Abstract
The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels. For (1), we confirmed that 12 AD-associated coding common SNPs and five nonsynonymous rare variants are in linkage disequilibrium with the IGAP SNPs. For (2), the IGAP SNPs in CELF1 and MS4A6A were associated with expression of their neighboring genes, MYBPC3 and MS4A6A, respectively, in blood. The IGAP SNP in DSG2 was an expression quantitative trait loci (eQTL) for DLGAP1 and NETO1 in the human frontal cortex. The IGAP SNPs in ABCA7, CD2AP, and CD33 each acted as eQTL for AD-associated genes in brain. Our approach for identifying proxies and examining eQTL highlighted potentially impactful, novel gene regulatory phenomena pertinent to the AD phenotype.
| Original language | English |
|---|---|
| Pages (from-to) | 135-146 |
| Number of pages | 12 |
| Journal | Neurobiology of Aging |
| Volume | 74 |
| DOIs | |
| State | Published - Feb 2019 |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Inc.
Funding
The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle), and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904), the EU Joint Program–Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM-Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435. ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC are collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, and 2U01HL096917 from the NIH (NHLBI, NINDS, NIA, and NIDCD) and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607, and AG033040 and NINDS [R01 NS017950]). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03–012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. All studies are grateful to their participants, faculty, and staff. The content of these articles is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services. The work done by the North American Brain Expression Consortium (NABEC) was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services (project number ZIA AG000932-04), and by a Research Grant from the Department of Defense (W81XWH-09-2–0128). The National Institutes of Health–National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. The authors thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01); NACC, U01 AG016976; NIA LOAD, U24 AG026395, R01AG041797; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, AG02365; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE, as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and 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: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. 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. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05–14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. 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: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by the National Cell Repository for Alzheimer's Disease (U24 AG21886) and National Institute on Aging (K25 AG043546, UL1TR000117, the UK-ADC P30 AG028383, R01 AG045775, and R01 AG057187). We thank Dr. Paul Roy Health, University of Sheffield, for providing additional information on gene expression dataset GSE66333 and GSE29652. The Alzheimer's Disease Sequencing Project (ADSP) comprises two Alzheimer's Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak-Vance and U01 AG052409 to Drs. Seshadri and Fornage. Data generation and harmonization in the Follow-up Phases are supported by U54AG052427 (to Drs. Schellenberg and Wang). Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by study investigators, the NIA funded Alzheimer's Disease Centers (ADCs), and the National Alzheimer's Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes (dbGaP) funded by NIH. This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included study investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. This work was supported by the National Cell Repository for Alzheimer's Disease ( U24 AG21886 ) and National Institute on Aging ( K25 AG043546 , UL1TR000117 , the UK-ADC P30 AG028383 , R01 AG045775 , and R01 AG057187 ). We thank Dr. Paul Roy Health, University of Sheffield, for providing additional information on gene expression dataset GSE66333 and GSE29652.
