Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

TitleWhole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsLalli MA, Bettcher BM, Arcila ML, Garcia G, Guzman C, Madrigal L, Ramirez L, Acosta-Uribe J, Baena A, Wojta KJ, Coppola G, Fitch R, de Both MD, Huentelman MJ, Reiman EM, Brunkow ME, Glusman G, Roach JC, Kao AW, Lopera F, Kosik KS
JournalMol Psychiatry
Date Published2015 Nov
KeywordsAdult, Age of Onset, Aged, Alzheimer Disease, Chemokine CCL11, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, Enzyme-Linked Immunosorbent Assay, Female, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide
Abstract<p>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.</p>
Alternate JournalMol. Psychiatry
PubMed ID26324103
PubMed Central IDPMC4759097
Grant ListK23 AG042492 / AG / NIA NIH HHS / United States
K23 AG042492-01 / AG / NIA NIH HHS / United States