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1. Cerebral white matter hyperintensities indicate severity and progression of coronary artery calcification

Author

Markus Kneihsl, Thomas Gattringer, Edith Hofer, Peter P. Rainer, Gerhard Ranner, Simon Fandler-Höfler, Melanie Haidegger, Sabine Perl, Christian Enzinger, and Reinhold Schmidt

Subjects
Coronary artery calcification, White matter hyperintensities, Cerebral small vessel disease, Aging, Medicine, Science
Abstract

Abstract Cerebral white matter hyperintensities (WMH) have been associated with subclinical atherosclerosis including coronary artery calcification (CAC). However, previous studies on this association are limited by only cross-sectional analysis. We aimed to explore the relationship between WMH and CAC in elderly individuals both cross-sectionally and longitudinally. The study population consisted of elderly stroke- and dementia-free participants from the community-based Austrian Stroke Prevention Family Study (ASPFS). WMH volume and CAC levels (via Agatston score) were analyzed at baseline and after a 6-year follow-up period. Of 324 study participants (median age: 68 years), 115 underwent follow-up. Baseline WMH volume (median: 4.1 cm3) positively correlated with baseline CAC levels in multivariable analysis correcting for common vascular risk factors (p = 0.010). While baseline CAC levels were not predictive for WMH progression (p = 0.447), baseline WMH volume was associated CAC progression (median Agatston score progression: 27) in multivariable analysis (ß = 66.3 ± 22.3 [per cm3], p = 0.004). Ten of 11 participants (91%) with severe WMH (Fazekas Scale: 3) at baseline showed significant CAC progression > 100 during follow-up. In this community-based cohort of elderly individuals, WMH were associated with CAC and predictive of its progression over a 6-year follow-up. Screening for coronary artery disease might be considered in people with more severe WMH.

Published
2024
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2. The relationship between plasma free fatty acids, cognitive function and structural integrity of the brain in middle-aged healthy humans

Author

Markus Herrmann, Sebastian Simstich, Eva Fritz-Petrin, Reinhold Schmidt, Edith Hofer, Günter Fauler, and Wolfgang Herrmann

Subjects
Male, medicine.medical_specialty, NCI-GC-MS, Aging, Linoleic acid, Fatty Acids, Nonesterified, Temporal lobe, memory, chemistry.chemical_compound, Atrophy, Cognition, Internal medicine, Fatty Acids, Omega-6, Fatty Acids, Omega-3, Medicine, Aging brain, Dementia, Humans, Prospective Studies, Stroke, cognitive function, Aged, Retrospective Studies, chemistry.chemical_classification, business.industry, PFBBr, Brain, free fatty acids, Cell Biology, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Endocrinology, chemistry, Female, business, Polyunsaturated fatty acid, Research Paper
Abstract

Background: The cerebral composition of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) is believed to influence cognitive function and structural damage of the aging brain. However, existing data is inconsistent. Materials and Methods: This retrospective study explored the association between free plasma PUFA concentrations, cognitive function and brain structure atrophy in a well-characterized community-dwelling cohort of elderly individuals without stroke and dementia. Ten different fatty acids were analyzed in stored plasma samples from 391 non-demented elderly individuals by gas chromatography mass spectrometry. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in a subset of 167 individuals. Results: Higher plasma concentrations of free ω-6 PUFAs (p = 0.042), and, in particular, linoleic acid (p = 0.01), were significantly associated with lower executive function. No significant association existed between ω-3 PUFA concentrations and cognitive functioning. The volume of the frontal lobes was inversely associated with ω-6 PUFAs, whereas ω-3 PUFAs were positively related with temporal lobe volumes. All associations did not withstand correction for multiple comparisons. Conclusions: Our study suggests subtle effects of PUFA imbalances on cognition and brain structure. Yet the observed associations are weak and unlikely to be of clinical relevance. The brain regions that seem to be most sensitive to imbalances of ω-3 and ω-6 PUFAs are the frontal and temporal lobes.

Published
2021

3. Prediction of dementia using diffusion tensor MRI measures: the OPTIMAL collaboration

Author

D Tozer, Lukas Pirpamer, Edith Hofer, Saima Hilal, Marco Duering, Robin G. Morris, Reinhold Schmidt, Hugh S. Markus, Anil M. Tuladhar, Christopher Chen, Marco Egle, Frank-Erik de Leeuw, James Wason, Martin Dichgans, Egle, Marco [0000-0002-5247-7068], Hilal, Saima [0000-0001-5434-5635], Tuladhar, AM [0000-0002-4815-2834], Chen, Christopher [0000-0002-1047-9225], Markus, Hugh S [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, diagnostic imaging [Cognitive Dysfunction], Prospective data, Disease, Mri model, methods [Diffusion Tensor Imaging], diagnostic imaging [White Matter], White matter, Cohort Studies, Physical medicine and rehabilitation, Cognition, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, ddc:610, diagnostic imaging [Dementia], Prospective Studies, Vascular dementia, business.industry, vascular dementia, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], White Matter, cerebrovascular disease, Psychiatry and Mental health, medicine.anatomical_structure, Diffusion Tensor Imaging, Cerebral Small Vessel Diseases, alzheimer's disease, Surgery, Neurology (clinical), diagnostic imaging [Cerebral Small Vessel Diseases], business, Diffusion MRI, dementia, MRI
Abstract

ObjectivesIt has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.MethodsAmong the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.ResultsThe DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.ConclusionsOur results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.

