title: A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline.
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.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Mert R
authors.initials: MR
authors.lastname: Sabuncu
authors.forename: April N
authors.initials: AN
authors.lastname: Allen
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: Anne
authors.initials: A
authors.lastname: Nicholson-Weller
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D061212:Memory, Episodic; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011951:Receptors, Complement / Q000235:genetics* / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; D011951:Receptors, Complement