@article{25916577ed7f4029838945fb161c7d6a,
title = "Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease",
abstract = "Background: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. Methods: A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 839 rare variants (MAF < 1/ (2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ϵ4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. Conclusions: This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ϵ4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.",
keywords = "Gene-based association of rare variants, Imaging genetics, PSEN1, Whole genome sequencing",
author = "Kwangsik Nho and Emrin Horgusluoglu and Sungeun Kim and Risacher, {Shannon L.} and Dokyoon Kim and Tatiana Foroud and Aisen, {Paul S.} and Petersen, {Ronald C.} and Jack, {Clifford R.} and Shaw, {Leslie M.} and Trojanowski, {John Q.} and Weiner, {Michael W.} and Green, {Robert C.} and Toga, {Arthur W.} and Saykin, {Andrew J.}",
note = "Funding Information: Data used in preparation of this article were obtained from the Alzheimer{\textquoteright}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. 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. Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}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{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, 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.; Medpace, 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{\textquoteright}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. Samples from the National Cell Repository for AD (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (AIG), were used in this study. Funding for the WGS was provided by the Alzheimer{\textquoteright}s Association and the Brin Wojcicki Foundation. Additional support for data analysis was provided by NLM R00 LM011384, NIA R01 AG19771, NIA P30 AG10133, DOD W81XWH-14-2-0151, NCAA 14132004, and NCATS UL1 TR001108. Funding Information: Publication of this article has been funded by NIH U01 AG024904. This article has been published as part of BMC Medical Genomics Volume 9 Supplement 1, 2016. Selected articles from the 5th Translational Bioinformatics Conference (TBC 2015): medical genomics. The full contents of the supplement are available online https://bmcmedgenomics.biomedcentral.com/articles/ supplements/volume-9-supplement-1. Publisher Copyright: {\textcopyright} 2016 The Author(s).",
year = "2016",
month = aug,
day = "12",
doi = "10.1186/s12920-016-0190-9",
language = "English (US)",
volume = "9",
journal = "BMC Medical Genomics",
issn = "1755-8794",
publisher = "BioMed Central",
}