Published
2022
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4. Association of vitamin D metabolites with cognitive function and brain atrophy in elderly individuals - the Austrian stroke prevention study

Author

Sieglinde Zelzer, Eva Fritz-Petrin, Edith Hofer, Markus Herrmann, Reinhold Schmidt, Andreas Meinitzer, Walter Goessler, and Sebastian Simstich

Subjects
Male, Aging, medicine.medical_specialty, Metabolite, vitamin D metabolites, Neuropsychological Tests, Neuroprotection, memory, chemistry.chemical_compound, Executive Function, Atrophy, Cognition, Tandem Mass Spectrometry, Internal medicine, medicine, Vitamin D and neurology, Dementia, Humans, LC-MS/MS, Vitamin D, Stroke, cognitive function, Aged, business.industry, Brain, Cell Biology, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Endocrinology, chemistry, Austria, Cohort, Female, business, Research Paper, dementia, Chromatography, Liquid
Abstract

Background Vitamin D is a well-established regulator of calcium and phosphate metabolism that has neurotrophic and neuroprotective properties. Deficiency of vitamin D has been proposed to promote cognitive dysfunction and brain atrophy. However, existing studies provide inconsistent results. Here we aimed to investigate the association between vitamin D metabolites, cognitive function and brain atrophy in a cohort of well-characterized community-dwelling elderly individuals with normal neurological status and without history of stroke and dementia. Methods 25(OH)D3, 25(OH)D2 and 24,25(OH)2D3 were measured by liquid-chromatography tandem mass-spectrometry in serum samples from 390 community-dwelling elderly individuals. All participants underwent thorough neuropsychiatric tests capturing memory, executive function and visuopractical skills. In 139 of these individuals, MRI of the brain was performed in order to capture neurodegenerative and vascular changes. Results Total 25(OH)D (s=0.003, 0.037), 24,25(OH)2D3 (s=0.0456, p=0.010) and vitamin D metabolite ratio (VMR) (s=0.0467, p=0.012) were significantly related to memory function. Adjustment for multiple testing weakened these relationships, but trends (p≤0.10) remained. 24,25(OH)2D3 and VMR showed similar trends also for visuopractical skills and global cognitive function. No significant relationships existed between vitamin D metabolites and MRI derived indices of neurodegeneration and vascular changes. Sub-group analyses of individuals with low concentrations of 25(OH)D and 24,25(OH)2D3 showed significantly worse memory function compared to individuals with normal or high concentrations. Conclusions Vitamin D deficient individuals appear to have a modest reduction of memory function without structural brain atrophy. Future studies should explore if vitamin D supplementation can improve cognitive function.

Published
2021

5. Microstructural Tissue Changes in Alzheimer Disease Brains: Insights from Magnetization Transfer Imaging

Author

A. Damulina, S. Ropele, Petra Schwingenschuh, Marisa Koini, Lukas Pirpamer, Christian Enzinger, Edith Hofer, Reinhold Schmidt, and I. Colonna

Subjects
Male, medicine.medical_specialty, Constructional Praxis, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Alzheimer Disease, Internal medicine, Cortex (anatomy), medicine, Humans, Cognitive Dysfunction, Radiology, Nuclear Medicine and imaging, Magnetization transfer imaging, Prospective Studies, Magnetization transfer, Prospective cohort study, Aged, Aged, 80 and over, business.industry, Adult Brain, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, medicine.anatomical_structure, Cardiology, Female, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract

BACKGROUND AND PURPOSE: Reductions in magnetization transfer ratio have been associated with brain microstructural damage. We aim to compare magnetization transfer ratio in global and regional GM and WM between individuals with Alzheimer disease and healthy control participants to analyze the relationship between magnetization transfer ratio and cognitive functioning in Alzheimer disease. MATERIALS AND METHODS: In this prospective study, participants with Alzheimer disease and a group of age-matched healthy control participants underwent clinical examinations and 3T MR imaging. Magnetization transfer ratios were determined in the cortex, AD-signature regions, normal-appearing WM, and WM hyperintensities. RESULTS: Seventy-seven study participants (mean age ± SD, 72 ± 8 years; 47 female) and 77 age-matched healthy control participants (mean age ± SD, 72 ± 8 years; 44 female) were evaluated. Magnetization transfer ratio values were lower in patients with Alzheimer disease than in healthy control participants in all investigated regions. When adjusting for atrophy and extent of WM hyperintensities, significant differences were seen in the global cortex (OR = 0.47; 95% CI: 0.22, 0.97; P = .04), in Alzheimer disease–signature regions (OR = 0.31; 95% CI: 0.14, 0.67; P = .003), in normal-appearing WM (OR = 0.59; 95% CI: 0.39, 0.88; P = .01), and in WM hyperintensities (OR = 0.18; 95% CI: 0.09, 0.33; P ≤ .001). The magnetization transfer ratio in these regions was an independent determinant of AD. When correcting for atrophy and WM hyperintensity extent, lower GM magnetization transfer ratios were associated with poorer global cognition, language function, and constructional praxis. CONCLUSIONS: Alzheimer disease is associated with magnetization transfer ratio reductions in GM and WM regions of the brain. Lower magnetization transfer ratios in the entire cortex and AD-signature regions contribute to cognitive impairment independent of brain atrophy and WM damage.

