Amyloid Precursor Protein A713T Mutation in Calabrian Patients with Alzheimer's Disease: A Population Genomics Approach to Estimate Inheritance from a Common Ancestor

Abstract

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.

Keywords: A713T; APP; Alzheimer’s disease; amyloid; common ancestor; genetics; neurodegeneration; population genomics.

Figure 1

Genetic structure based on genome-wide haplotype-sharing pattern. (A) Schematic representation of fineSTRUCTURE hierarchical clustering showing the relationships among analyzed patients and the Italian healthy controls. Population clusters were defined by considering a posterior probability threshold higher than 90%. The full fineSTRUCTURE tree is shown in Supplementary Figure S3. (B) Principal component analysis based on chunkcount coancestry matrix, obtained from CHROMOPAINTER profiles; the top two components have been plotted in a scatterplot.

Figure 2

Sharing of extended genomic regions and tMRCA estimation. (A) Observed genomic regions tagging the APPA713T mutation shared among pairs of patients. The blue vertical bars highlight the genomic region of 300 SNPs and 1.7 Mbp shared among five of the seven patients. (B) Estimated tMRCA based on the highlighted genomic region.