Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers

Abstract

Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease.

Figure 1

Identity By Descent (IBD) Mapping. IBD segments were determined for each pair of genomes in our study and plotted as tracks within the center of the circle. Labels indicate which two genomes are being compared in each track. The six individuals in the study are labeled Early (E) 1 and 2, Mean (M) 1 and 2, and Late (L) 1 and 2, depending on the age at onset. IBD segments between the two early outliers (Early 1 and Early 2) are shown red. IBD segments between the two late outliers (Late 1 and Late 2) are shown in green. Numbered chromosomes are shown in the outermost track, with centromeres drawn in black. Within the chromosomes, nonsynonymous variants (NSVs) tracking with AAO are plotted as colored circles. A: The only region of IBD shared across all six genomes contains the causal PSEN1 p.Glu280Ala mutation. B: A stretch of IBD unique to the late-onset pair contains 3 rare variants. C: A stretch of IBD unique to the early-onset pair contains 6 nonsynonymous variants in 5 genes.