Published
2021

6. Genetic architecture of orbital telorism

Author

Hieab H.H. Adams, Edith Hofer, M. Arfan Ikram, Lukas Pirpamer, Natalie Terzikhan, Meike W. Vernooij, Tavia E. Evans, Caroline C W Klaver, Sander Lamballais, Ziyi Xiong, Reinhold Schmidt, Mikolaj A Pawlak, Maria J. Knol, Manfred Kayser, Epidemiology, Clinical Genetics, Genetic Identification, Ophthalmology, and Radiology & Nuclear Medicine

Subjects
Intraclass correlation, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Hypotelorism, Genetics, medicine, Humans, Hypertelorism, education, Molecular Biology, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Reproducibility of Results, General Medicine, Heritability, medicine.disease, Genetic architecture, Genetic Loci, Evolutionary biology, medicine.symptom, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 251528.pdf (Publisher’s version ) (Open Access) The interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs' centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985-0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P

Published
2022

7. Intracranial Pulsatility in Relation to Severity and Progression of Cerebral White Matter Hyperintensities

Author

Christian Enzinger, Susanna Horner, Reinhold Schmidt, Daniela Pinter, Thomas Gattringer, Kurt Niederkorn, Simon Fandler-Höfler, Edith Hofer, Markus Kneihsl, Sebastian Eppinger, and Melanie Haidegger

Subjects
Male, Middle Cerebral Artery, medicine.medical_specialty, Ultrasonography, Doppler, Transcranial, Severity of Illness Index, White matter, Internal medicine, medicine, Humans, Aged, Advanced and Specialized Nursing, Cerebral white matter, business.industry, Middle Aged, Magnetic Resonance Imaging, White Matter, Hyperintensity, medicine.anatomical_structure, Cerebral Small Vessel Diseases, Cerebrovascular Circulation, Pulsatile Flow, Stroke, Lacunar, Disease Progression, Cardiology, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose: Previous studies suggested an association between increased intracranial arterial pulsatility and the severity of microangiopathic white matter hyperintensities (WMH). However, possible confounders such as age and hypertension were seldomly considered and longitudinal data are lacking. We here aimed to explore whether increased middle cerebral artery pulsatility is associated with baseline severity and progression of cerebral small vessel disease–related WMH in elderly individuals. Methods: The study population consisted of elderly participants from the community-based ASPS (Austrian Stroke Prevention Study). Baseline and follow-up assessment comprised transcranial Doppler sonography, brain magnetic resonance imaging, and clinical/laboratory examination of vascular risk factors. Pulsatility index on transcranial Doppler sonography was averaged from baseline indices of both middle cerebral arteries and was correlated with baseline WMH severity and WMH progression over a median follow-up period of 5 years in uni- and multivariable analyses. WMH severity was graded according to the Fazekas scale, and WMH load was quantified by semiautomated volumetric assessment. Results: The study cohort comprised 491 participants (mean age: 60.7±6.9 years; female: 48.5%). Pulsatility index was increased in participants with more severe WMH at baseline ( P s : 0.097, P =0.099). In multivariable analyses, only arterial hypertension remained significantly associated with baseline severity ( P =0.04) and progression ( P =0.008) of WMH, although transcranial Doppler sonography pulsatility index was not predictive ( P >0.1, respectively). Conclusions: This community-based cohort study of elderly individuals does not support the pulsatility index of the middle cerebral artery on transcranial Doppler sonography as an independent marker of microangiopathic WMH severity and progression over time.

Published
2020

8. Serum neurofilament light levels in normal aging and their association with morphologic brain changes

Author

Michael Khalil, Jens Kuhle, Edith Hofer, Lukas Pirpamer, Christian Enzinger, Christian Barro, Pascal Benkert, David Leppert, Reinhold Schmidt, Franz Fazekas, Margarete M Voortman, and Stefan Ropele

Subjects
Male, 0301 basic medicine, Aging, Pathology, General Physics and Astronomy, Cognition, 0302 clinical medicine, Cerebrospinal fluid, Leukoencephalopathies, Neurofilament Proteins, Longitudinal Studies, lcsh:Science, Subclinical infection, Aged, 80 and over, education.field_of_study, Multidisciplinary, medicine.diagnostic_test, Brain, Middle Aged, Magnetic Resonance Imaging, Brain size, Female, medicine.symptom, Adult, medicine.medical_specialty, Neurofilament, Science, Population, Brain damage, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Atrophy, medicine, Humans, education, Aged, business.industry, Magnetic resonance imaging, General Chemistry, medicine.disease, Cross-Sectional Studies, 030104 developmental biology, lcsh:Q, business, Biomarkers, Neurological disorders, 030217 neurology & neurosurgery
Abstract

Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner., Neurofilament (NfL) levels in CSF and blood have been established as a biomarker of neuronal damage in neurodegenerative diseases, and there is an age-dependent increase in NfL levels in CSF. Here the authors demonstrate that serum NfL levels increase in healthy aging people and predict and correlate with brain volume loss.

Published
2020

9. Simple MRI score aids prediction of dementia in cerebral small vessel disease

Author

Anil M. Tuladhar, Reinhold E. Schmidt, James Wason, Edith Hofer, Marisa Koini, Ali Amin Al Olama, Esther M.C. van Leijsen, Hugh S. Markus, Robin G. Morris, Frank-Erik de Leeuw, Amin Al Olama, Ali [0000-0002-7178-3431], Tuladhar, Anil M [0000-0002-4815-2834], and Apollo - University of Cambridge Repository

Subjects
Male, Pediatrics, medicine.medical_specialty, Neuroimaging, 030204 cardiovascular system & hematology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, medicine, Dementia, Humans, Prospective Studies, Cognitive decline, Prospective cohort study, Stroke, Aged, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Magnetic Resonance Imaging, Confidence interval, Clinical trial, Cerebral Small Vessel Diseases, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo determine whether a simple small vessel disease (SVD) score, which uses information available on rapid visual assessment of clinical MRI scans, predicts risk of cognitive decline and dementia, above that provided by simple clinical measures.MethodsThree prospective longitudinal cohort studies (SCANS [St George's Cognition and Neuroimaging in Stroke], RUN DMC [Radboud University Nijmegen Diffusion Imaging and Magnetic Resonance Imaging Cohort], and the ASPS [Austrian Stroke Prevention Study]), which covered a range of SVD severity from mild and asymptomatic to severe and symptomatic, were included. In all studies, MRI was performed at baseline, cognitive tests repeated during follow-up, and progression to dementia recorded prospectively. Outcome measures were cognitive decline and onset of dementia during follow-up. We determined whether the SVD score predicted risk of cognitive decline and future dementia. We also determined whether using the score to select a group of patients with more severe disease would reduce sample sizes for clinical intervention trials.ResultsIn a pooled analysis of all 3 cohorts, the score improved prediction of dementia (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.81–0.89) compared with that from clinical risk factors alone (AUC, 0.76; 95% CI, 0.71–0.81). Predictive performance was higher in patients with more severe SVD. Power calculations showed selecting patients with a higher score reduced sample sizes required for hypothetical clinical trials by 40%–66% depending on the outcome measure used.ConclusionsA simple SVD score, easily obtainable from clinical MRI scans and therefore applicable in routine clinical practice, aided prediction of future dementia risk.

