Prioritizing Alzheimer's Disease Genetic Variants

To identify potential functional risk variants and genes at each
associated locus, we first annotated a list of prioritized variants from the 24
associated loci (excluding APOE) (n = 1,873).
This variant list combined variants in LD with the sentinel variants
(r² ≥ 0.5) using INFERNO^{160 (link)} LD expansion
(n = 1,339) and variants with suggestive significance
(P < 10⁻⁵) and LD
(r² ≥ 0.5) with the sentinel variants for
the 24 associated loci (excluding APOE) (n =
1,421 variants). We then identified variants with regulatory potential in this
set of variants using four programs that incorporate various annotations to
identify likely regulatory variants: RegulomeDB^{56 (link)}, HaploReg v.4.1 (refs. ^{57 (link),161 (link)}), GWAS4D^{59 (link)}, and the Ensembl Regulatory Build^{58 (link)}. We used the ChromHMM (core 15-state
model) as ‘source epigenomes’ for the HaploReg analyses. We used
immune (Monocytes-CD14⁺, GM12878 lymphoblastoid, HSMM myoblast) and
brain (NH-A astroctyes) for the Ensembl Regulatory Build analyses. We then used
the list of 1,873 prioritized variants to search for genes functionally linked
via eQTLs in LOAD relevant tissues including various brain and blood tissue
types, including all immune-related cell types, most specifically myeloid cells
(macrophages and monocytes) and B-lymphoid cells, which are cell types
implicated in LOAD and neurodegeneration by a number of recent studies^{14 (link),45 (link),162 (link),163 (link)}. While their specificity may be lower
for identifying Alzheimer’s disease risk eQTLs, we included whole blood
cell studies in our Alzheimer’s disease–relevant tissue class due
to their high correlation of eQTLs with Alzheimer’s
disease–relevant tissues (70% with brain^{164 (link)}; 51–70% for monocytes and
lymphoblastoid cell lines^{165 (link)})
and their large sample sizes that allow for increased discovery power. See the
Supplementary Notefor details on the eQTL databases and studies searched, and Supplementary Table 13 for sample
sizes of each database/study.
Formal co-localization testing of our summary Stage 1 results was
conducted using (1) COLOC^{166 (link)}via INFERNO and (2) Summary Mendelian Randomization (SMR)-Heidi
analysis^{167 (link)}. The
approximate Bayes factor (ABF), which was used to assess significance in the
INFERNO COLOC analysis, is a summary measure that provides an alternative to the
P value for the identification of associations as
significant. SMR-Heidi analysis, which employs a heterogeneity test (HEIDI test)
to distinguish pleiotropy or causality (a single genetic variant affecting both
gene expression and the trait) from linkage (two distinct genetic variants in
LD, one affecting gene expression and one affecting trait), was also employed
for co-localization analysis. Genes located less than 1 Mb from the GWAS
sentinel variants that pass a 5% Benjamini–Hochberg FDR-corrected SMR
P-value significance threshold and a HEIDI
P-value > 0.05 threshold were considered
significant. The Westra eQTL^{168 (link)} summary data and Consortium for the Architecture of Gene
Expression (CAGE) eQTL summary data were used for analysis. These datasets,
conducted in whole blood, are large eQTL studies (Westra: discovery phase
n = 5,311, replication phase n = 2,775;
CAGE: n = 2,765), and while there is some overlap in samples
between the two datasets, CAGE provides finer coverage. The ADGC reference panel
dataset referenced above for GCTA COJO analysis was used for LD
calculations.

