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 on...

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Bibliographic Details
Published in:	Molecular psychiatry Vol. 20; no. 11; pp. 1294 - 1300
Main Authors:	Lalli, M A, Bettcher, B M, Arcila, M L, Garcia, G, Guzman, C, Madrigal, L, Ramirez, L, Acosta-Uribe, J, Baena, A, Wojta, K J, Coppola, G, Fitch, R, de Both, M D, Huentelman, M J, Reiman, E M, Brunkow, M E, Glusman, G, Roach, J C, Kao, A W, Lopera, F, Kosik, K S
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2015 Nature Publishing Group
Subjects:	13/21 45 45/23 45/43 631/208 692/699 Adult Age Age of Onset Aged Alzheimer Disease - blood Alzheimer Disease - complications Alzheimer Disease - genetics Alzheimer's disease Behavioral Sciences Biological Psychology Chemokine CCL11 - blood Chemokine CCL11 - genetics Chemokines Chromosomes, Human, Pair 17 - genetics Cognition Disorders - etiology Cognition Disorders - genetics Cognitive ability Cohort Studies Developmental biology Enzyme-Linked Immunosorbent Assay Female Genes Genetic aspects Genome-Wide Association Study Genomes Genotype Haplotypes Health risk assessment Humans Immediate Communication Male Medicine Medicine & Public Health Middle Aged Mutation Neurosciences Pharmacotherapy Physiological aspects Polymorphism, Single Nucleotide - genetics Psychiatry Research centers Risk factors Single nucleotide polymorphisms United States Los Angeles California Colombia San Francisco California Santa Barbara California California United States > US
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-senior authors.
ISSN:	1359-4184 1476-5578
DOI:	10.1038/mp.2015.131