Published
2020

10. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Author

Pilar Delgado, Shuo Li, Matthew Paradise, Qiong Yang, Ami Tsuchida, Uwe Völker, Maria J. Knol, Wanting Zhao, Wei Wen, Marie-Gabrielle Duperron, David-Alexandre Trégouët, Mark E. Bastin, Hans J. Grabe, Aniket Mishra, Jean Shin, Stefan Frenzel, Alexa S. Beiser, Jiyang Jiang, Mathieu Bourgey, Henry Brodaty, Jayandra J. Himali, Hieab H.H. Adams, Ralph L. Sacco, Murali Sargurupremraj, Nicole Dueker, Margaret J. Wright, Quentin Le Grand, Christopher Chen, Tomáš Paus, Katharina Wittfeld, Stéphanie Debette, Tavia E. Evans, Constance Bordes, Nicola J. Armstrong, Parva Pedram, M. Arfan Ikram, Gennady V. Roshchupkin, Pascale Marquis, Tatjana Rundek, Anbupalam Thalamuthu, Helena Schmidt, Sudha Seshadri, Takahiro Konuma, Anne Joutel, Joanna M. Wardlaw, Michelle Luciano, Israel Fernandez-Cadenas, Robin Bülow, Jose R. Romero, Maria del C. Valdés Hernández, Meike W. Vernooij, Melissa Macalli, Claudia L. Satizabal, Caty Carrera, Ching-Yu Cheng, Piyush G. Gampawar, Ycheng Zhu, Karen A. Mather, Alexander Teumer, Ian J. Deary, Guillaume Bourque, Saima Hilal, Rick M. Tankard, Reinhold E. Schmidt, Yukinori Okada, Yasaman Saba, Sabrina Schilling, Julian N. Trollor, Tien Yin Wong, Perminder S. Sachdev, Mark Lathrop, Omar (Tbc) Soukarieh, Junyi Zhang, Zoe Morris, Edith Hofer, Christophe Tzourio, Florian Dubost, Bernard Mazoyer, and Susanna Muñoz Maniega

Subjects
Pathology, medicine.medical_specialty, medicine.anatomical_structure, cardiovascular system, medicine, Genomics, Disease, Small vessel, Biology, Perivascular space
Abstract

Perivascular space burden (PVS) is an emerging and possibly the earliest magnetic resonance imaging (MRI)-marker of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. Its molecular underpinnings are unknown. Genome-wide and whole-exome association studies in 40,095 participants (21 population-based cohorts, 66.3±8.6 years) revealed 24 genome-wide significant PVS risk loci. These showed association with white matter PVS already at age 20, suggesting an important role of early-life factors. PVS loci were enriched in genes causing early-onset leukodystrophies and genes expressed in fetal brain endothelial cells. Mendelian randomization analyses supported causal associations of high blood pressure with basal ganglia (BG) and hippocampal PVS, and of BG PVS with stroke. Transcriptome-wide association studies suggest causal implication of 11 genes, to prioritize for experimental follow-up as putative biotargets for cSVD. Two-thirds of PVS loci point to novel pathways, involving extracellular matrix, membrane transport, and developmental processes, with enrichment in targets of existing drugs for vascular/cognitive disorders.

Published
2021

11. Predicting atrial fibrillation after cryptogenic stroke via a clinical risk score-a prospective observational study

Author

Egbert Bisping, Harald Mangge, Simon Fandler-Höfler, Edith Hofer, Markus Kneihsl, Sebastian Eppinger, Thomas Gattringer, Isabella Colonna, Daniel Scherr, Melanie Haidegger, Franz Fazekas, and Christian Enzinger

Subjects
medicine.medical_specialty, Atrial enlargement, medicine.drug_class, Ventricular Function, Left, Risk Factors, Internal medicine, Atrial Fibrillation, medicine, Natriuretic peptide, Humans, Stroke, Ischemic Stroke, Framingham Risk Score, Ejection fraction, business.industry, Atrial fibrillation, Stroke Volume, medicine.disease, Neurology, Cardiology, Biomarker (medicine), Observational study, Neurology (clinical), medicine.symptom, business
Abstract

BACKGROUND AND PURPOSE Atrial fibrillation (AF) often remains undiagnosed in cryptogenic stroke (CS), mostly because of limited availability of cardiac long-term rhythm monitoring. There is an unmet need for a pre-selection of CS patients benefitting from such work-up. A clinical risk score was therefore developed for the prediction of AF after CS and its performance was evaluated over 1 year of follow-up. METHODS Our proposed risk score ranges from 0 to 16 points and comprises variables known to be associated with occult AF in CS patients including age, N-terminal pro-brain natriuretic peptide, electrocardiographic and echocardiographic features (supraventricular premature beats, atrial runs, atrial enlargement, left ventricular ejection fraction) and brain imaging markers (multi-territory/prior cortical infarction). All CS patients admitted to our Stroke Unit between March 2018 and August 2019 were prospectively followed for AF detection over 1 year after discharge. RESULTS During the 1-year follow-up, 24 (16%) out of 150 CS patients with AF (detected via electrocardiogram controls, n = 18; loop recorder monitoring, n = 6) were diagnosed. Our predefined AF Risk Score (cutoff ≥4 points; highest Youden's index) had a sensitivity of 92% and a specificity of 67% for 1-year prediction of AF. Notably, only two CS patients with

