Genetic variation at CR1 increases risk of cerebral amyloid angiopathy

Abstract

Objective: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences ␤-amyloid (A␤) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular A␤ deposition. Methods:We performed a case-control genetic association study of 89 individuals with CAArelated ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICHfree control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. Results GLOSSARYA␤ ϭ ␤-amyloid; AD ϭ Alzheimer disease; BA ϭ Brodmann area; CAA ϭ cerebral amyloid angiopathy; CAA-ICH ϭ cerebral amyloid angiopathy-related intracerebral hemorrhage; CI ϭ confidence interval; GOCHA ϭ Genetics Of Cerebral Hemorrhage on Anticoagulation; GWAS ϭ genome-wide association studies; HR ϭ hazard ratio; HTN-ICH ϭ hypertension-related intracerebral hemorrhage; ICH ϭ intracerebral hemorrhage; MAF ϭ minor allele frequency; MAP ϭ Rush Memory and Aging Project; OR ϭ odds ratio; PCA ϭ principal component analysis; ROS ϭ Religious Order Study; SNP ϭ single nucleotide polymorphism.Cerebral amyloid angiopathy (CAA) is characterized by ␤-amyloid (A␤) peptide deposition in the walls of arterial vessels of the cerebral cortex and cerebellum. 1,2 Like the amyloid plaques in Alzheimer disease (AD), vascular amyloid is composed of a proteolytic fragment (A␤) of the ␤-amyloid precursor protein. A␤ deposition is responsible for a variety of clinical consequences, including acute intracerebral hemorrhage (ICH).3-6 CAA-related ICH 7 accounts for between 15% and 40% of all nontraumatic ICH in elderly individuals and is associated with mortality rates of

A kernel machine method for detecting effects of interaction between multidimensional variable sets: An imaging genetics application

“…The associations between the two genes and AD have been identified and replicated by a number of independent studies [see e.g., Harold et al, 2009; Hollingworth et al, 2011; Lambert et al, 2009; Naj et al, 2011], in addition to Lambert et al [2013], and their potential contributions to the mechanism of AD have been under active investigation [Biffi et al, 2012; Chibnik et al, 2011; Thambisetty et al, 2013]. Moreover, recent studies show that many of the AD risk genes have potential roles in relationship with CVD risk factors, such as hypertension, hypercholesterolemia, and obesity [Guerreiro et al, 2012; Liu et al, 2014].…”

Risk Factors Associated With Early vs Delayed Dementia After Intracerebral Hemorrhage

“…4,11,12 Particiapnts were selected among consecutive patients age ≥ 18 years, admitted to Massachusetts General Hospital (MGH) from January 2006 to December 2013 with primary ICH, i.e. not related to trauma, conversion of an ischemic infarct, rupture of a vascular malformation / aneurysm, or a brain tumor (Figure 1).…”

Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease

“…Some studies have also reported low expression of CR1 in some brain regions (Chibnik et al 2011; Bralten et al 2011), and CR1 interacted with APOE and participated in the clearance of β amyloid (Aβ) peptide. Aβ is the principal constituent of amyloid plaques that is one of the major brain lesions of individuals with AD (Thambisetty et al 2013; Lambert et al 2009; Biffi et al 2012). …”