@article{fac2a7c5849e4fefae709041b49e05ff,
title = "Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer{\textquoteright}s disease",
abstract = "Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer{\textquoteright}s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.",
keywords = "AD, Alzheimer{\textquoteright}s disease, CAA, Cerebral amyloid angiopathy, GWAS, Genome-wide association study, LINC-PINT, Splicing",
author = "Reddy, {Joseph S.} and Mariet Allen and Ho, {Charlotte C.G.} and Oatman, {Stephanie R.} and {\"O}zkan I{\c s} and Quicksall, {Zachary S.} and Xue Wang and Jiangli Jin and Patel, {Tulsi A.} and Carnwath, {Troy P.} and Nguyen, {Thuy T.} and Malphrus, {Kimberly G.} and Lincoln, {Sarah J.} and Carrasquillo, {Minerva M.} and Crook, {Julia E.} and Takahisa Kanekiyo and Murray, {Melissa E.} and Guojun Bu and Dickson, {Dennis W.} and Nil{\"u}fer Ertekin-Taner",
note = "Funding Information: The authors thank the patients and their families for their participation, without whom these studies would not have been possible. We thank our colleagues at the Mayo Clinic genome analysis core (GAC) for their collaboration, particular gratitude to Bruce Eckloff, Dr. Julie Cunningham, Dr. Yanhong Wu and Julie Lau, as well as Dr. Asha Nair, Pritha Chanana, Daniel O{\textquoteright}Brien and Dr. Yan Asmann in the Mayo Clinic bioinformatics core (BIC). We are grateful to our colleague Dr. Laura Lewis-Tuffin in the Cell and Tissue Analysis Shared Resource Lab at Mayo Clinic for her consultation on imaging and sorting experiments. We also acknowledge the efforts of the AMP-AD RNAseq reprocessing team, in particular Dr. Kirsten Dang, Dr. Thanneer Perumal and Dr. Ben Logsdon at Sage Bionetworks. MC-CAA study: The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (10.7303/syn2580853). The Mayo Clinic AD-CAA study was led by Dr. Guojun Bu and Dr. Nil{\"u}fer Ertekin-Taner at the, Mayo Clinic, Jacksonville, FL as part of the multi-PI RF1AG051504 (MPIs Bu and Ertekin-Taner) using samples from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50AG016574, R37AG027924, Cure Alzheimer{\textquoteright}s Fund, and support from Mayo Foundation. AMP-AD RNASeq datasets: This study is a cross-consortia project using RNAseq data generated through grants U01AG046152, U01AG046170, and U01AG046139. For the Mayo RNAseq study: The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org/ ). Study data were provided by the following sources: The Mayo Clinic Alzheimers Disease Genetic Studies, led by Dr. Nil{\"u}fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimers Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. For the ROSMAP study: The results published here are in whole or in part based on data obtained from the AMP-AD Knowledge Portal ( https://adknowledgeportal.synapse.org ). Study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq) RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu . For the MSBB study: The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org/ ). These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. GTEx : The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The sQTL data used for the analyses described in this manuscript were queried from the GTEx Portal on 05/22/2020. Funding Information: The authors thank the patients and their families for their participation, without whom these studies would not have been possible. We thank our colleagues at the Mayo Clinic genome analysis core (GAC) for their collaboration, particular gratitude to Bruce Eckloff, Dr. Julie Cunningham, Dr. Yanhong Wu and Julie Lau, as well as Dr. Asha Nair, Pritha Chanana, Daniel O{\textquoteright}Brien and Dr. Yan Asmann in the Mayo Clinic bioinformatics core (BIC). We are grateful to our colleague Dr. Laura Lewis-Tuffin in the Cell and Tissue Analysis Shared Resource Lab at Mayo Clinic for her consultation on imaging and sorting experiments. We also acknowledge the efforts of the AMP-AD RNAseq reprocessing team, in particular Dr. Kirsten Dang, Dr. Thanneer Perumal and Dr. Ben Logsdon at Sage Bionetworks. MC-CAA study: The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (10.7303/syn2580853). Funding Information: This work was supported by National Institute on Aging [RF1 AG051504 to N.E.T and G.B and U01 AG046139; to N.E.T and R01 AG061796 to N.E.T]. Data collection was supported through funding by NIA grants P50AG016574, R37AG027924, Cure Alzheimer{\textquoteright}s Fund, and support from Mayo Foundation. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s40478-021-01199-2",
language = "English (US)",
volume = "9",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",
}