Published
2021

12. White Matter Hyperintensities in Alzheimer’s Disease: A Lesion Probability Mapping Study

Author

Edith Hofer, Lukas Pirpamer, Christian Langkammer, Peter Dal-Bianco, Stephan Seiler, Anna Damulina, Walter Struhal, Marco Duering, Reinhold Schmidt, Gerhard Ransmayr, Thomas Benke, and Franz Fazekas

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Fluid-attenuated inversion recovery, behavioral disciplines and activities, Cohort Studies, Coronary artery disease, Lesion, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Diabetes mellitus, Internal medicine, mental disorders, Humans, Medicine, Dementia, Longitudinal Studies, Prospective Studies, Registries, Cognitive decline, Aged, Aged, 80 and over, Brain Mapping, medicine.diagnostic_test, business.industry, General Neuroscience, Brain, Magnetic resonance imaging, General Medicine, Middle Aged, medicine.disease, White Matter, Hyperintensity, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Austria, Cardiology, Female, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background/objective Higher white matter hyperintensity (WMH) load has been reported in Alzheimer's disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps. Methods The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed. Results There were no significant between-group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients. Conclusion In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location.

Published
2019

13. Nigral iron deposition in common tremor disorders

Author

Edith Hofer, Karoline Wenzel, Lukas Pirpamer, Stephan Seiler, Petra Schwingenschuh, Reinhold Schmidt, Sebastian Franthal, Hannes Deutschmann, Petra Katschnig-Winter, Franz Fazekas, Nina Homayoon, Christian Langkammer, Mariella Kögl, and Stefan Ropele

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Movement disorders, brain iron accumulation, R2 Star, Iron, Iron deposition, Substantia nigra, tremor in dystonia, tremor‐dominant Parkinson's disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Tremor, medicine, Humans, In patient, essential tremor, Aged, Dystonia, Aged, 80 and over, Essential tremor, business.industry, Brief Report, Parkinson Disease, Middle Aged, medicine.disease, Magnetic Resonance Imaging, nervous system diseases, Substantia Nigra, 030104 developmental biology, Neurology, Iron content, Brief Reports, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Objective We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties. Methods Mean nigral R2* rates were measured in 40 patients with tremor‐dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls. Results Tremor‐dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor‐dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non‐PD tremor patients was 67.5% and 60%. Conclusion Iron content in the substantia nigra is significantly higher in tremor‐dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2018

14. Hospital admissions of acute cerebrovascular diseases during and after the first wave of the COVID-19 pandemic: a state-wide experience from Austria

Author

Christian Enzinger, Simon Fandler-Höfler, Wolfgang Köle, Edith Hofer, Reinhold Schmidt, Markus Kneihsl, Karl-Heinz Tscheliessnigg, Almut-Michaela Frank, and Thomas Gattringer

Subjects
Corona virus disease 2019, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Transient ischaemic attack, medicine.medical_treatment, Intracranial haemorrhage, Brain Ischemia, Short Commentary, symbols.namesake, Internal medicine, Ischaemic stroke, Pandemic, medicine, Humans, Poisson regression, cardiovascular diseases, Pandemics, Neuroradiology, Retrospective Studies, Acute stroke care, business.industry, SARS-CoV-2, COVID-19, Thrombolysis, Hospitals, Medical documents, Hospitalization, Stroke, Cerebrovascular Disorders, Neurology, Austria, symbols, Neurology (clinical), business
Abstract

We investigated hospital admission rates for the entire spectrum of acute cerebrovascular diseases and of recanalization treatments for ischaemic stroke (IS) in the Austrian federal state of Styria during and also after the first coronavirus disease 2019 (COVID-19) wave. We retrospectively identified all patients with transient ischaemic attack (TIA), IS and non-traumatic intracranial haemorrhage (ICH; including intracerebral, subdural and subarachnoid bleeding types) admitted to one of the 11 public hospitals in Styria (covering > 95% of inhospital cerebrovascular events in this region). Information was extracted from the electronic medical documentation network connecting all public Styrian hospitals. We analysed two periods of interest: (1) three peak months of the first COVID-19 wave (March–May 2020), and (2) three recovery months thereafter (June–August 2020), compared to respective periods 4 years prior (2016–2019) using Poisson regression. In the three peak months of the first COVID-19 wave, there was an overall decline in hospital admissions for acute cerebrovascular diseases (RR = 0.83, 95% CI 0.78–0.89, p p p = 0.02), but not for IS (RR = 0.93, 95% CI 0.85–1, p = 0.08). Thrombolysis and thrombectomy numbers were not different compared to respective months 4 years prior. In the recovery period after the first COVID-19 wave, TIA (RR = 0.82, 95% CI 0.71–0.96, p = 0.011) and ICH (RR = 0.86, 95% CI 0.74–0.99, p = 0.045) hospitalizations remained lower, while the frequency of IS and recanalization treatments was unchanged. In this state-wide analysis covering all types of acute cerebrovascular diseases, hospital admissions for TIA and ICH were reduced during and also after the first wave of the COVID-19 pandemic, but hospitalizations and recanalization treatments for IS were not affected in these two periods.

