| A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline. | |
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MedLine Citation:
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PMID: 22343410 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D' = 1, r(2)= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q. |
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Authors:
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Brendan T Keenan; Joshua M Shulman; Lori B Chibnik; Towfique Raj; Dong Tran; Mert R Sabuncu; ; April N Allen; Jason J Corneveaux; John A Hardy; Matthew J Huentelman; Cynthia A Lemere; Amanda J Myers; Anne Nicholson-Weller; Eric M Reiman; Denis A Evans; David A Bennett; Philip L De Jager |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2012-02-17 |
Journal Detail:
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Title: Human molecular genetics Volume: 21 ISSN: 1460-2083 ISO Abbreviation: Hum. Mol. Genet. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-04-25 Completed Date: 2012-09-13 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: England |
Other Details:
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Languages: eng Pagination: 2377-88 Citation Subset: IM |
Affiliation:
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Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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genetics,
metabolism,
pathology Apolipoprotein E4 / genetics, metabolism* Cognition Disorders / genetics*, metabolism Female Gene Frequency Genome-Wide Association Study Genotype Haplotypes Humans Memory, Episodic Middle Aged Odds Ratio Phenotype Plaque, Amyloid / metabolism Polymorphism, Single Nucleotide Receptors, Complement / genetics*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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K01 AG030514/AG/NIA NIH HHS; K01AG024079/AG/NIA NIH HHS; K08 AG034290/AG/NIA NIH HHS; K08 AG034290/AG/NIA NIH HHS; K25 EB013649/EB/NIBIB NIH HHS; P30 AG010129/AG/NIA NIH HHS; P30 AG10161/AG/NIA NIH HHS; P30 AG19610/AG/NIA NIH HHS; P50 AG16573/AG/NIA NIH HHS; P50 AG16574/AG/NIA NIH HHS; R01 AG015819/AG/NIA NIH HHS; R01 AG017917/AG/NIA NIH HHS; R01 AG023193/AG/NIA NIH HHS; R01 AG034504/AG/NIA NIH HHS; R01 AG11101/AG/NIA NIH HHS; R01 AG15819/AG/NIA NIH HHS; R01 AG179917/AG/NIA NIH HHS; R01 AG30146/AG/NIA NIH HHS; R01NS059873/NS/NINDS NIH HHS; U01 AG016976/AG/NIA NIH HHS; U01 AG016976/AG/NIA NIH HHS; U01 AG024904/AG/NIA NIH HHS; U24NS051872/NS/NINDS NIH HHS; UO1HL084744/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apolipoprotein E4; 0/Receptors, Complement |
| Investigator | |
Investigator/Affiliation:
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Alessandro Biffi / ; Christopher Anderson / ; Jonathan Rosand / |
| Comments/Corrections | |
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