Kara L. Hamilton-Nelson, United States of America
University of Miami John P. Hussman Institute for Human GenomicsAuthor Of 2 Presentations
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.
WHOLE GENOME SEQUENCING IN PUERTO RICAN FAMILIES IDENTIFIES RARE VARIANTS FOR ALZHEIMER DISEASE
Abstract
Aims
The ancestral genetic heterogeneity of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease(AD). In this study, we performed whole-genome sequencing(WGS) in PR multiplex families and analyzed existing WGS in an independent PR case-control dataset(PR10/66), to identify rare causal variants influencing AD through linkage and segregation-based approaches.
Methods
WGS was performed in 100 individuals(61 affected) from 23 multiplex PR families. Parametric linkage analysis was performed and known AD genes were screened. To identify novel loci within the linkage region, we filtered variants using minor allele frequency(MAF), function potential CADD score, and segregation with AD within the families. Findings from the PR families were further evaluated using the PR10/66 dataset.
Results
A genome-wide significant linkage peak was found on 9p21 with HLOD score of 5.1, supported by 9 families with the strongest signal in Fam#87663(HLOD=1.8). 9p21 overlaps with the region previously reported in two linkage studies. The region harbors C9orf72 gene, but no expanded repeats in C9orf72 gene were observed in the PRADI families. We prioritized 7 variants that were observed in Fam#87663, were rare(MAF<0.01), have high functional potential(CADD>10) and showed evidence for association(P<0.05). Remarkably, a missense variant (rs35199210;CADD=20.3) in gene UNC13B segregated in two families, and another rare missense variant (rs41276043;CADD=25.0) in UNC13B gene segregated in a third family.
Conclusions
WGS in PR multiplex families suggested several novel candidates for AD, demonstrating the importance of family-based studies in discovering rare variants. Analysis is underway to assess the functional relevance of these candidates in AD.