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. 2014 Oct;10(5 Suppl):S277-S283.e10.
doi: 10.1016/j.jalz.2013.09.005. Epub 2013 Nov 13.

Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease

Matthew A Lalli  1 , Hannah C Cox  2 , Mary L Arcila  1 , Liliana Cadavid  3 , Sonia Moreno  3 , Gloria Garcia  3 , Lucia Madrigal  3 , Eric M Reiman  4 , Mauricio Arcos-Burgos  5 , Gabriel Bedoya  6 , Mary E Brunkow  2 , Gustavo Glusman  2 , Jared C Roach  2 , Leroy Hood  2 , Kenneth S Kosik  7 , Francisco Lopera  3
Affiliations

Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease

Matthew A Lalli et al. Alzheimers Dement. 2014 Oct.

Abstract

Background: A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics.

Methods: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation.

Results: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2-12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11-25) generations ago. We infer a western European geographic origin of the shared haplotype.

Conclusions: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.

Keywords: Alzheimer’s disease; PSEN1; population genetics; whole-genome sequencing.

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Conflict of interest statement

Potential conflicts of interest

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Geographical map of E280A carriers and a pedigree reconstructed from historical and genealogical accounts
A) Twenty-four families affected with EOFAD caused by E280A are highlighted on the map of the Department of Antioquia, Colombia. B) For 13 of the recruited families with E280A, genealogical records demonstrate a common pair of founders in 1745. The living members of this family are distributed throughout most of the regions indicated in panel A, consistent with the hypothesis that all affected individuals in Antioquia share an even more distant common founder with a similar dispersal pattern of descendants. EOFAD, early-onset familial Alzheimer’s disease.
Figure 2
Figure 2. Minimal haplotype containing E280A
All carriers of E280A share a minimal common haplotype spanning 1.8 Mb surrounding PSEN1 E280A from rs2158987-rs10135303 (chr14:72696625-74484310). Positions are given in GRCh37 coordinates. For a complete list of the SNPs on this haplotype, please refer to Supp. Table E1.
Figure 3
Figure 3. Estimation of mutation age by DMLE
After 100,000 burn-in runs, the age of the mutation was simulated 100,000 times by DMLE. Mutation age is estimated in generation time, g. A 95% credible interval (CI) is shaded between 11–24 generations. A red line indicates the maximum likelihood estimated age of the mutation at 15.3 generations.
Figure 4
Figure 4. Geographic origin of the haplotype spanning E280A
Using the ancestry reference panel comprising the populations depicted in (A), LAMP-LD and MULTIMIX unanimously estimate a European ancestry of E280A in (B) for the haplotypes containing E280A (E280+). Continental ancestry estimation is also shown for haplotypes spanning the region that do not contain the mutation (E280A−). Similarly, using the reference ancestry panels depicted (C), both algorithms strongly support a Western European origin for haplotypes bearing E280A (D). Abbreviations: CEU, Utah Residents (CEPH) with Northern and Western European ancestry. FIN, Finnish in Finland. GBR, British in England and Scotland. HGDP, Human Genome Diversity Project. IBS, Iberian population in Spain. TSI, Toscani in Italia. YRI, Yoruba in Ibadan, Nigeria.
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