Abstract
The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.
| Original language | English |
|---|---|
| Article number | 105880 |
| Journal | Neurobiology of Disease |
| Volume | 174 |
| DOIs | |
| State | Published - Nov 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors
Funding
The ADGC cohorts include: Adult Changes in Thought (ACT) (UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657), the Alzheimer's Disease Centers (ADC) (P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), the Chicago Health and Aging Project (CHAP) (R01 AG11101, RC4 AG039085, K23 AG030944), Indianapolis Ibadan (R01 AG009956, P30 AG010133), the Memory and Aging Project (MAP) (R01 AG17917), Mayo Clinic (MAYO) (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504, P50 AG016574), Mayo Parkinson's Disease controls (NS039764, NS071674, 5RC2HG005605), University of Miami (R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048), the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE) (R01 AG09029, R01 AG025259), the National Cell Repository for Alzheimer's Disease (NCRAD) (U24 AG21886), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD) (R01 AG041797), the Religious Orders Study (ROS) (P30 AG10161, R01 AG15819), the Texas Alzheimer's Research and Care Consortium (TARCC) (funded by the Darrell K Royal Texas Alzheimer's Initiative), Vanderbilt University/Case Western Reserve University (VAN/CWRU) (R01 AG019757, R01 AG021547, R01 AG027944, R01 AG028786, P01 NS026630, and Alzheimer's Association), the Washington Heights-Inwood Columbia Aging Project (WHICAP) (RF1 AG054023), the University of Washington Families (VA Research Merit Grant, NIA: P50AG005136, R01AG041797, NINDS: R01NS069719), the Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer (EFIGA) (RF1 AG015473), the University of Toronto (UT) (funded by Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research), and Genetic Differences (GD) (R01 AG007584). 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. This work was supported by grants the National Institute on Aging R56AG057191, R01AG057187, R21AG061551, R01AG054060, and the UK-ADC P30AG072946.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.We are extremely grateful to the research volunteers, clinicians, and staff who made this study 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 NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). The Alzheimer's Disease Sequencing Project (ADSP) is comprised of 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. Sequencing for the Follow Up Study (FUS) is supported through U01AG057659 (to Drs. PericakVance, Mayeux, and Vardarajan) and U01AG062943 (to Drs. Pericak-Vance and Mayeux). Data generation and harmonization in the Follow-up Phase is supported by U54AG052427 (to Drs. Schellenberg and Wang). The FUS Phase analysis of sequence data is supported through U01AG058589 (to Drs. Destefano, Boerwinkle, De Jager, Fornage, Seshadri, and Wijsman), U01AG058654 (to Drs. Haines, Bush, Farrer, Martin, and Pericak-Vance), U01AG058635 (to Dr. Goate), RF1AG058066 (to Drs. Haines, Pericak-Vance, and Scott), RF1AG057519 (to Drs. Farrer and Jun), R01AG048927 (to Dr. Farrer), and RF1AG054074 (to Drs. Pericak-Vance and Beecham). The ADGC cohorts include: Adult Changes in Thought (ACT) (UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657), the Alzheimer's Disease Centers (ADC) (P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), the Chicago Health and Aging Project (CHAP) (R01 AG11101, RC4 AG039085, K23 AG030944), Indianapolis Ibadan (R01 AG009956, P30 AG010133), the Memory and Aging Project (MAP) (R01 AG17917), Mayo Clinic (MAYO) (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504, P50 AG016574), Mayo Parkinson's Disease controls (NS039764, NS071674, 5RC2HG005605), University of Miami (R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048), the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE) (R01 AG09029, R01 AG025259), the National Cell Repository for Alzheimer's Disease (NCRAD) (U24 AG21886), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD) (R01 AG041797), the Religious Orders Study (ROS) (P30 AG10161, R01 AG15819), the Texas Alzheimer's Research and Care Consortium (TARCC) (funded by the Darrell K Royal Texas Alzheimer's Initiative), Vanderbilt University/Case Western Reserve University (VAN/CWRU) (R01 AG019757, R01 AG021547, R01 AG027944, R01 AG028786, P01 NS026630, and Alzheimer's Association), the Washington Heights-Inwood Columbia Aging Project (WHICAP) (RF1 AG054023), the University of Washington Families (VA Research Merit Grant, NIA: P50AG005136, R01AG041797, NINDS: R01NS069719), the Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer (EFIGA) (RF1 AG015473), the University of Toronto (UT) (funded by Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research), and Genetic Differences (GD) (R01 AG007584). 