The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization

Roxanna S Korologou-Linden*, Laxmi Bhatta, Ben M Brumpton, Laura D Howe, Louise A C Millard, Katarina Kolaric, Yoav Ben-Shlomo, Dylan M. Williams, George Davey Smith, Emma L Anderson, Evangelia Stergiakouli , Neil M Davies

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.
Original languageEnglish
Article number4726
Number of pages14
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 11 Aug 2022

Bibliographical note

Funding Information:
This work was supported by a BRACE Alzheimer’s charity (BR16/028) grant awarded to E.S., L.D.H., E.L.A., and G.D.S. It is also part of a project entitled ‘social and economic consequences of health: causal inference methods and longitudinal, intergenerational data’, which is part of the Health Foundation’s Social and Economic Value of Health Research Programme (Award 807293). The Health Foundation is an independent charity committed to improving health and health care for people in the UK. R.K.L. was supported by a Wellcome Trust PhD studentship (Grant ref.: 215193/Z18/Z) and previously BRACE Alzheimer’s charity (BR16/028). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC_UU_00011/1]. E.L.A. was funded by a UK Medical Research Council Skills Development Fellowship [MR/P014437/1]. N.M.D. is supported by an Economics and Social Research Council (ESRC) Future Research Leaders grant [ES/N000757/1] and the Norwegian Research Council Grant number 295989. L.D.H. is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). L.A.C.M. is funded by a University of Bristol Vice-Chancellor’s Fellowship. L.B. and B.M.B. receive support from the K.G. Jebsen Center for Genetic Epidemiology funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for education, research, and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The PheWAS analysis was conducted using the UK Biobank Resource under Application Number 16729. The genotyping in HUNT was financed by the National Institute of Health (NIH); University of Michigan; The Research Council of Norway; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The HUNT Study is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. For the follow-up Mendelian randomization analyses, we used output from the MRC IEU UK Biobank GWAS pipeline. The MRC IEU UK Biobank GWAS pipeline was developed by B. Elsworth, R. Mitchell, C. Raistrick, L. Paternoster, G. Hemani, T. Gaunt ( https://doi.org/10.5523/bris.pnoat8cxo0u52p6ynfaekeigi ). The Alzheimer’s GWAS included IGAP, ADSP, and PGC. We acknowledge the members of the Psychiatric Genomics Consortium. 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 the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), funded by the NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to G. Schellenberg, L.A. Farrer, M.A. Pericak-Vance, R. Mayeux, and J.L. Haines); U01AG049505 to S. Seshadri; U01AG049506 to E. Boerwinkle; U01AG049507 to E. Wijsman; and U01AG049508 to A. Goate. Data generation and harmonization in the follow-up Phases is supported by U54AG052427 (to G. Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), the Alzheimer’s Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson’s Disease controls, the University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer’s Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer’s Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGUREA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts with funding provided by 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study which is conducted as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). The 3 LSACs are the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), 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 the 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 the NIA and at the Database for Genotypes and Phenotypes (dbGaP) funded by the NIH. This research was partly supported by the Intramural Research Program of the NIH and the National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by the NIA and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. We also thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips were funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24AG021886, U01AG016976, and the Alzheimer’s Association grant ADGC–10–196728.

Funding Information:
This work was supported by a BRACE Alzheimer’s charity (BR16/028) grant awarded to E.S., L.D.H., E.L.A., and G.D.S. It is also part of a project entitled ‘social and economic consequences of health: causal inference methods and longitudinal, intergenerational data’, which is part of the Health Foundation’s Social and Economic Value of Health Research Programme (Award 807293). The Health Foundation is an independent charity committed to improving health and health care for people in the UK. R.K.L. was supported by a Wellcome Trust PhD studentship (Grant ref.: 215193/Z18/Z) and previously BRACE Alzheimer’s charity (BR16/028). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC_UU_00011/1]. E.L.A. was funded by a UK Medical Research Council Skills Development Fellowship [MR/P014437/1]. N.M.D. is supported by an Economics and Social Research Council (ESRC) Future Research Leaders grant [ES/N000757/1] and the Norwegian Research Council Grant number 295989. L.D.H. is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). L.A.C.M. is funded by a University of Bristol Vice-Chancellor’s Fellowship. L.B. and B.M.B. receive support from the K.G. Jebsen Center for Genetic Epidemiology funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for education, research, and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The PheWAS analysis was conducted using the UK Biobank Resource under Application Number 16729. The genotyping in HUNT was financed by the National Institute of Health (NIH); University of Michigan; The Research Council of Norway; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The HUNT Study is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. For the follow-up Mendelian randomization analyses, we used output from the MRC IEU UK Biobank GWAS pipeline. The MRC IEU UK Biobank GWAS pipeline was developed by B. Elsworth, R. Mitchell, C. Raistrick, L. Paternoster, G. Hemani, T. Gaunt (https://doi.org/10.5523/bris.pnoat8cxo0u52p6ynfaekeigi). The Alzheimer’s GWAS included IGAP, ADSP, and PGC. We acknowledge the members of the Psychiatric Genomics Consortium. 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 the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), funded by the NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to G. Schellenberg, L.A. Farrer, M.A. Pericak-Vance, R. Mayeux, and J.L. Haines); U01AG049505 to S. Seshadri; U01AG049506 to E. Boerwinkle; U01AG049507 to E. Wijsman; and U01AG049508 to A. Goate. Data generation and harmonization in the follow-up Phases is supported by U54AG052427 (to G. Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), the Alzheimer’s Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson’s Disease controls, the University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer’s Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer’s Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGUREA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts with funding provided by 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study which is conducted as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). The 3 LSACs are the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), 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 the 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 the NIA and at the Database for Genotypes and Phenotypes (dbGaP) funded by the NIH. This research was partly supported by the Intramural Research Program of the NIH and the National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by the NIA and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. We also thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips were funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24AG021886, U01AG016976, and the Alzheimer’s Association grant ADGC–10–196728.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Cognitive ageing
  • Diseases of the nervous system
  • Genetic variation

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