Published
2021

15. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

Published
2021

16. Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI

Author

Christian Enzinger, Christian Langkammer, Edith Hofer, Reinhold E. Schmidt, Stefan Ropele, Marco Duering, Maximilian Sackl, Christian Tinauer, Lukas Pirpamer, Martin Soellradl, Benno Gesierich, and Anna Damulina

Subjects
Aged, 80 and over, Brain Chemistry, Pediatrics, medicine.medical_specialty, business.industry, Iron, MEDLINE, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Temporal lobe, Text mining, Alzheimer Disease, medicine, Cognitive deterioration, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Alzheimer's disease, Prospective cohort study, business, Aged
Abstract

Background Deep gray matter structures in patients with Alzheimer disease (AD) contain higher brain iron concentrations. However, few studies have included neocortical areas, which are challenging to assess with MRI. Purpose To investigate baseline and change in brain iron levels using MRI at 3 T with R2* relaxation rate mapping in individuals with AD compared with healthy control (HC) participants. Materials and Methods In this prospective study, participants with AD recruited between 2010 and 2016 and age-matched HC participants selected from 2010 to 2014 were evaluated. Of 100 participants with AD, 56 underwent subsequent neuropsychological testing and brain MRI at a mean follow-up of 17 months. All participants underwent 3-T MRI, including R2* mapping corrected for macroscopic B0 field inhomogeneities. Anatomic structures were segmented, and median R2* values were calculated in the neocortex and cortical lobes, basal ganglia (BG), hippocampi, and thalami. Multivariable linear regression analysis was applied to study the difference in R2* levels between groups and the association between longitudinal changes in R2* values and cognition in the AD group. Results A total of 100 participants with AD (mean age, 73 years ± 9 [standard deviation]; 58 women) and 100 age-matched HC participants (mean age, 73 years ± 9; 60 women) were evaluated. Median R2* levels were higher in the AD group than in the HC group in the BG (HC, 29.0 sec

Published
2020

17. Stroke

Author

Paul M. Thompson, Joshua C. Bis, Julian N. Trollor, Siggi Siggurdsson, Leonie Lampe, Piyush Gampawar, Myriam Fornage, Neda Jahanshad, Dina Vojinovic, Jiyang Jiang, Christophe Tzourio, Helena Schmidt, Shuo Li, Ian J. Deary, Lewis C. Becker, Karen A. Mather, Najaf Amin, Rui Xia, Bernard Mazoyer, Arno Villringer, Albert V. Smith, Henry Brodaty, Jeroen van der Grond, Vilmundur Gudnason, Rainer Malik, Christine Fennema-Notestine, Brian G. Kral, Asta Håberg, Clinton B. Wright, David C. Liewald, Sudha Seshadri, Claudia L. Satizabal, Bruce M. Psaty, Ralph L. Sacco, Reinhold Schmidt, Lisa R. Yanek, Mark Jenkinson, Qiong Yang, Jose R. Romero, Fidel Alfaro-Almagro, Philippe Amouyel, Margaret J. Wright, William T. Longstreth, Muralidharan Sargurupremraj, Mark E. Bastin, John B.J. Kwok, M. Arfan Ikram, David J. Stott, Nicole Dueker, Lukas Pirpamer, Perminder S. Sachdev, Stéphanie Debette, Edith Hofer, Ludovica Griffanti, Alexa S. Beiser, Nicola J. Armstrong, Stephen M. Smith, Lloyd T. Elliott, Wei Wen, J. Wouter Jukema, William S. Kremen, Markus Scholz, Anbupalam Thalamuthu, Peter R. Schofield, Clifford R. Jack, Stella Trompet, Gennady V. Roshchupkin, Matthias L. Schroeter, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Meike W. Vernooij, Maria J. Knol, Pauline Maillard, Charles DeCarli, Jonathan Marchini, Rebecca F. Gottesman, Paul A. Nyquist, Martin Dichgans, Zoe Morris, Cornelia M. van Duijn, David Ames, Veronica A. Witte, Hieab H.H. Adams, Mark A. Logue, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, and Clinical Genetics

Subjects
Male, Aging, Cardiorespiratory Medicine and Haematology, 0302 clinical medicine, pathology [Brain], pathology [White Matter], 2.1 Biological and endogenous factors, risk factors, Aetiology, genetics [Genetic Predisposition to Disease], 0303 health sciences, neuroimaging, Middle Aged, White Matter, Cerebral Small Vessel Diseases, Stroke, medicine.anatomical_structure, VINTAGE, Neurological, Deep white matter hyperintensities, Female, diagnostic imaging [Cerebral Small Vessel Diseases], Cardiology and Cardiovascular Medicine, Cartography, white matter, Biotechnology, brain, Clinical Sciences, Article, diagnostic imaging [White Matter], White matter, 03 medical and health sciences, Clinical Research, Genetic variation, Genetics, Acquired Cognitive Impairment, medicine, Humans, Genetic Predisposition to Disease, ddc:610, HEALTHY, diagnostic imaging [Brain], 030304 developmental biology, Aged, Advanced and Specialized Nursing, Neurology & Neurosurgery, genome-wide association study, business.industry, Prevention, Human Genome, Neurosciences, Brain Disorders, Clinical neurology, Periventricular white matter hyperintensities, genetics [Cerebral Small Vessel Diseases], pathology [Cerebral Small Vessel Diseases], Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Published
2020

