Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset
Por:
Homann, J, Osburg, T, Ohlei, O, Dobricic, V, Deecke, L, Bos, I, Vandenberghe, R, Gabel, S, Scheltens, P, Teunissen, CE, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Lleo, A, Alcolea, D, Popp, J, Clark, C, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, Wittig, M, Franke, A, Lill, CM, Blennow, K, Zetterberg, H, Lovestone, S, Streffer, J, ten Kate, M, Vos, SJB, Barkhof, F, Visser, PJ, Bertram, L
Publicada:
21 mar 2022
Resumen:
Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.
Filiaciones:
Homann, J:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Osburg, T:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Ohlei, O:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Dobricic, V:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Deecke, L:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Bos, I:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Vrije Univ Amsterdam, Amsterdam Neurosci, Amsterdam Univ Med Ctr, Dept Neurol,Alzheimer Ctr Amsterdam, Amsterdam, Netherlands
Vandenberghe, R:
Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium
Univ Hosp Leuven, Neurol Serv, Leuven, Belgium
Gabel, S:
Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium
Scheltens, P:
Vrije Univ Amsterdam, Amsterdam Neurosci, Amsterdam Univ Med Ctr, Dept Neurol,Alzheimer Ctr Amsterdam, Amsterdam, Netherlands
Teunissen, CE:
Vrije Univ, Amsterdam Univ Med Ctr, Amsterdam Neurosci, Neurochem Lab,Dept Clin Chem, Amsterdam, Netherlands
Engelborghs, S:
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Univ Ziekenhuis Brussel, Dept Neurol, Brussels, Belgium
Univ Ziekenhuis Brussel, Ctr Neurosci, Brussels, Belgium
Vrije Univ Brussel VUB, Brussels, Belgium
Frisoni, G:
Univ Geneva, Dept Psychiat, Geneva, Switzerland
IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, Brescia, Italy
Blin, O:
AIX Marseille Univ, Inst Neurosci Timone, Marseille, France
Richardson, JC:
GlaxoSmithKline R&D, Neurosci Therapeut Area, Stevenage, Herts, England
Bordet, R:
Univ Lille, Lille Neurosci & Cognit, INSERM, CHU Lille, Lille, France
Lleo, A:
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Alcolea, D:
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Popp, J:
Univ Hosp Psychiat Zurich, Dept Geriatr Psychiat, Zurich, Switzerland
Univ Hosp Lausanne, Dept Psychiat, Old Age Psychiat, Lausanne, Switzerland
Clark, C:
Univ Hosp Psychiat Zurich, Dept Geriatr Psychiat, Zurich, Switzerland
Peyratout, G:
Univ Hosp Lausanne, Dept Psychiat, Old Age Psychiat, Lausanne, Switzerland
Martinez-Lage, P:
CITA Alzheimer Fdn, Ctr Res & Adv Therapies, Dept Neurol, Donostia San Sebastian, Spain
Tainta, M:
CITA Alzheimer Fdn, Ctr Res & Adv Therapies, Dept Neurol, Donostia San Sebastian, Spain
Dobson, RJB:
Kings Coll London, Inst Psychiat Psychol & Neurosci IoPPN, Dept Biostat & Hlth Informat, London, England
South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr, London, England
Kings Coll London, London, England
UCL, Hlth Data Res UK London, London, England
UCL, Inst Hlth Informat, London, England
Univ Coll London Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London, England
Legido-Quigley, C:
Steno Diabet Ctr, Copenhagen, Denmark
Kings Coll London, Inst Pharmaceut Sci, London, England
Sleegers, K:
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
VIB, Ctr Mol Neurol, Complex Genet Alzheimers Dis Grp, Antwerp, Belgium
Van Broeckhoven, C:
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium
Wittig, M:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Franke, A:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Lill, CM:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Imperial Coll London, Sch Publ Hlth, Ageing Epidemiol Res Unit, London, England
Blennow, K:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Zetterberg, H:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
UCL, Dept Neurodegenerat Dis, Queen Sq Inst Neurol, Queen Sq, London, England
UCL, UK Dementia Res Inst, London, England
Lovestone, S:
Univ Oxford, Dept Psychiat, Oxford, England
Streffer, J:
Univ Antwerp, Inst Born Bunge, Reference Ctr Biol Markers Dementia BIODEM, Antwerp, Belgium
Janssen R&D LLC, Beerse, Belgium
AC Immune SA, EPFL Innovat Pk, Lausanne, Switzerland
ten Kate, M:
Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium
Univ Amsterdam, Med Ctr, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam, Netherlands
Vos, SJB:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Barkhof, F:
Univ Amsterdam, Med Ctr, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam, Netherlands
UCL, Inst Neurol, London, England
UCL, Inst Healthcare Engn, London, England
Visser, PJ:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium
Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
Bertram, L:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Oslo, Dept Psychol, Oslo, Norway
Green Published, gold
|