| Funders | Funder number |
|---|---|
| ADGC | RC2 AG036528 |
| Membership of the Alzheimer's Disease Genetics Consortium is provided in the Acknowledgments | |
| Biomedical Laboratory Research Program | |
| Cohorts for Heart and Aging Research in Genomic | R01 AG033193 |
| DOD ADNI | |
| EUROSPAN | |
| Glaxo Smith Kline | |
| Hersenstichting Nederland Breinbrekend Werk | |
| Institut de Neuropatologia | |
| International Parkinson Fonds | |
| Kronos Science | AG041232 |
| MRC London Brain Bank for Neurodegenerative Diseases | |
| NIA/NIH | |
| NWO-RFBR | 047.017.043 |
| National Cell Repository for Alzheimer's Disease | U24 AG21886 |
| National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site | |
| Netherlands Consortium for Healthy Aging | 050-060-810 |
| Netherlands Genomics Initiative | |
| Netherlands Organization of Scientific Research NWO | 911-03–012, 175.010.2005.011 |
| Newcastle Brain Tissue Resource | |
| North Bristol NHS Trust Research and Innovation Department and DeNDRoN | |
| Quality of Life and Management of the Living Resources” of 5th Framework Programme | QLG2-CT-2002-01254 |
| RIDE2 | |
| Research Institute for Diseases in the Elderly | |
| South West Dementia Brain Bank | |
| Steiermärkische Krankenanstalten Gesellschaft | |
| Stichting Vanderes | |
| UK-ADC | P30 AG028383 |
| US Department of Veterans Affairs Administration | |
| National Institutes of Health (NIH) | U01 AG024904 |
| U.S. Department of Defense | W81XWH-09-2–0128, W81XWH-12-2-0012 |
| Howard Hughes Medical Institute | |
| U.S. Department of Health and Human Services | ZIA AG000932-04 |
| National Institute of Mental Health | MH60451 |
| National Institute on Aging | R01AG023629, UK-ADC P30 AG028383, UL1TR000117, U01AG016976, U24AG041689, AG033193, R01 AG057187, U01 AG032984, K25 AG043546, R01 AG045775, U24AG026395 |
| National Heart, Lung, and Blood Institute (NHLBI) | RC2HL102419, HL105756 |
| National Institute on Deafness and Other Communication Disorders | N01HC85081, U01HL080295, N01HC85082, N01HC85080, N01HC85086, N01HC85083, R01-HL70825, N01HC85079, HHSN268200800007C, U01HL130114, N01HC55222 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01AG20098, AG033040, N01-HC-25195, AG049607, R01 NS017950, NS39764, HHSN268201500001I, R01s AG054076, R01AG15928 |
| National Institute of Biomedical Imaging and Bioengineering | |
| U.S. National Library of Medicine | |
| Alzheimer's Association | |
| Lance Armstrong Foundation | IIRG-05–14147, IIRG-08-89720 |
| Biomedical Laboratory Research and Development, VA Office of Research and Development | |
| DoD Alzheimer's Disease Neuroimaging Initiative | |
| Astrobiology Research Trust | |
| Wellcome Trust | |
| Banner Alzheimer’s Foundation | |
| Seventh Framework Programme | HEALTH-F4-2007-201413 |
| BRACE | |
| Higher Education Funding Council for England | |
| EU Joint Programme – Neurodegenerative Disease Research | |
| University of Utah Gastroenterology Division in the Department of Internal Medicine | |
| National Alzheimer's Coordinating Center | |
| Nederlandse Hersenbank | |
| Canadian Institutes of Health Research | |
| UK Medical Research Council, Engineering and Physical Sciences Research Council | |
| Coins for Alzheimer's Research Trust | |
| Newcastle University | |
| European Commission | |
| ZonMw Memorabel | |
| Erasmus Universiteit Rotterdam | |
| Russian Foundation for Basic Research | |
| Austrian Science Fund/FWF | P20545-P05, I904, P13180 |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Erasmus Medisch Centrum | 014-93-015 |
| Ministerie van Onderwijs, Cultuur en Wetenschap | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Ministry of Science, ICT and Future Planning | |
| Oesterreichische Nationalbank | 2U01HL096899, U01 2U01HL096812, 2U01HL096814, 2U01HL096902, 2U01HL096917, HHSN268201100006C, HHSN268201100005C, HHSN268201100008C, HHSN268201100007C, HHSN268201100009C, 15435, HHSN268201100011C, HHSN268201100010C, HHSN268201100012C |
| Österreichische Forschungsförderungsgesellschaft | 827462 |
| Sixth Framework Programme | 018947, LSHG-CT-2006-01947 |
| Universitat de Barcelona | |
| Internationale Stichting Alzheimer Onderzoek | |
| Medizinische Universität Graz |
Keywords
- ADGC
- ADSP
- GWAS
- Neuroinflammation
- WES
ASJC Scopus subject areas
- General Neuroscience
- Aging
- Clinical Neurology
- Developmental Biology
- Geriatrics and Gerontology
