Abstract
Introduction Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. Methods We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. Results Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. Discussion We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.
| Original language | English |
|---|---|
| Pages (from-to) | 121-129 |
| Number of pages | 9 |
| Journal | Alzheimer's and Dementia |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2016 |
Bibliographical note
Publisher Copyright:© 2016 The Alzheimer's Association.
Funding
The authors thank the participants and staff of the many centers that were involved in data collection for their important contributions to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. This work was supported by grants from NIH (R01AG11380, R01AG21136, R01AG31272, R01AG042611, and R01 AG 042437), the Alzheimer''s Association (MNIRG-11- 205368), the Utah Science, Technology, and Research Initiative, the Utah State University Agricultural Experiment Station, the McMillan Family Trust, and the Brigham Young University Gerontology Program. The National Institutes of Health, National Institute on Aging (NIH-NIA) also supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; NIAGADS U24 AG041689; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, and R01AG33193; Columbia University, P50 AG008702, and R37 AG015473; Duke University, P30 AG028377 and AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146 and R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138 and P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, and 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017 and R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, and R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582 and UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501 and P01 AG019724; University of Kentucky, P30 AG028383 and AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, and AG02365; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, and AG019757; University ofWashington, P50 AG005136; University ofWisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681 and P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by National Institute of Neurological Disorders and Stroke grant # NS39764, National Institute of Mental Health MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by National Institute on Aging grant AG041232 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 Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Company, Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer''s Association, Alzheimer''s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and National Institute on Aging grants U01 AG024904, RC2 AG036535, and K01 AG030514. P.G.R. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institutes of Health Research. 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. Whole-genome 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: Alzheimer''s Association; Alzheimer''s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol- Myers Squibb Company; 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.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; 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 Rev December 5, 2013 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 Neuroimaging at the University of Southern California. The authors further acknowledge Dr. Donald Lehmann and Dr. Mario Cortina-Borja for their kind help with the synergy factor analyses. This study was made possible by the Texas Alzheimer''s Research and Care Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer''s Disease and Related Disorders. Investigators from TARCC include Baylor College of Medicine: Rachelle Doody, Mimi M. Dang, Valory Pavlik, Wen Chan, Paul Massman, Eveleen Darby, Monica Rodriguear, and Aisha Khaleeq; Texas Tech University Health Sciences Center: Chuang-Kuo Wu, Matthew Lambert, Victoria Perez, and Michelle Hernandez; University of North Texas Health Science Center: Thomas Fairchild, Janice Knebl, Sid E. O''Bryant, James R. Hall, Leigh Johnson, Robert C. Barber, Douglas Mains, Lisa Alvarez, and Rosemary McCallum; University of Texas Southwestern Medical Center: Perrie Adams, Munro Cullum, Roger Rosenberg, Benjamin Williams, Mary Quiceno, Joan Reisch, Ryan Huebinger, Natalie Martinez, and Janet Smith; University of Texas Health Science Center-San Antonio: Donald Royall, Raymond Palmer, and Marsha Polk; Texas A&M University Health Science Center: Farida Sohrabji, Steve Balsis, and Rajesh Miranda; Essentia Institute of Rural Health: Stephen C. Waring; University of North Carolina: Kirk C. Wilhelmsen, Jeffrey L. Tilson, and Scott Chasse. This study was made possible by the Texas Alzheimer's Research and Care Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders . Investigators from TARCC include Baylor College of Medicine: Rachelle Doody, Mimi M. Dang, Valory Pavlik, Wen Chan, Paul Massman, Eveleen Darby, Monica Rodriguear, and Aisha Khaleeq; Texas Tech University Health Sciences Center: Chuang-Kuo Wu, Matthew Lambert, Victoria Perez, and Michelle Hernandez; University of North Texas Health Science Center: Thomas Fairchild, Janice Knebl, Sid E. O'Bryant, James R. Hall, Leigh Johnson, Robert C. Barber, Douglas Mains, Lisa Alvarez, and Rosemary McCallum; University of Texas Southwestern Medical Center: Perrie Adams, Munro Cullum, Roger Rosenberg, Benjamin Williams, Mary Quiceno, Joan Reisch, Ryan Huebinger, Natalie Martinez, and Janet Smith; University of Texas Health Science Center\u2013San Antonio: Donald Royall, Raymond Palmer, and Marsha Polk; Texas A&M University Health Science Center: Farida Sohrabji, Steve Balsis, and Rajesh Miranda; Essentia Institute of Rural Health: Stephen C. Waring; University of North Carolina: Kirk C. Wilhelmsen, Jeffrey L. Tilson, and Scott Chasse. 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 . This work was supported by grants from NIH ( R01AG11380 , R01AG21136 , R01AG31272 , R01AG042611 , and R01 AG 042437 ), the Alzheimer's Association ( MNIRG-11-205368 ), the Utah Science, Technology, and Research Initiative , the Utah State University Agricultural Experiment Station , the McMillan Family Trust , and the Brigham Young University Gerontology Program . Whole-genome 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: Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen Idec Inc. ; Bristol-Myers Squibb Company ; 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. ; Medpace, Inc. ; Merck & Co., Inc. ; Meso Scale Diagnostics, LLC. ; NeuroRx Research ; Neurotrack Technologies ; 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 Rev December 5, 2013 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 Neuroimaging at the University of Southern California.
