Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging
Year: 2018
Type: review
Study design: Observational Study
Abstract: Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25–35% of the amyloid variance in different datasets, of which 14–17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.
Source: Molecular Psychiatry
Authors: for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Qi Yan, Kwangsik Nho, Jorge L. Del-Aguila, Xingbin Wang, Shannon L. Risacher, Kang-Hsien Fan, Beth E. Snitz, Howard J. Aizenstein, Chester A. Mathis, Oscar L. Lopez, F. Yesim Demirci, Eleanor Feingold, William E. Klunk, Andrew J. Saykin, Carlos Cruchaga, M. Ilyas Kamboh
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Awards: G104586243, Genetic Architecture of Alzheimer’s disease Proteinopathies, Identifying Rare Variants that Increase Risk for Alzheimer's Disease, Alzheimer neuroimaging-biomarkers in pre-clinical cognitive decline from a population-based study, The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease, Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease, Roles of Gray Matter Brain Aging and Small Vessel Disease in AD Pathophysiology, Alzheimer's Disease Research Center, USING QUANTITATIVE TRAITS TO IDENTIFY NOVEL GENES FOR ALZHEIMERS DISEASE AND OTHER COMPLEX TRAITS, G4119534169, G4475667458, Search for the Alzheimers Genes, G5324093878, EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)", Alzheimer's Disease Neuroimaging Initiative, Integrating Neuroimaging, Multi-omics, and Clinical Data in Complex Disease, G5850682332, IDENTIFYING RARE VARIANTS THAT INCREASE RISK FOR ALZHEIMER'S DISEASE, Alzheimer's Disease Research Center, Healthy Aging and Senile Dementia, G764699806, AMYLOID PATHOLOGY AND COGNITION IN NORMAL ELDERLY, Neurogenesis in Adult Brain: Gene Networks and Alzheimer’s Disease, G8895907669, G9000070217, G9000072650, G9000122335, G9000208814, G9000217785, G9000300274, Alzheimer Disease Research Center, Alzheimer's Disease Research Center, Alzheimer's Disease Neuroimaging Initiative (ADNI4), Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Predictors of Altered CNS Structure, Function, and Connectomics in the Elderly using a Health Disparities Framework, Roles of Gray Matter Brain Aging and Small Vessel Disease in AD Pathophysiology
OpenAlex ID: W2898262363