Haimeng Bai, United States of America
Case Western Reserve University Cleveland Institute for Computational BiologyAuthor Of 1 Presentation
ANALYSES OF PROTEIN VARIATION ILLUSTRATES THE SPECTRUM BETWEEN MENDELIAN AND COMPLEX DEMENTIA DISORDERS
Abstract
Aims
Unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene-based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impact on protein function before computing gene-based statistical associations is critical.
Methods
We used semantic similarity to identify candidate genes associated with Mendelian disorders that share phenotypic features with AD. Spatial algorithms were used to identify Alzheimer’s Disease Sequencing Project (ADSP) variants significantly clustered within 3D protein structures with known ClinVar pathogenic variants, relative to benign variants from ExAC. We completed gene-based testing using only identified variants and compared these results to published gene-based results. Finally, we assessed differences in case percentage and age-of-onset between carriers of identified variants and non-carriers.
Results
A total of 230 of 1,365 ADSP missense variants in 26 genes were proximal to known pathogenic variants. Four genes associated with AD status using gene-based testing (EPM2A, SERPINI1, PSEN1 and TREM2), either with improved p-values or nominally the same but with attenuated sample sizes. In total, 79.6% of variant carriers were cases, compared to 55.4% of non-carriers. Carriers of identified variants in SERPINI1, PSEN1 and TREM2 were, on average, younger at age-of-onset than non-carriers.
Conclusions
We have identified subsets of missense variants likely to impact the function of proteins associated with neurodegenerative diseases in the ADSP. We demonstrated that carriers of these variants are more likely to be cases and have an earlier age-of-onset than non-carriers.