. 2014 Mar;19(3):351-7.

doi: 10.1038/mp.2013.19. Epub 2013 Feb 19.

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

V K Ramanan¹, S L Risacher², K Nho², S Kim³, S Swaminathan⁴, L Shen³, T M Foroud⁵, H Hakonarson⁶, M J Huentelman⁷, P S Aisen⁸, R C Petersen⁹, R C Green¹⁰, C R Jack¹¹, R A Koeppe¹², W J Jagust¹³, M W Weiner¹⁴, A J Saykin⁵; Alzheimer’s Disease Neuroimaging Initiative

Affiliations

¹ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA.
² Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
³ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ The Translational Genomics Institute (TGen), Phoenix, AZ, USA.
⁸ Department of Neuroscience, University of California, San Diego, CA, USA.
⁹ Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
¹⁰ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
¹² Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of California, Berkeley, CA, USA.
¹⁴ 1] Departments of Radiology, Medicine, and Psychiatry, University of California, San Francisco, CA, USA [2] Department of Veterans Affairs Medical Center, San Francisco, CA, USA.

PMID: 23419831
PMCID: PMC3661739
DOI: 10.1038/mp.2013.19

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

V K Ramanan et al. Mol Psychiatry. 2014 Mar.

. 2014 Mar;19(3):351-7.

doi: 10.1038/mp.2013.19. Epub 2013 Feb 19.

Authors

Affiliations

¹ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA.
² Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
³ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ The Translational Genomics Institute (TGen), Phoenix, AZ, USA.
⁸ Department of Neuroscience, University of California, San Diego, CA, USA.
⁹ Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
¹⁰ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
¹² Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of California, Berkeley, CA, USA.
¹⁴ 1] Departments of Radiology, Medicine, and Psychiatry, University of California, San Francisco, CA, USA [2] Department of Veterans Affairs Medical Center, San Francisco, CA, USA.

PMID: 23419831
PMCID: PMC3661739
DOI: 10.1038/mp.2013.19

Abstract

Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

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Conflict of interest statement

CONFLICT OF INTEREST

Dr. Jagust has served as a consultant to TauRx Therapeutics LTD, GE Healthcare, Siemens, Synarc, and Janssen Alzheimer Immunotherapy. Dr. Weiner has served on scientific advisory boards for Eli Lilly, Araclon, Institut Catala de Neurociencies Aplicades, the Gulf War Veterans Illnesses Advisory Committee, Biogen Idec, and Pfizer; has served as a consultant to Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics LDT, Bayer Healthcare, Biogen Idec, Exonhit Therapeutics, Servier, Synarc, Janssen, Harvard University, and KLJ Associates; has received funding for travel from NeuroVigil, Inc., CHRU Hôpital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Eli Lilly, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer’s Disease, the AD/PD Meeting, Paul Sabatier University, Novartis, Tohoku University, Fundacio ACE, and Travel eDreams, Inc.; has received honoraria from NeuroVigil, Inc., Institut Catala de Neurociencies Aplicades, PMDA/Japanese Ministry of Health, Labour, and Welfare, Tohoku University, and the Alzheimer’s Drug Discovery Foundation; has received research support from Merck and Avid; and has stock options for Synarc and Elan. Dr. Saykin has received investigator-initiated research funding from Welch Allyn and Siemens Healthcare and has served as a consultant or advisory board member for Siemens Healthcare and Eli Lilly. The other authors declare no conflict of interest.

Figures

**Figure 1. Quantile-quantile (Q-Q) plot of observed −log₁₀ p-values from the GWAS of cortical Aβ load versus those expected under the null hypothesis**
The Q-Q plot exhibits no evidence of genomic inflation (PLINK-calculated λ = 1.00) or population stratification in the GWAS. An additive genetic model was used and age, gender, and diagnosis were applied as covariates. Analyses were restricted to subjects with non-Hispanic Caucasian (CEU or TSI) ancestry as determined by genetic clustering. Observed −log₁₀ p-values > 8 are represented along the top of the plot as red triangles, while all other values are represented as red dots.

**Figure 2. Manhattan plot of observed −log₁₀ p-values from the GWAS of cortical Aβ load**
More than six million SNPs were tested for association to global cortical Aβ burden under an additive genetic model and applying age, gender, and diagnosis as covariates. Genome-wide significant associations (exceeding the threshold represented by the red line) were identified on chromosome 19 within *APOE* and its neighboring genes and on chromosome 3 at the *BCHE* locus. Suggestive associations (exceeding the threshold represented by the blue line) were identified on five additional chromosomes. Annotations are provided for genome-wide significant associations and for the top three suggestive associations.

**Figure 3. Regional association plots for the loci exhibiting genome-wide significant association to cortical Aβ burden**
Magnified association plots are displayed for the regions around A) rs429358 within *APOE* and B) rs509208 at the *BCHE* locus. SNPs are plotted based on their GWAS −log₁₀ p-values (left vertical axis) and their genomic position (NCBI build 36). Genes in these regions are labeled with arrows denoting their 5′-to-3′ orientation, and the red color scale of r² values is used to label SNPs based on their degree of linkage disequilibrium with the annotated peak SNP. Recombination rates calculated from 1000 Genomes Project reference data are also displayed in a blue line corresponding to the right vertical axis.

**Figure 4. *APOE* ε4 and rs509208 (*BCHE*) appear to exhibit independent, additive effects on cortical Aβ levels**
Mean cortical Aβ levels (adjusted for age, gender, and diagnosis) ± standard errors are displayed based on A) the number of *APOE* ε4 allele copies and B) rs509208 genotype. Presence of at least one copy of the ε4 allele was significantly associated with increased Aβ burden (Cohen’s d = 0.71), as was presence of at least one copy of the minor allele (G) of rs509208 (Cohen’s d = 0.52). These loci appeared to exert additive effects on Aβ levels (panel C): subjects having both risk factors exhibited significantly greater Aβ burden than subjects having either factor in isolation, and no significant epistasis modeled as an interaction was identified.

See this image and copyright information in PMC

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APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

Affiliations

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous