Larry D. Adams, United States of America
University of Miami John P. Hussman Institute for Human GenomicsAuthor Of 1 Presentation
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.