| Funders | Funder number |
|---|---|
| Johnson and Johnson Pharmaceutical Research and Development | |
| Northern California Institute for Research and Education | |
| GE Healthcare | |
| Texas Alzheimer's Research and Care Consortium | |
| Biomedical Laboratory Research Program | |
| North Bristol NHS Trust Research and Innovation Department and DeNDRoN | |
| Merck | |
| Banner Alzheimer’s Foundation | |
| Coins for Alzheimer's Research Trust | |
| Bayer Schering | |
| Medical Research Council-São Paulo Research Foundation | |
| Marsha Polk | |
| Netherlands Brain Bank | |
| Lance Armstrong Foundation | |
| Leigh Johnson | |
| Internationale Stichting Alzheimer Onderzoek | |
| Texas Alzheimer''s Research and Care Consortium | |
| Schering Plough Co | |
| Hersenstichting Nederland Breinbrekend Werk | |
| Alzheimer''s Association, Alzheimer''s Drug Discovery Foundation | |
| Newcastle Brain Tissue Resource | |
| Synarc, Inc. | |
| Janssen Alzheimer Immunotherapy Research and Development | |
| Utah Science Technology and Research | |
| Institut de Neuropatologia | |
| National Institute of Biomedical Imaging and Bioengineering | |
| Higher Education Funding Council for England | |
| Charles A Dana Foundation | |
| Takeda Pharmaceutical Company Limited | |
| Bristol Myers Squibb Company | |
| South West Dementia Brain Bank | |
| Eli Lilly and Company | |
| BRACE | |
| IXICO plc | |
| University of North Texas Health Science Center | |
| Fujirebio Inc. | |
| Wellcome Trust | |
| Abbott Laboratories | |
| Medpace, Inc. | |
| F. Hoffmann-La Roche AG | |
| Biomedical Laboratory Research and Development, VA Office of Research and Development | |
| Merck & Co., Inc. | |
| Brigham Young University–Hawaii | |
| Novartis | |
| Eisai Global Clinical Development | |
| Stichting Vanderes | |
| Astrobiology Research Trust | |
| Universitat de Barcelona | |
| Eaton Corporation | |
| DoD Alzheimer's Disease Neuroimaging Initiative | |
| Baylor College of Medicine | |
| Bristol-Myers Squibb | |
| GlaxoSmithKline | |
| Newcastle University | |
| Texas Council on Alzheimer's Disease and Related Disorders | |
| Eisai Incorporated | |
| Utah Agricultural Experiment Station | |
| McMillan Family Trust | |
| DoD Alzheimer's Disease Neuroimaging Initiative | |
| US Department of Veterans Affairs Administration | |
| Araclon Biotech | |
| DOD ADNI | |
| MRC London Brain Bank for Neurodegenerative Diseases | |
| Pfizer | |
| NIA/NIH | |
| International Parkinson Fonds | |
| AstraZeneca | |
| Genentech Incorporated | |
| Johnson and Johnson Pharmaceutical Research and Development | |
| Alzheimer's Drug Discovery Foundation | |
| Texas Council on Alzheimer''s Disease and Related Disorders | |
| Innogenetics | |
| Howard Hughes Medical Institute | |
| Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center | |
| National Institute on Aging | P50AG005144, R01AG033193, P50AG005146, RC2AG036535, P50AG005142, R01AG035137, U19AG010483, U24AG021886, R01AG019085, R01AG025259, U01AG016976, R01AG021136, P01AG010491, R01AG013616, R01AG042437, P50AG005133, RC2AG036528, R01AG012101, P50AG005134, U19AG024904, K01AG030514, P30AG013854, P30AG028383, R01AG027944, U24AG056270, P50AG016582, P50AG005136, P50AG025688, R01AG022374, P50AG005138, P50AG023501, R01AG041232, R01AG041797, R01AG021547, P50AG005681, P50AG008671, P30AG028377, R37AG015473, R01AG041718, R01AG026916, R01AG030146, P01AG019724, R01AG031272, R01AG011380, U01AG006781, P50AG033514, P50AG016573, P50AG016574, P30AG010133, P30AG013846, R01AG030653, P50AG016570, R01AG017917, P01AG002219, R01AG007562, R01AG015819, U01AG032984, R01AG042611, RC2AG036502, R01AG026390, R01AG019757, R01AG020688, R01AG031581, P30AG008017, U24AG026395, P30AG010124, P30AG012300, U24AG041689, P30AG010161, P01AG003991, U01AG017173, P30AG019610, P30AG010129, P30AG008051, P50AG008702 |