18. Global and regional development of the human cerebral cortex: Molecular architecture and occupational aptitudes

Author

M. Arfan Ikram, Lukas Pirpamer, Daniel E. Vosberg, Edith Hofer, David Ames, Sandra van der Auwera-Palitschka, Zdenka Pausova, Xueqiu Jian, Henry Brodaty, André M. M. Sousa, Linda Ding, Tavia E. Evans, William S. Kremen, Jean Shin, Steven Tilley, Fabrice Crivello, Christophe Tzourio, Karen A. Mather, Peter R. Schofield, Joanna M. Wardlaw, Joshua C. Bis, Tomáš Paus, Bernard Mazoyer, Myriam Fornage, Thomas H. Mosley, Natalie Terzikhan, Nathan A. Gillespie, Hans J. Grabe, Michelle Luciano, Mathew A. Harris, Nenad Sestan, Wei Wen, Sherif Karama, Reinhold Schmidt, Shaojie Ma, Katharina Wittfeld, Lindsay B. Lewis, Arno Villringer, Hieab H.H. Adams, Sudha Seshadri, Neda Jahanshad, Jiyang Jiang, Sophie Maingault, Yasaman Saba, Qiong Yang, Frauke Beyer, Stéphanie Debette, Nicola J. Armstrong, Markus Scholz, Carol E. Franz, Margaret J. Wright, Shuo Li, Rebecca F. Gottesman, Aniket Mishra, Perminder S. Sachdev, Yash Patel, John B.J. Kwok, Anbupalam Thalamuthu, Helena Schmidt, Amaia Carrion-Castillo, Robin Bülow, Mark E. Bastin, Markus Loeffler, Ian E. Deary, Stefan Frenzel, Julian N. Trollor, Gennady V. Roshchupkin, A. Veronica Witte, Epidemiology, Medical Informatics, Radiology & Nuclear Medicine, Neurology, the ENIGMA Consortium, for the neuroCHARGE Working Group, and the neuroCHARGE Working Group

Subjects
rho GTP-Binding Proteins, Male, Aptitude, Genome-wide association study, brain development, cortical surface area, 0302 clinical medicine, Form perception, Intracranial volume, genetics [RNA-Binding Proteins], genetics [Form Perception], Visual Cortex, media_common, Cerebral Cortex, Aged, 80 and over, 0303 health sciences, Principal Component Analysis, Career Choice, Microfilament Proteins, genomeide association study, RNA-Binding Proteins, Gene Expression Regulation, Developmental, Cognition, growth & development [Visual Cortex], Middle Aged, medicine.anatomical_structure, VINTAGE, Cerebral cortex, growth & development [Cerebral Cortex], Original Article, Female, Adult, endocrine system, Adolescent, Cognitive Neuroscience, media_common.quotation_subject, tau Proteins, Biology, occupational aptitude, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Regional development, medicine, Humans, ddc:610, 030304 developmental biology, Genetic association, Aged, physiology [Aptitude], genome-wide association study, 9. Industry and infrastructure, cortical thickness, Brain Cortical Thickness, Form Perception, genetics [tau Proteins], genetics [rho GTP-Binding Proteins], genetics [Microfilament Proteins], Transcriptome, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

Published
2020

19. Minor Structural Differences in the Cervical Spine Between Patients With Cervical Dystonia and Age-Matched Healthy Controls

Author

Petra Katschnig-Winter, Christian Enzinger, Dennis Bohlsen, Marton Magyar, Stephan Seiler, Edith Hofer, Sebastian Franthal, Nina Homayoon, Mariella Kögl, Karoline Wenzel, Hannes Deutschmann, Franz Fazekas, Reinhold Schmidt, and Petra Schwingenschuh

Subjects
medicine.medical_specialty, cervical dystonia, cervical spine, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, inter-rater reliability, Rating scale, medicine, In patient, Cervical dystonia, lcsh:Neurology. Diseases of the nervous system, Original Research, Dystonia, 030222 orthopedics, structural, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Focal dystonia, medicine.disease, Cervical spine, Inter-rater reliability, Neurology, Radiology, Neurology (clinical), business, 030217 neurology & neurosurgery, MRI
Abstract

Background: Cervical dystonia is the most common form of focal dystonia. The frequency and pattern of degenerative changes of the cervical spine in patients with cervical dystonia and their relation to clinical symptoms remain unclear as no direct comparison to healthy controls has been performed yet. Here, we used magnetic resonance imaging (MRI) to investigate (1) whether structural abnormalities of the cervical spine are more common in patients with cervical dystonia compared to age-matched healthy controls, (2) if there are clinical predictors for abnormalities on MRI, and (3) to calculate the inter-rater reliability of the respective radiological scales. Methods: Twenty-five consecutive patients with cervical dystonia and 20 age-matched healthy controls were included in the study. MRI scans of the cervical spine were analyzed separately by three experienced raters blinded to clinical information, applying different MRI rating scales. Structural abnormalities were compared between groups for upper, middle, and lower cervical spine segments. The associations between scores differentiating both groups and clinical parameters were assessed in dystonia patients. Additionally, inter-rater reliability of the MRI scales was calculated. Results: Comparing structural abnormalities, we found minor differences in the middle cervical spine, indicated by a higher MRI total score in patients but no significant correlation between clinical parameters and MRI changes. Inter-rater reliability was satisfying for most of the MRI rating scales. Conclusion: Our results do not provide evidence for a role of MRI of the cervical spine in the routine work-up of patients with cervical dystonia in the absence of specific clinical signs or symptoms.

Published
2020

20. The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study

Author

Markus Herrmann, Reinhold Schmidt, Edith Hofer, Gerhard Ransmayr, Jasmin Rabensteiner, Peter Dal-Bianco, Eva Fritz-Petrin, Thomas Benke, and Günter Fauler

Subjects
Male, Aging, medicine.medical_specialty, Disease, folate, Cohort Studies, Atrophy, Cognition, Folic Acid, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, Vitamin B12, cognitive function, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Brain, Retrospective cohort study, Cell Biology, vitamin B12, homocysteine, Middle Aged, medicine.disease, Cognitive test, Vitamin B 12, Austria, Brain size, Female, business, Research Paper, dementia
Abstract

Background Dementia, and in particular Alzheimer's disease (AD), is a debilitating progressive disease with high prevalence in our society. Vitamin B12 and folate deficiency are potential modifiable risk factors. However, previous studies reported inconsistent results. Results The average concentrations of all biochemical markers were within the respective reference ranges. Cross-sectional and longitudinal analyses did not reveal significant associations between biochemical markers and cognitive function, global or regional brain volume, cortical thickness or cortical surface area, neither in controls nor in AD patients. Conclusions Variations of direct and indirect markers of B12 and folate status are not associated with cognitive dysfunction and brain atrophy. Methods This retrospective study explored the association between biochemical markers of B12 and folate status, cognitive function and MRI-based brain atrophy in cognitive normal elderly (controls) and AD patients. Folate, total and active vitamin B12 and MMA were measured in blood samples from 378 controls and 217 AD patients. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in 155 controls and 217 AD patients. In a subset of participants cognitive testing (n=234) and MRI (n=182) was repeated after an average median between 1.25 and 6.25 years.

