Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease.
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.
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, USA.
Matthew A
MA
Lalli
Institute for Systems Biology, Seattle, WA, USA.
Hannah C
HC
Cox
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, USA.
Mary L
ML
Arcila
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Liliana
L
Cadavid
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Sonia
S
Moreno
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Gloria
G
Garcia
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Lucia
L
Madrigal
Banner Alzheimer's Institute, Phoenix, AZ, USA.
Eric M
EM
Reiman
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia; Translational Genomics Group, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia.
Mauricio
M
Arcos-Burgos
Grupo de Genetica Molecular (GENMOL), Universidad de Antioquia, Medellín, Colombia.
Gabriel
G
Bedoya
Institute for Systems Biology, Seattle, WA, USA.
Mary E
ME
Brunkow
Institute for Systems Biology, Seattle, WA, USA.
Gustavo
G
Glusman
Institute for Systems Biology, Seattle, WA, USA.
Jared C
JC
Roach
Institute for Systems Biology, Seattle, WA, USA.
Leroy
L
Hood
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, USA. Electronic address: kosik@lifesci.ucsb.edu.
Kenneth S
KS
Kosik
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Francisco
F
Lopera
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D003105:Colombia; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D044465:White People / Q000235:genetics
C508853:PSEN1 protein, human; D053764:Presenilin-1
Alzheimer’s disease; PSEN1; population genetics; whole-genome sequencing