 8619; E-mail: t.thornton-wells@vanderbilt.edu.
Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.ucla.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
Abstract: The genetic etiology of late-onset Alzheimer's disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B, and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p = 9.13 × 10−12; LILV: p = 8.17 × 10−13). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles.
