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. 2015 Nov;20(11):1294-300.
doi: 10.1038/mp.2015.131. Epub 2015 Sep 1.

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

M A Lalli  1 , B M Bettcher  2 , M L Arcila  1 , G Garcia  3 , C Guzman  3 , L Madrigal  3 , L Ramirez  3 , J Acosta-Uribe  3 , A Baena  3 , K J Wojta  4 , G Coppola  4 , R Fitch  2 , M D de Both  5 , M J Huentelman  5 , E M Reiman  5   6 , M E Brunkow  7 , G Glusman  7 , J C Roach  7 , A W Kao  2 , F Lopera  3 , K S Kosik  1
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Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

M A Lalli et al. Mol Psychiatry. 2015 Nov.

Abstract

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.

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Figures

Figure 1
Figure 1
Manhattan plot of genome-wide association results for age of mild-cognitive impairment in our cohort. Red line indicates genome-wide significance (P<5E−08) and blue line indicates nominally associated loci (P<5E−06).
Figure 2
Figure 2
Carriers of rs9909184, the top associated single-nucleotide polymorphism (SNP) in this study and marker of the protective haplotype, show a ~10-year delay in age at onset for mild-cognitive impairment (MCI).
Figure 3
Figure 3
Regional association plot on chromosome 17 at the top associated single-nucleotide polymorphism (SNP) for age at onset of mild-cognitive impairment reveals the associated locus is a haplotype spanning a chemokine gene cluster. This haplotype includes a missense polymorphism (A23T) in the coding region of CCL11 (red arrow).
Figure 4
Figure 4
The associated haplotype decouples plasma eotaxin-1 levels from age in haplotype carriers. Shaded regions show 95% confidence limits for the mean.
See this image and copyright information in PMC

References

    1. 1Lo AW, Ho C, Cummings J, Kosik KS. Parallel discovery of Alzheimer's therapeutics. Sci Transl Med 2014; 6: 3008228. - PubMed
    1. 2Acosta-Baena N, Sepulveda-Falla D, Lopera-Gomez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol 2011; 10: 213–220. - PubMed
    1. 3Li YJ, Scott WK, Hedges DJ, Zhang FY, Gaskell PC, Nance MA et al. Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 2002; 70: 985–993. - PMC - PubMed
    1. 4Pedersen NL, Posner SF, Gatz M. Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins. Am J Med Genet 2001; 105: 724–728. - PubMed
    1. 5Marchani EE, Bird TD, Steinbart EJ, Rosenthal E, Yu CE, Schellenberg GD et al. Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families. Am J Med Genet B 2010; 153B: 1031–1041. - PMC - PubMed

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