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Kunkle B.W., Grenier-Boley B., Sims R., Bis J.C., Damotte V., Naj A.C., Boland A., Vronskaya M., van der Lee S.J., Amlie-Wolf A., Bellenguez C., Frizatti A., Chouraki V., Martin E.R., Sleegers K., Badarinarayan N., Jakobsdottir J., Hamilton-Nelson K.L., Moreno-Grau S., Olaso R., Raybould R., Chen Y., Kuzma A.B., Hiltunen M., Morgan T., Ahmad S., Vardarajan B.N., Epelbaum J., Hoffmann P., Boada M., Beecham G.W., Garnier J.G., Harold D., Fitzpatrick A.L., Valladares O., Moutet M.L., Gerrish A., Smith A.V., Qu L., Bacq D., Denning N., Jian X., Zhao Y., Del Zompo M., Fox N.C., Choi S.H., Mateo I., Hughes J.T., Adams H.H., Malamon J., Sanchez-Garcia F., Patel Y., Brody J.A., Dombroski B.A., Deniz Naranjo M.C., Daniilidou M., Eiriksdottir G., Mukherjee S., Wallon D., Uphill J., Aspelund T., Cantwell L.B., Garzia F., Galimberti D., Hofer E., Butkiewicz M., Fin B., Scarpini E., Sarnowski C., Bush W.S., Meslage S., Kornhuber J., White C.C., Song Y., Barber R.C., Engelborghs S., Sordon S., 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Masullo C., Crocco E.A., DeCarli C., Bisceglio G., Dick M., Ma L., Duara R., Graff-Radford N.R., Evans D.A., Hodges A., Faber K.M., Scherer M., Fallon K.B., Riemenschneider M., Fardo D.W., Heun R., Farlow M.R., Kölsch H., Ferris S., Leber M., Foroud T.M., Heuser I., Galasko D.R., Giegling I., Gearing M., Hüll M., Geschwind D.H., Gilbert J.R., Morris J., Green R.C., Mayo K., Growdon J.H., Feulner T., Hamilton R.L., Harrell L.E., Drichel D., Honig L.S., Cushion T.D., Huentelman M.J., Hollingworth P., Hulette C.M., Hyman B.T., Marshall R., Jarvik G.P., Meggy A., Abner E., Menzies G.E., Jin L.W., Leonenko G., Real L.M., Jun G.R., Baldwin C.T., Grozeva D., Karydas A., Russo G., Kaye J.A., Kim R., Jessen F., Kowall N.W., Vellas B., Kramer J.H., Vardy E., LaFerla F.M., Jöckel K.H., Lah J.J., Dichgans M., Leverenz J.B., Mann D., Levey A.I., Pickering-Brown S., Lieberman A.P., Klopp N., Lunetta K.L., Wichmann H.E., Lyketsos C.G., Morgan K., Marson D.C., Brown K., Martiniuk F., Medway C., Mash 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Publication 2019

Alzheimer disease Apoe B lymphoid cells Blood Brain Cell Epigenomes Gene expression Genes Genes locus Genetic variants Heterogeneity Macrophages Monocytes Myeloid cells Myoblast Neurodegeneration Replication Smrp Tissues

