Title | Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Yan Q, Nho K, Del-Aguila JL, Wang X, Risacher SL, Fan K-H, Snitz BE, Aizenstein HJ, Mathis CA, Lopez OL, F Demirci Y, Feingold E, Klunk WE, Saykin AJ, Cruchaga C, M Kamboh I |
Corporate Authors | Alzheimer’s Disease Neuroimaging Initiative(ADNI) |
Journal | Mol Psychiatry |
Volume | 26 |
Issue | 1 |
Pagination | 309-321 |
Date Published | 2021 01 |
ISSN | 1476-5578 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Aniline Compounds, Apolipoprotein E4, Brain, Endophenotypes, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Positron-Emission Tomography, Thiazoles |
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 C-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. |
DOI | 10.1038/s41380-018-0246-7 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/30361487?dopt=Abstract |
page_expo | External |
Alternate Journal | Mol Psychiatry |
PubMed ID | 30361487 |
PubMed Central ID | PMC6219464 |
Grant List | P30 AG066444 / AG / NIA NIH HHS / United States R01 AG064877 / AG / NIA NIH HHS / United States R01 AG052521 / AG / NIA NIH HHS / United States RF1 AG053303 / AG / NIA NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States P01 AG026276 / AG / NIA NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States RF1 AG044546 / AG / NIA NIH HHS / United States RF1 AG025516 / AG / NIA NIH HHS / United States P30 AG066468 / AG / NIA NIH HHS / United States R01 AG041718 / AG / NIA NIH HHS / United States P01 AG025204 / AG / NIA NIH HHS / United States R01 AG044546 / AG / NIA NIH HHS / United States R03 AG054936 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States R37 AG025516 / AG / NIA NIH HHS / United States U19 AG024904 / AG / NIA NIH HHS / United States R01 AG030653 / AG / NIA NIH HHS / United States R01 LM012535 / LM / NLM NIH HHS / United States |
Theme by Danetsoft and Danang Probo Sayekti inspired by Maksimer