Abstract
APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 108-117 |
| Number of pages | 10 |
| Journal | Molecular Psychiatry |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
Funding
The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIAGADS, U24-AG041689; NIA LOAD, U24 AG026395, U24 AG026390; MIRAGE: R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; U01 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, MO1RR00096, and UL1 RR029893; 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, 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, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; 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; 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 no. 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 AG034504 to AJM, The Banner Alzheimer\u2019s Foundation, The Johnnie B. Byrd Sr. Alzheimer\u2019s 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),SouthWest Dementia Brain Bank (funding via numerous sources, including the Higher Education Funding Council for England (HEFCE), Alzheimer\u2019s 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. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. 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, Medpace, Merck, Novartis AG, Pfizer, F Homan-La Roche, Schering-Plough, Synarc, Alzheimer\u2019s Association, Alzheimer\u2019s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank Dr D Stephen Snyder and Dr Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer\u2019s 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 the Wellcome Trust, Howard Hughes Medical Institute, and Canadian Institute of Health. CHARGE AGES: The AGES-Reykjavik Study is funded by NIH contract N01-AG-12100 (NIA with contributions from the NEI, NIDCD and NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative\u2013Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center and the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). Celine Bellenguez received personal fees from Genoscrenn unrelated to current study. HS reports grants from Austrian Science Fond (FWF) and \u00D6sterreichische Nationalbank Anniversary Fund during the conduct of the study. FP reports grants from DISTALZ Labex of Excellence (ANR). NF reports payment from Janessen Alzheimer\u2019s Immunotherapty and Pfizer to University College London for contracted image analyses and payment from Bristol Myers Squibb, Eli Lilly, GE Healthcare, Novartis and Sanofi to University College London for consultant services. JH received personal fees from Eisai, Eli Lilly and Roche, outside the current study. AMG received grants from NIA, Genentech, Pfizer and Astra Zeneca, as well as personal fees from Finnegan HC, Cognition Therapeutics, Dickstein Shapiro, Genentech and Amgen, all unrelated to the current study. In addition, AMG has a patent (US20070258898) issued and a patent with royalties paid by Taconic. WM received grants from Eli Lilly and Lundbeck. J-FD received grants and personal fees from IPSEN and Novartis and personal fees from Newron. HH reports personal fees and non-financial support from Boehringer-Ingelheim, Bristol-Myers-Squibb, Elan Corporation, Novartis, Eisai Inc., Pfizer, Sanofi-Aventis, Roche Pharmaceutical Diagnostics, GlaxoSmithKline-Biologicals, Jung-Diagnostics, Avid, Eli Lilly and Cytox and personal fees from GE Healthcare. In addition, HH has pending patents entitled \u2018Method for predicting whether subjects with mild cognitive impairment (MCI) will develop Alzheimer's disease\u2019, \u20183-Hydroxykynurenin im Serum als diagnostischer Marker fUr die Demenz vom Alzheimer-Typ\u2019, \u2018Neurodegenerative markers for psychiatric conditions\u2019, \u2018Ratio A ~ 2/40 im Plasma in der Fruh-und Differentialdiagnose der Alzheimer Krankheit\u2019, Liquordiagnostisches in vitro Verfahren zur Diagnose von Demenz-ErkrankUngen und neuroinfJammatorischen Erkrankungen\u2019, \u2018In vitro Verfahren zur Diagnose von neurodegenerativen Erkrankungen\u2019 and \u2018In vitro Verfahren zur Diagnose und Fruhdiagnose von neurodegenerativen Erkrankungen\u2019. EBL received personal fees from Up to Date unrelated to the current study. MO received research grants from the Medical Research Council during the course of, but unrelated to, the current study. EMR received personal fees from AstraZeneca, CereSpir, Eisai, Eli Lilly, GlaxoSmithKline and Sanofi and research contracts from Avid/Eli Lilly and Genetech, all unrelated to the current study. JW is a full-time employee and shareholder of Pfizer (2012\u2013present) and a former full-time employee of F. Hoffmann-La Roche (2010\u20132012). AW is a full-time employee and shareholder of Pfizer (2013\u2013present). MAP-V received personal fees from Athena Neurosciences unrelated to the current study. The other authors declare no conflict of interest. ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01 HL096917 (Mosley) and R01-HL093029; NHGRI contract U01-HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. EADI This work was supported by the National Foundation for Alzheimer\u2019s disease and related disorders, the Institut Pasteur de Lille and the Centre National de G\u00E9notypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Sant\u00E9 et de la Recherche M\u00E9dicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synth\u00E9labo. The Fondation pour la Recherche M\u00E9dicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salari\u00E9s, Direction G\u00E9n\u00E9rale de la Sant\u00E9, MGEN, Institut de laLong\u00E9vit\u00E9, Agence Fran\u00E7aise de S\u00E9curit\u00E9 Sanitaire des Produits de Sant\u00E9, the Aquitaine and Bourgogne RegionalCouncils, Fondation de France and the joint French Ministry of Research/INSERM \u2018Cohortes et collections de donn\u00E9es biologiques\u2019 programme. Lille G\u00E9nop\u00F4le received an unconditional grant from Eisai. ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria\u2019s Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer\u2019s Research UK (ARUK) and the Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the MRC. ARUK supported sample collections at the South West Dementia Bank and the Universities of Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer\u2019s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL NIHR Department of Neurodegenerative Disease collection was supported by the UCLH/UCL NIHR Biomedical Centre and Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by Lundbeck SA. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia and by the Alfried Krupp von Bohlen und Halbach- Stiftung. The GERAD1 Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Fundaci\u00F3 ACE: would like to thank patients and controls who participated in this project. This work has been funded by the Fundaci\u00F3n Alzheimur (Murcia), the Ministerio de Educaci\u00F3n y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de Espa\u00F1a), Corporaci\u00F3n Tecnol\u00F3gica de Andaluc\u00EDa (08/211) and Agencia IDEA (841318) (Consejer\u00EDa de Innovaci\u00F3n, Junta de Andaluc\u00EDa). We thank Ms Trinitat Port-Carb\u00F3 and her family for their generous support of Fundaci\u00F3 ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Belgium sample collection: Research at the Antwerp site is funded in part by the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research (SAO-FRA), a Methusalem Excellence Grant of the Flemish Government, the Research Foundation Flanders (FWO), the Special Research Fund of the University of Antwerp, Belgium. KB is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Italian sample collections: The Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by a grant from the Italian ministry of Health (RFPS-2006-7-334858) and grant RF-2010-2319722. The Milan site was supported by a grant from the \u2018fondazione Monzino\u2019. We thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr Annalisa LoGerfo for her technical assistance in the DNA purification studies. Erasmus Rucphen Family Study: We thank the participants from the Genetic Research in Isolated Populations in the Erasmus Rucphen Family Study who made this work possible. This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB1 and CMSB2) in the framework of the Netherlands Genomics Initiative (NGI). Spanish sample collection: The Madrid site (MB) was supported by grants of the Ministerio de Educaci\u00F3n y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundaci\u00F3nRam\u00F3n Areces to the CBMSO. We thank I Sastre and Dr A Mart\u00EDnez-Garc\u00EDa for the preparation and control of the DNA collection, and Dr P Gil and Dr P Coria for their cooperation in the cases/ controls recruitment. We are grateful to the Asociaci\u00F3n de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital and the Nordic Centre of Excellence in Neurodegeneration. Cardiovascular Health Study (CHS): This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, R01AG027058 and R01AG033193 (Seshadri) from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute\u2019s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGAII) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Dr Seshadri and Dr DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010.
ASJC Scopus subject areas
- Molecular Biology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health