Corresponding Organization : University of Miami

Other organizations : Inserm, Cardiff University, University of Washington, University of Pennsylvania, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Paris-Saclay, Erasmus MC, Institut Pasteur de Lille, VIB-UAntwerp Center for Molecular Neurology, Icelandic Heart Association, Fundació ACE, Boston University, University of Eastern Finland, Columbia University, Université Paris Cité, University of Bonn, Dublin City University, University College London, UK Dementia Research Institute, University of Michigan–Ann Arbor, Brown Foundation, University of Cagliari, Centro de Investigación Biomédica en Red, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Universidad de Cantabria, King's College London, Hospital Universitario de Gran Canaria Doctor Negrín, Aristotle University of Thessaloniki, Université de Rouen Normandie, Normandie Université, MRC Prion Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Medical University of Graz, Case Western Reserve University, Friedrich-Alexander-Universität Erlangen-Nürnberg, Broad Institute, University of North Texas, University of North Texas Health Science Center, University of Antwerp, Saarland University, The University of Texas Southwestern Medical Center, KU Leuven, Johns Hopkins University, Martin Luther University Halle-Wittenberg, Harvard University, University of Oxford, National Institute on Aging, Baylor College of Medicine, University of Southampton, Massachusetts General Hospital, Karolinska University Hospital, German Center for Neurodegenerative Diseases, Indiana University – Purdue University Indianapolis, Uppsala University, University Hospital Bonn, University of Duisburg-Essen, University of Pittsburgh, University of Nottingham, Queen's Medical Centre, Albert Einstein College of Medicine, University of Parma, Medical University of Lodz, Trinity College Dublin, St. James's Hospital, Instituto de Salud Carlos III, Kaiser Permanente Washington Health Research Institute, University of Mississippi Medical Center, University of Bari Aldo Moro, Fundació Clínic per a la Recerca Biomèdica, University Hospital Mútua de Terrassa, Mútua Terrassa, Mayo Clinic in Arizona, Centre Hospitalier Universitaire de Lille, Fondazione Santa Lucia, The University of Texas Health Science Center at Houston, Translational Genomics Research Institute, Université de Lille, The Lundquist Institute, Harbor–UCLA Medical Center, Hôpital Broca, Assistance Publique – Hôpitaux de Paris, Geriatric Research Education and Clinical Center, Veterans Health Administration, Université de Bordeaux, Icahn School of Medicine at Mount Sinai, Institut du Cerveau, Sorbonne Université, Centre National de la Recherche Scientifique, University of Perugia, University of Cambridge, Neuropsychiatrie : Recherche Epidemiologique et Clinique, VA Puget Sound Health Care System, Pitié-Salpêtrière Hospital, Queen's University Belfast, Texas Tech University Health Sciences Center, Texas Tech University, Kuopio University Hospital, Stockholm University, Karolinska Institutet, University of Wisconsin–Madison, AXA Research Fund, Universidade de Santiago de Compostela, Centre for Biomedical Network Research on Rare Diseases, Rush University Medical Center, Central Institute of Mental Health, Heidelberg University, University Hospital Heidelberg, Banner Sun Health Research Institute, Northwestern University, Swedish Medical Center, University of California, San Francisco, Duke University, Brigham Young University, University of Kansas Medical Center, University of Pisa, Washington University in St. Louis, USF Health Byrd Alzheimer's Institute, University of South Florida, Fred Hutch Cancer Center, Bruce W. Carter VA Medical Center, Mayo Clinic in Florida, University of Southern California, Università Cattolica del Sacro Cuore, University of California, Davis, University of California, Irvine, Mount Sinai Medical Center, Universität Hamburg, University Medical Center Hamburg-Eppendorf, University of Alabama at Birmingham, University of Kentucky, New York University, University of Cologne, Charité - Universitätsmedizin Berlin, University of California, San Diego, Emory University, University of Freiburg, University of California, Los Angeles, Brigham and Women's Hospital, Hospital Universitario de Valme, University of Zurich, Oregon Health & Science University, Université de Toulouse, Newcastle Hospitals - Campus for Ageing and Vitality, Newcastle University, LMU Klinikum, Cleveland Clinic, Lou Ruvo Brain Institute, University of Manchester, Manchester Academic Health Science Centre, Helmholtz Zentrum München, Life & Brain (Germany), University Hospital of Wales, Leipzig University, Central University Hospital of Asturias, National Institutes of Health, University of Florence, University of Colorado Denver, Istituti di Ricovero e Cura a Carattere Scientifico, John Radcliffe Hospital, University of Toronto, Occupational Cancer Research Centre, University of Bristol, University of North Carolina at Chapel Hill, National Institute of Neurological Disorders and Stroke, Casa Sollievo della Sofferenza, Hospital La Paz Institute for Health Research, Oasi Maria SS, Columbia University Irving Medical Center, Hospital de Sant Pau, Somerset Partnership NHS Foundation Trust, Wellcome Sanger Institute, Southmead Hospital, Université de Montpellier, Utah State University, Centre Hospitalier du Rouvray, Children's Hospital of Philadelphia, University of Iceland, Institute for Neurodegenerative Disorders

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Protocol cited in 17 other protocols

Variable analysis

independent variables

List of prioritized variants from the 24 associated loci (excluding APOE) (n = 1,873)
Variants in LD with the sentinel variants (r^2 ≥ 0.5) using INFERNO LD expansion (n = 1,339)
Variants with suggestive significance (P < 10^-5) and LD (r^2 ≥ 0.5) with the sentinel variants for the 24 associated loci (excluding APOE) (n = 1,421 variants)

dependent variables

Potential functional risk variants and genes at each associated locus

control variables

APOE locus (excluded from the analysis)

positive controls

Not specified

negative controls

Not specified

Annotations

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