Article

A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline

Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Human Molecular Genetics (Impact Factor: 6.68). 03/2012; 21(10):2377-88. DOI: 10.1093/hmg/dds054
Source: PubMed

ABSTRACT 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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Available from: Amanda J Myers, Aug 17, 2015
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    • "Two studies integrated multi-modal data including imaging , genetics and/or cognitive data to improve the classification accuracy (Yu et al. 2012), as well as the prediction accuracy, of neuropsychological performance (Wang et al. 2012b). One study identified a significant association of one coding variant in CR1 gene with episodic memory decline (Keenan et al. 2012). SNPs previously associated with AD, white matter hyperintensity (WMH), and MRI-identified infarcts were also investigated (Mukherjee et al. 2012b). "
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    • "This coding variant was associated with AD susceptibility, a composite score of episodic memory decline, and increased neuritic pathology in a study cohort primarily consisting of non-Hispanic Caucasian individuals. Moreover , their results suggested that this rare variant could account for the effect of the index GWA single nucleotide polymorphism (SNP) rs6656401 on episodic memory decline (Keenan et al., 2012). "
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    ABSTRACT: We previously described an intragenic functional copy number variation (CNV) in complement receptor 1 (CR1) that is associated with Alzheimer disease (AD) risk. A recent study, however, reported a rare CR1 coding variant p.Ser1610Thr (rs4844609) associated with AD susceptibility, explaining the effect of genome wide association (GWA) top single nucleotide polymorphism rs6656401. We assessed the role of the Ser1610Thr variant in AD pathogenesis and the effect on AD-related endophenotypes in a Flanders-Belgian cohort. We evaluated whether this rare variant rather than the CR1 CNV could explain the association of CR1 in our population. The Ser1610Thr variant was not associated with AD, memory impairment, total tau, amyloid β1-42 or tau phosphorylated at threonine 181 levels. It did not explain (part of) the association of genome wide association top single-nucleotide polymorphisms rs3818361/rs6656401, nor of the CR1 CNV, with AD in our cohort, whereas the CR1 CNV and rs3818361/rs6656401 represented the same association signal. These findings question a role for the Ser1610Thr variant in AD risk and related endophenotypes, and reaffirm our previous observation that the CR1 CNV could be the true functional risk factor explaining the association between CR1 and AD.
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