Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.
We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.
Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, CA, USA.
M A
MA
Lalli
Memory and Aging Center, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
B M
BM
Bettcher
Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, CA, USA.
M L
ML
Arcila
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
G
G
Garcia
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
C
C
Guzman
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
L
L
Madrigal
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
L
L
Ramirez
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
J
J
Acosta-Uribe
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
A
A
Baena
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA.
K J
KJ
Wojta
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA.
G
G
Coppola
Memory and Aging Center, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
R
R
Fitch
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
M D
MD
de Both
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
M J
MJ
Huentelman
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.|Banner Alzheimer's Institute, Department of Psychiatry, University of Arizona, Tucson, AZ, USA.
E M
EM
Reiman
Institute for Systems Biology, Seattle, WA, USA.
M E
ME
Brunkow
Institute for Systems Biology, Seattle, WA, USA.
G
G
Glusman
Institute for Systems Biology, Seattle, WA, USA.
J C
JC
Roach
Memory and Aging Center, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
A W
AW
Kao
Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
F
F
Lopera
Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, CA, USA.
K S
KS
Kosik
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000150:complications / Q000235:genetics*; D054413:Chemokine CCL11 / Q000097:blood / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D054413:Chemokine CCL11