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 Programme - Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steierm\u00E4rkische 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 is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 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 \u201CQuality of Life and Management of the Living Resources\u201D 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 manuscripts 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 FUS cohorts include: the Alzheimer's Disease Centers (ADC) (P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), Alzheimer's Disease Neuroimaging Initiative (ADNI) (U19AG024904), Amish Protective Variant Study (RF1AG058066), Cache County Study (R01AG11380, R01AG031272, R01AG21136, RF1AG054052), Case Western Reserve University Brain Bank (CWRUBB) (P50AG008012), Case Western Reserve University Rapid Decline (CWRURD) (RF1AG058267, NU38CK000480), CubanAmerican Alzheimer's Disease Initiative (CuAADI) (3U01AG052410), Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) (5R37AG015473, RF1AG015473, R56AG051876), Genetic and Environmental Risk Factors for Alzheimer's disease Among African Americans Study (GenerAAtions) (2R01AG09029, R01AG025259, 2R01AG048927), Gwangju Alzheimer's and Related Dementias Study (GARD) (U01AG062602), Hussman Institute for Human Genomics Brain Bank (HIHGBB) (R01AG027944, Alzheimer's Association \u201CIdentification of Rare Variants in Alzheimer Disease\u201D), Ibadan Study of Aging (IBADAN) (5R01AG009956), Mexican Health and Aging Study (MHAS) (R01AG018016), Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) (2R01AG09029, R01AG025259, 2R01AG048927), Northern Manhattan Study (NOMAS) (R01NS29993), Peru Alzheimer's Disease Initiative (PeADI) (RF1AG054074), Puerto Rican 1066 (PR1066) (Wellcome Trust (GR066133/GR080002), European Research Council (340755)), Puerto Rican Alzheimer Disease Initiative (PRADI) (RF1AG054074), Reasons for Geographic and Racial Differences in Stroke (REGARDS) (U01NS041588), Research in African American Alzheimer Disease Initiative (REAAADI) (U01AG052410), Rush Alzheimer's Disease Center (ROSMAP) (P30AG10161, P30AG72975, R01AG15819, R01AG17919, U01AG46152, U01AG61356), University of Miami Brain Endowment Bank (MBB), and University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT) (U01AG052410, R01AG028786). The four LSACs are: the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), The American Genome Center at the Uniformed Services University of the Health Sciences (U01AG057659), and the Washington University Genome Institute (U54HG003079). 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 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. 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 Programme - Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steierm\u00E4rkische 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 is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 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 \u201CQuality of Life and Management of the Living Resources\u201D 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 manuscripts 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 Alzheimer's Disease Sequencing Project (ADSP) is comprised of 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. 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 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 grants the National Institute on Aging R56AG057191 , R01AG057187 , R21AG061551 , R01AG054060 , and the UK-ADC P30AG072946 . 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 NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).
| Funders | Funder number |
|---|---|
| Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer | |
| Alzheimer's Disease Research Center, University of Pittsburgh | |
