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

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Title: Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.
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
Source: Molecular Psychiatry. Nov2015, Vol. 20 Issue 11, p1294-1300. 7p.
Subjects: Genomes, Alzheimer's disease, Autosomal recessive polycystic kidney, Single nucleotide polymorphisms, Chemokines, Genetic polymorphisms
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. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.
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  Data: <searchLink fieldCode="AR" term="%22Lalli%2C+M+A%22">Lalli, M A</searchLink><br /><searchLink fieldCode="AR" term="%22Bettcher%2C+B+M%22">Bettcher, B M</searchLink><br /><searchLink fieldCode="AR" term="%22Arcila%2C+M+L%22">Arcila, M L</searchLink><br /><searchLink fieldCode="AR" term="%22Garcia%2C+G%22">Garcia, G</searchLink><br /><searchLink fieldCode="AR" term="%22Guzman%2C+C%22">Guzman, C</searchLink><br /><searchLink fieldCode="AR" term="%22Madrigal%2C+L%22">Madrigal, L</searchLink><br /><searchLink fieldCode="AR" term="%22Ramirez%2C+L%22">Ramirez, L</searchLink><br /><searchLink fieldCode="AR" term="%22Acosta-Uribe%2C+J%22">Acosta-Uribe, J</searchLink><br /><searchLink fieldCode="AR" term="%22Baena%2C+A%22">Baena, A</searchLink><br /><searchLink fieldCode="AR" term="%22Wojta%2C+K+J%22">Wojta, K J</searchLink><br /><searchLink fieldCode="AR" term="%22Coppola%2C+G%22">Coppola, G</searchLink><br /><searchLink fieldCode="AR" term="%22Fitch%2C+R%22">Fitch, R</searchLink><br /><searchLink fieldCode="AR" term="%22de+Both%2C+M+D%22">de Both, M D</searchLink><br /><searchLink fieldCode="AR" term="%22Huentelman%2C+M+J%22">Huentelman, M J</searchLink><br /><searchLink fieldCode="AR" term="%22Reiman%2C+E+M%22">Reiman, E M</searchLink><br /><searchLink fieldCode="AR" term="%22Brunkow%2C+M+E%22">Brunkow, M E</searchLink><br /><searchLink fieldCode="AR" term="%22Glusman%2C+G%22">Glusman, G</searchLink><br /><searchLink fieldCode="AR" term="%22Roach%2C+J+C%22">Roach, J C</searchLink><br /><searchLink fieldCode="AR" term="%22Kao%2C+A+W%22">Kao, A W</searchLink><br /><searchLink fieldCode="AR" term="%22Lopera%2C+F%22">Lopera, F</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Molecular+Psychiatry%22">Molecular Psychiatry</searchLink>. Nov2015, Vol. 20 Issue 11, p1294-1300. 7p.
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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