Format

Send to

Choose Destination
Mol Psychiatry. 2018 Oct 25. doi: 10.1038/s41380-018-0246-7. [Epub ahead of print]

Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging.

Author information

1
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
2
Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.
3
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
5
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
7
Alzheimer Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA.
8
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
9
Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA.
10
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. kamboh@pitt.edu.
11
Alzheimer Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA. kamboh@pitt.edu.
12
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. kamboh@pitt.edu.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center