Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning
Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning
ABSTRACT Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to: 1. identify common genetic variants associated with these CSF profiles; 2. assess the role of associated variants in AD pathophysiology and 3. explore potential sex differences. We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested, whether biomarker PCs mediate SNP risk effects on AD, and stratified and interaction models probed sex-specific effects. Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 and GRIN2D) and three were previously described (APOE, TMEM160B and CHI3L). GRIN2D was associated with synaptic functioning, whereas rs145791381 was associated with biomarker evidence of inflammation. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. The results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
K¨1?¨1kali Fahri、Blennow Kaj、Scheltens Philip、Teunissen Charlotte E、Engelborghs Sebastiaan、Blin Oliver、Richardson Jill C、Bordet R¨|gis、Lle¨? Alberto、Alcolea Daniel、Popp Julius、Peyratout Gwendoline、Tainta Mikel、Legido-Quigley Cristina、Lill Christina M、Visser Pieter Jelle、Ohlei Olena、Bos Isabelle J、Prokopenko Dmitry、Frisoni Giovanni B、Neumann Alexander、Clark Christopher、Kate Mara ten、Andreasson Ulf、Zetterberg Henrik、Barkhof Frederik、Martinez-Lage Pablo、Dobson Richard JB、Vandenberghe Rik、Streffer Johannes、Tijms Betty M、EMIF-AD & ADNI study group、Tanzi Rudolph E、Vos Stephanie、Lovestone Simon、Bertram Lars、Sleegers Kristel、Van Broeckhoven Christine
Complex Genetics of Alzheimer?ˉs Disease Group, VIB Center for Molecular Neurology, VIB||Department of Biomedical Sciences, University of AntwerpDepartment of Psychiatry and Neurochemistry, University of Gothenburg||Clinical Neurochemistry Laboratory, Sahlgrenska University HospitalAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCDepartment of Neurology and Memory Clinic, Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB)||Department of Biomedical Sciences, University of AntwerpClinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital||Department of Biomedical Sciences, University of AntwerpNeurosciences Therapeutic Area, GlaxoSmithKline R&DNeuroscience & Cognition, CHU de Lille, University of LilleMemory Unit, Neurology Department, Hospital de Sant Pau, Barcelona and Centro de Investigaci¨?n Biom¨|dica en Red en enfermedades Neurodegenerativas (CIBERNED)Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona and Centro de Investigaci¨?n Biom¨|dica en Red en enfermedades Neurodegenerativas (CIBERNED)Department of Geriatric Psychiatry, University Hospital of Psychiatry Z¨1richDepartment of Psychiatry, University Hospital of LausanneCenter for Research and Advanced Therapies, CITA?aAlzheimer Foundation||Zumarraga Hospital, Osakidetza, Integrated Health Organization (OSI) Goierri-Urola GariaSteno Diabetes CenterL¨1beck Interdisciplinary Platform for Genome Analytics, University of L¨1beck||Institute of Epidemiology and Social Medicine, University of M¨1nster||Ageing Epidemiology Research Unit, School of Public Health, Imperial CollegeAlzheimer Centrum Limburg, Maastricht University||Alzheimer Center and Department of Neurology, VU University Medical Center||Department of Biomedical Sciences, University of AntwerpL¨1beck Interdisciplinary Platform for Genome Analytics, University of L¨1beckNetherlands Institute for Health Services ResearchGenetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General HospitalMemory Center, Department of Rehabilitation and Geriatrics, Geneva University and University HospitalsComplex Genetics of Alzheimer?ˉs Disease Group, VIB Center for Molecular Neurology, VIB||Department of Biomedical Sciences, University of AntwerpDepartment of Geriatric Psychiatry, University Hospital of Psychiatry Z¨1richAlzheimer Center and Department of Neurology, VU University Medical Center||Department of Radiology and Nuclear Medicine, VU University Medical CenterDepartment of Psychiatry and Neurochemistry, University of Gothenburg||Clinical Neurochemistry Laboratory, Sahlgrenska University HospitalDepartment of Psychiatry and Neurochemistry, University of Gothenburg||Department of Neurodgenerative Disease, UCL Institute of Neurology||Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital||UK Dementia Research Institute, University College London||Hong Kong Center for Neurodegenerative DiseasesDepartment of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit||Queen Square Institute of Neurology and Centre for Medical Image Computing, University College LondonCenter for Research and Advanced Therapies, CITA?aAlzheimer FoundationDepartment of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King?ˉs College London||NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King?ˉs College London||Health Data Research UK London, University College London||Institute of Health Informatics, University College London||The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College LondonLaboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven||Neurology Service, University Hospital LeuvenDepartment of Biomedical Sciences, University of Antwerp||Janssen Medical Ltd||Institute of Pharmaceutical Sciences, King?ˉs College LondonAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCGenetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General HospitalAlzheimer Centrum Limburg, Maastricht UniversityDepartment of Psychiatry, University of OxfordL¨1beck Interdisciplinary Platform for Genome Analytics, University of L¨1beck||Centre for Lifespan Changes in Brain and Cognition, University of OsloComplex Genetics of Alzheimer?ˉs Disease Group, VIB Center for Molecular Neurology, VIB||Department of Biomedical Sciences, University of AntwerpNeurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB||Department of Biomedical Sciences, University of Antwerp
神经病学、精神病学基础医学医学研究方法
K¨1?¨1kali Fahri,Blennow Kaj,Scheltens Philip,Teunissen Charlotte E,Engelborghs Sebastiaan,Blin Oliver,Richardson Jill C,Bordet R¨|gis,Lle¨? Alberto,Alcolea Daniel,Popp Julius,Peyratout Gwendoline,Tainta Mikel,Legido-Quigley Cristina,Lill Christina M,Visser Pieter Jelle,Ohlei Olena,Bos Isabelle J,Prokopenko Dmitry,Frisoni Giovanni B,Neumann Alexander,Clark Christopher,Kate Mara ten,Andreasson Ulf,Zetterberg Henrik,Barkhof Frederik,Martinez-Lage Pablo,Dobson Richard JB,Vandenberghe Rik,Streffer Johannes,Tijms Betty M,EMIF-AD & ADNI study group,Tanzi Rudolph E,Vos Stephanie,Lovestone Simon,Bertram Lars,Sleegers Kristel,Van Broeckhoven Christine.Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning[EB/OL].(2025-03-28)[2025-04-26].https://www.medrxiv.org/content/10.1101/2022.08.02.22278185.点此复制
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