Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels

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Abstract

Background: Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain. Methods: We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10-8 and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3. Results: Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression. Conclusions: Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).

Original languageEnglish
Article number439
JournalBMC Genomics
Volume17
DOIs
StatePublished - Jun 29 2016

Bibliographical note

Funding Information:
Publication of this article was funded by Brigham Young University’s Department of Biology. This article has been published as part of BMC Genomics Volume 17 Supplement 3, 2016: Selected articles from the 12th Annual Biotechnology and Bioinformatics Symposium: genomics. The full contents of the supplement are available online at https://bmcgenomics.biomedcentral.com/articles/ supplements/volume-17-supplement-3.

Funding Information:
The authors acknowledge that many scientists contributed in developing the clinical and genetic resources necessary to collect these data and complete this project. The authors also gratefully acknowledge the efforts of hundreds of individuals who participated as subjects in these studies. This work was supported by grants from NIH (R01 AG035053, R01 AG042611, P50 AG05681, P01 AG03991, P01 AG026276), the Alzheimer’s Association (MNIRG-11-205368), and the Brigham Young University Gerontology Program. We also acknowledge the Alzheimer’s Disease Genetics Consortium (ADGC) and Genetic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD) for providing genotype data used in this work. GERAD was supported by the Medical Research Council (Grant nu 503480), Alzheimer’s Research UK (Grant nu 503176), the Wellcome Trust (Grant nu 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant nu 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC–10–196728. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; ElanPharma-ceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Med-pace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Some of the samples used in this study were genotyped by the ADGC and GERAD. ADGC is supported by grants from the NIH (#U01AG032984) and GERAD from the Wellcome Trust (GR082604MA) and the Medical Research Council (G0300429). Some data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. The ADNI Executive Committee consists of: Michael Weiner, MD UC San Francisco; Paul Aisen, MD UC San Diego; Ronald Petersen, MD, PhD Mayo Clinic, Rochester; Clifford R. Jack, Jr., MD Mayo Clinic, Rochester; William Jagust, MD UC Berkeley; John Q. Trojanowki, MD, PhD U Pennsylvania; Arthur W. Toga, PhD USC; Laurel Beckett, PhD UC Davis; Robert C. Green, MD, MPH Brigham and Women’s Hospital/Harvard Medical School; Andrew J. Saykin, PsyD Indiana University; John Morris, MD Washington University St. Louis; Leslie M. Shaw University of Pennsylvania. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/ how_to_apply/ADNI_Acknowledgement_List.pdf

Publisher Copyright:
© 2016 The Author(s).

Keywords

  • Brain
  • CSF
  • Cancer
  • PAP

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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