| Alzheimer's Association | |
| Texas Alzheimer's Research and Care Consortium | |
| Medizinische Universität Graz | |
| Medical Research Council | |
| Erasmus Universiteit Rotterdam | |
| Ministry of Science, ICT and Future Planning | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Multi-Institutional Research in Alzheimer's Genetic Epidemiology | |
| Membership of the Alzheimer's Disease Genetics Consortium is provided in the Acknowledgments | |
| Toronto Western Hospital University of Toronto | |
| National Human Genome Research Institute | |
| University of Utah Gastroenterology Division in the Department of Internal Medicine | |
| Research Institute for Diseases in the Elderly | |
| EU Joint Programme – Neurodegenerative Disease Research | |
| Banner Sun Health Research Institute | |
| Netherlands Genomics Initiative | |
| National Institutes of Health (NIH) | |
| European Commission | |
| Wellcome Trust | |
| Russian Foundation for Basic Research | |
| Prospective Dementia Registry-Austria | |
| VAN | |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Steiermärkische Krankenanstalten Gesellschaft | |
| University of Washington Families | |
| Vanderbilt University/Case Western Reserve University | |
| Erasmus Rucphen Family Study | |
| International Alzheimer's Disease | |
| Seventh Framework Programme | |
| ZonMw Memorabel | |
| U.S. National Library of Medicine | |
| Center for Neurodegenerative Disease Research | |
| Darrell K Royal Texas Alzheimer's Initiative | |
| Uniformed Services University of the Health Sciences | |
| UK-ADC | |
| U.S. Department of Health and Human Services | |
| RIDE2 | |
| EUROSPAN | |
| Hussman Institute for Human Genomics Brain Bank | |
| NIA/NIH | |
| Amish Protective Variant Study | |
| National Alzheimer's Coordinating Center | |
| Research in African American Alzheimer Disease Initiative | |
| American Genome Center | |
| Ministerie van Onderwijs, Cultuur en Wetenschap | |
| Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center | |
| University of Miami/Case Western/North Carolina A&T African American | |
| Miami Clinical and Translational Science Institute, University of Miami | AG027944, A2011048, IIRG09133827, AG021547, R01 AG019085, R01 AG027944, R01 AG09029, AG010491, AG019757, R01 AG025259, R01 AG028786 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01AG20098, R01AG023629, AG033040, N01-HC-25195, R01NS069719, AG049607, R01 NS017950, R01s AG054076, R01AG15928 |
| National Institute on Aging | R01AG057187, R01AG054060, AG033193, R56AG057191, U01 AG032984, R21AG061551 |
| ADGC | RC2 AG036528, U01 AG032984 |
| CubanAmerican Alzheimer's Disease Initiative | 3U01AG052410 |
| University of California San Diego Health | P50 AG023501, P01 AG019724, P50 AG005131 |
| University of Alabama | P50 AG016582 |
| The Pennsylvania State University | U24-AG041689-01, U24 AG026395, U01AG016976 |
| National Cell Repository for Alzheimer's Disease | U24 AG21886 |
| National Heart, Lung, and Blood Institute (NHLBI) | 2U01HL096899, RC2HL102419, U01 2U01HL096812, HHSN268201100008C, 2U01HL096814, 2U01HL096902, 2U01HL096917, HL105756 |
| The George Washington University | P30 AG062677, P50 AG005681, P30 AG066514, P30 AG066515, P30 AG066518, P30 AG066519, P30 AG062715, P20 AG068053, P30 AG072931, P30 AG072975, P30 AG066462, P30 AG072976, P20 AG068077, P30 AG072977, P30 AG066444, P30 AG072972, P30 AG066468, P30 AG072973, P30 AG072978, P30 AG072979, P30 AG072958, P30AG072946, P30 AG072959, P30 AG062421, P30 AG079280, P30 AG062422, P30 AG066546, P30 AG066506, P01 AG03991, P30 AG066507, P30 AG062429, P30 AG066508, P30 AG066509, P30 AG066530, P20 AG068082, P30 AG066511, P30 AG066512, U24 AG072122, P20 AG068024, P30 AG072947 |
| National Institutes of Health (NIH) | RF1AG054074, RF1AG058066, U01AG058635, U01AG062943, U01AG057659, R01AG048927, UF1AG047133, U01 AG052409, RF1AG057519, U01AG049508, U01AG049505, U01AG049506, U01AG049507, U24 AG072122, U01 HG008657, U54AG052427, U01AG052411, U01AG058654, U01AG058589, U01AG052410 |
| Boston University School of Public Health/Boston University Medical Campus | P30 AG013846, U01 AG10483, R01 MH080295, R01AG33193, R01 AG017173, R01 CA129769 |
| Oesterreichische Nationalbank | 2U01HL096899, U01 2U01HL096812, 2U01HL096814, 2U01HL096902, 2U01HL096917, HHSN268201100006C, HHSN268201100005C, HHSN268201100008C, HHSN268201100007C, HHSN268201100009C, 15435, HHSN268201100011C, HHSN268201100010C, HHSN268201100012C |
