A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline
Brendan T Keenan1, Joshua M Shulman, Lori B Chibnik
1Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Human Molecular Genetics
|February 21, 2012
Summary
A specific variant in the Complement receptor 1 (CR1) gene significantly impacts episodic memory decline and Alzheimer's disease (AD) risk. This CR1 variant affects protein structure, influencing AD pathology and memory loss, particularly with APOE-ε4 interaction.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Complement receptor 1 (CR1) is a known genetic locus associated with Alzheimer's disease (AD) and related cognitive traits.
- CR1 influences episodic memory decline and the deposition of amyloid plaques in the brain.
Purpose of the Study:
- To identify functional variants within the CR1 gene associated with episodic memory decline.
- To elucidate the functional consequences and mechanisms underlying the association between CR1 variants and AD-related traits.
Main Methods:
- A functional fine-mapping approach was used in 1709 subjects from the Religious Orders Study and Rush Memory and Aging Project.
- 41 single-nucleotide polymorphisms (SNPs) within the CR1 linkage disequilibrium block were tested for association with episodic memory decline.
- Functional consequences of the top associated variant were examined, including interactions with APOE-ε4 and neuropathology.
Main Results:
- A coding variant, rs4844609 (Ser1610Thr), in the LHR-D region of CR1 was significantly associated with episodic memory decline.
- This variant explained the effect of the previously identified AD SNP rs6656401 on memory decline.
- The variant's effect was dependent on APOE-ε4 interaction and mediated by increased AD neuropathology; it was also associated with AD susceptibility.
Conclusions:
- A functional CR1 coding variant in the LHR-D domain influences episodic memory decline and AD susceptibility.
- This variant alters CR1 conformation, implicating C1q and MBL binding as potential mechanisms.
- CR1 may play a crucial role in the clearance of amyloid-beta (Aβ42) particles via C1q.
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