| National Center for Research Resources | M01RR000096, UL1RR029893 |
| NCRAD | U24 AG021886, U24 AG026395, U24 AG026390 |
| University of Texas Southwestern Medical Center | P30 AG012300 |
| National Institutes of Health (NIH) | MNIRG-11- 205368 |
| University of Southern Indiana | P30 AG10133 |
| National Human Genome Research Institute | U01HG006375, U01HG004610 |
| Rush University | R01 AG15819, R01 AG30146, R01 NS059873, P30 AG010161, R01 AG17917, R01 AG019085 |
| University of California Irvine | P50 AG016577, P50 AG016576, P50 AG016575, P50 AG016573 |
| Banner Sun Health Research Institute | P30 AG019610 |
| NIAGADS | U24 AG041689 |
| Kronos Science | AG041232 |
| Icahn School of Medicine at Mount Sinai | P01 AG002219, P50 AG005138 |
| Boston University School of Public Health/Boston University Medical Campus | P30 AG013846, U01 AG10483, R01 MH080295, R01AG33193, R01 AG017173, R01 AG025259, R01 CA129769 |
| U.S. Department of Defense | W81XWH-12-2-0012 |
| Miami Clinical and Translational Science Institute, University of Miami | AG027944, AG021547, R01 AG027944, AG019757, AG010491 |
| University of California Davis | P30 AG010129 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01NS059873, P50NS039764 |
| The George Washington University | P50 AG005681, P01 AG03991 |
| ADGC | RC2 AG036528, U01 AG032984 |
| University of Kentucky | P30 AG028383, AG05144 |
| National Association for Colitis and Crohn's Disease | U01 AG016976 |
| University of Southern California | P50 AG005142 |
| National Institute of Mental Health | P50MH060451, R01MH080295 |
| Group Health Research Institute | UO1 AG006781, UO1 HG006375, UO1 HG004610 |
| York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York | UL1 RR029893, P30 AG08051, 1RC2AG036502, 5R01AG012101, MO1RR00096, 5R01AG022374, 1R01AG035137, 5R01AG013616 |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR001445 |
| Canadian Institutes of Health Research | IIRG-05-14147, IIRG-08-89720 |
| Univ. of Northern British Columbia | P50 AG008702, R37 AG015473 |
| The Johns Hopkins University | R01 AG020688, P50 AG005146 |
| University of California, Los Angeles | P50 AG016570 |
| University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh | AG02365, AG041718, AG030653, P50 AG005133, AG07562 |
| Mayo Clinic Rochester | P50 AG016574 |
| University Research Committee, Emory University | AG025688 |
| Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment | MNIRG-11-205368 |
| University of California San Diego Health | P50 AG023501, P01 AG019724, P50 AG005131 |
| University of Northern Arizona | R01 AG031581 |
| Massachusetts General Hospital | P50 AG005134 |
| Duke-Kunshan University | AG05128, P30 AG028377 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA129769 |
| University ofWashington, University of Wisconsin | P50 AG033514, P50 AG005136 |
| University of Alabama | UL1RR02777, P50 AG016582 |
| Michigan Retirement Research Center, University of Michigan | P50 AG008671 |
| Northwestern Polytechnical University | P30 AG013854 |
| The Pennsylvania State University | P30 AG010124 |
| Oregon Health and Science University | P30 AG008017, R01 AG026916 |
Keywords
- ADGC
- ADNI
- Alzheimer's disease
- CD33
- CLU
- Epistasis
- MS4A4E
- Meta-analysis
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