| EFIGA | RF1 AG015473 |
| University of Texas Southwestern Medical Center | P30 AG012300 |
| Icahn School of Medicine at Mount Sinai | P01 AG002219, P50 AG005138 |
| Washington University Genome Institute | U24AG021886, U54HG003079 |
| University of Southern Indiana | P30 AG10133 |
| University of Kentucky | P30 AG028383, AG05144 |
| National Institute on Aging Late Onset Alzheimer's Disease Family Study | R01 AG15819, P30 AG10161 |
| Broad Institute Genome Center | U54HG003067 |
| University Research Committee, Emory University | AG025688 |
| York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York | UL1 RR029893, P30 AG08051, 1RC2AG036502, 5R01AG012101, 5R01AG022374, 1R01AG035137, 5R01AG013616 |
| Case Western Reserve University | R01 AG021547, RF1AG058267, R01 AG019757, P01 NS026630, NU38CK000480 |
| Baylor College of Medicine | U54 HG003273 |
| Washington Heights-Inwood Columbia Aging Project | RF1 AG054023 |
| Oregon Health and Science University | R01 AG026916, P30 AG008017 |
| Among African Americans Study | 2R01AG048927, 2R01AG09029 |
| University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh | AG02365, AG041718, AG030653, P50 AG005133, AG07562 |
| University of California Irvine | P50 AG016573 |
| Mayo Clinic Rochester | 5RC2HG005605, P50 AG016574, NS039764, NS071674, R01 NS080820, U01 AG046139, RF1 AG051504, R01 AG032990 |
| Austrian Science Fund/FWF | P20545-P05, I904, P13180 |
| Canadian Institutes of Health Research | RC2HL102419, AG033193, R01 AG007584 |
| Northern Manhattan Study | R01NS29993 |
| Cache County Study | RF1AG054052, R01AG21136, R01AG11380, R01AG031272 |
| The Johns Hopkins University | R01 AG020688, P50 AG005146 |
| Cohorts for Heart and Aging Research in Genomic | R01 AG033193 |
| Sixth Framework Programme | 018947, LSHG-CT-2006-01947 |
| NWO-RFBR | 047.017.043 |
| Netherlands Consortium for Healthy Aging | 050-060-810 |
| Columbia University | P50 AG008702, R37 AG015473 |
| Michigan Retirement Research Center, University of Michigan | P30 AG010124, P50 AG008671 |
| Chicago Health and Aging Project | R01 AG11101, R01 AG009956, R01 AG17917, RC4 AG039085, K23 AG030944 |
| Gwangju Alzheimer's and Related Dementias Study | U01AG062602 |
| Rush University | R01 AG30146, R01 NS059873 |
| National Institute on Deafness and Other Communication Disorders | N01HC85081, U01HL080295, N01HC85082, N01HC85080, N01HC85086, N01HC85083, R01-HL70825, N01HC85079, HHSN268200800007C, U01HL130114, N01HC55222 |
| Alzheimer's Disease Centers | P30 AG019610, P30 AG010133, P50 AG047270, P50 AG025688, P30 AG035982, P30 AG010161, P30 AG008051, P50 AG047366, P50 AG047266 |
| Peru Alzheimer's Disease Initiative | GR066133/GR080002, PR1066 |
| Estudio Familiar de Influencia Genetica en Alzheimer | R56AG051876, 5R37AG015473 |
| U.S. Department of Veterans Affairs | R01 AG041797, P50 AG005136 |
| University of Southern California | P50 AG005142 |
| H2020 European Research Council | 340755 |
| Erasmus Medisch Centrum | 014-93-015 |
| National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site | U24AG041689 |
| University of California, Los Angeles | P50 AG016570 |
| Seventh Framework Programme | HEALTH-F4- 2007-201413 |
| University of California Davis | P30 AG010129 |
| Netherlands Organization of Scientific Research NWO | 175.010.2005.011, 911-03-012 |
| Duke-Kunshan University | AG05128, P30 AG028377 |
| ROSMAP | P30AG72975, U01AG61356, U01AG46152, R01AG17919 |
| Quality of Life and Management of the Living Resources” of 5th Framework Programme | QLG2-CT-2002- 01254 |
| University of Wisconsin-Madison | P50 AG033514 |
| University of Northern Arizona | R01 AG031581 |
| Österreichische Forschungsförderungsgesellschaft | 827462 |
| Group Health Research Institute | UO1 AG006781, UO1 HG006375, UO1 HG004610 |
| Ibadan Study of Aging | 5R01AG009956 |
| Mexican Health and Aging Study | R01AG018016 |
| Massachusetts General Hospital | P50 AG005134 |
| Case Western Reserve University Brain Bank | P50AG008012 |
| DoD Alzheimer's Disease Neuroimaging Initiative | U19AG024904 |
| Puerto Rican Alzheimer Disease Initiative | U01NS041588 |
| Northwestern Polytechnical University | P30 AG013854 |
Keywords
- ABCA7
- APH1B
- Hippocampal sclerosis
- NACC
- PLCG2
- Pleiotropy
- SNP
- TDP-43
ASJC Scopus subject areas
- Neurology