Published
2020

21. Enlarged perivascular spaces and cognition A meta-analysis of 5 population-based studies

Author

Henry Völzke, Edith Hofer, Hieab H.H. Adams, Norbert Hosten, Saima Hilal, Christopher Chen, Chuen Seng Tan, Meike W. Vernooij, Mohamad Habes, M. Arfan Ikram, Hans J. Grabe, Jill Abrigo, Narayanaswamy Venketasubramanian, Reinhold Schmidt, Vincent Mok, M. Kamran Ikram, Epidemiology, Radiology & Nuclear Medicine, and Neurology

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Population, Brain Edema, diagnostic imaging [Brain Edema], Neuropsychological Tests, diagnostic imaging [Cognition Disorders], Article, Community Health Planning, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Internal medicine, Centrum semiovale, medicine, Dementia, Humans, pathology [Cerebral Arteries], ddc:610, Cognitive decline, education, Aged, education.field_of_study, business.industry, complications [Brain Edema], etiology [Cognition Disorders], Cerebral Arteries, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Confidence interval, 030104 developmental biology, Study of Health in Pomerania, Meta-analysis, Female, Neurology (clinical), Cognition Disorders, business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo investigate the association of enlarged perivascular spaces (ePVS) with cognition in elderly without dementia.MethodsWe included 5 studies from the Uniform Neuro-Imaging of Virchow-Robin Space Enlargement (UNIVRSE) consortium, namely the Austrian Stroke Prevention Family Study, Study of Health in Pomerania, Rotterdam Study, Epidemiology of Dementia in Singapore study, and Risk Index for Subclinical Brain Lesions in Hong Kong study. ePVS were counted in 4 regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) with harmonized rating across studies. Mini-Mental State Examination (MMSE) and general fluid cognitive ability factor (G-factor) were used to assess cognitive function. For each study, a linear regression model was performed to estimate the effect of ePVS on MMSE and G-factor. Estimates were pooled across studies with the use of inverse variance meta-analysis with fixed- or random-effect models when appropriate.ResultsThe final sample size consisted of 3,575 persons (age range 63.4–73.2 years, 50.6% women). Total ePVS counts were not significantly associated with MMSE score (mean difference per ePVS score increase 0.001, 95% confidence interval [CI] −0.007 to 0.008, p = 0.885) or G-factor (mean difference per ePVS score increase 0.002, 95% CI −0.001 to 0.006, p = 0.148) in age-, sex-, and education-adjusted models. Adjustments for cardiovascular risk factors and MRI markers did not change the results. Repeating the analyses with region-specific ePVS rendered similar results.ConclusionsIn this study, we found that ePVS counts were not associated with cognitive dysfunction in the general population. Future studies with longitudinal designs are warranted to examine whether ePVS contribute to cognitive decline.

Published
2018

22. Serum neurofilament light is sensitive to active cerebral small vessel disease

Author

Daniela Pinter, Simon Fandler, Michael Khalil, Christian Enzinger, Markus Kneihsl, Jens Kuhle, Edith Hofer, Stefan Ropele, Alexander Pichler, Franz Fazekas, Thomas Seifert-Held, Thomas Gattringer, Reinhold Schmidt, Margarete M Voortman, Lukas Pirpamer, Svenya Gröbke, and Christian Barro

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Pathology, Neurofilament light, Disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Neurofilament Proteins, Internal medicine, medicine, Humans, Stroke, Aged, medicine.diagnostic_test, business.industry, Mean age, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, 030104 developmental biology, Cerebral Small Vessel Diseases, Stroke, Lacunar, Biomarker (medicine), Female, Neurology (clinical), Small vessel, business, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

Published
2017

23. A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Author

Diana van Heemst, Lisa R. Yanek, Tamara B. Harris, Fabrice Crivello, Hieab H.H. Adams, Paul A. Nyquist, Bernard Mazoyer, Najaf Amin, Pauline Maillard, Diane M. Becker, Marian Beekman, Shuo Li, Ganesh Chauhan, Charles DeCarli, Wanting Zhao, Neda Jahanshad, Rasika A. Mathias, Cornelia M. van Duijn, Manon Bernard, Derrek P. Hibar, Alexa S. Beiser, Meike W. Vernooij, Vilmundur Gudnason, Joshua C. Bis, Tomáš Paus, Edith Hofer, Lei Yu, Stéphanie Debette, Helena Schmidt, M. Kamran Ikram, P. Eline Slagboom, Erik B. van den Akker, Lenore J. Launer, Stefan Boehringer, Kent D. Taylor, Maria J. Knol, Wiro J. Niessen, Kenneth Rice, Zdenka Pausova, Gennady V. Roshchupkin, Sven J. van der Lee, Philip L. De Jager, Ching-Yu Cheng, Sudha Seshadri, Qiong Yang, Konstantinos Arfanakis, Yasaman Saba, Jeroen van der Grond, W. T. Longstreth, Albert V. Smith, Claudia L. Satizabal, Oscar L. Lopez, Bruce M. Psaty, Christopher Chen, Philippe Amouyel, Josh W. Cheung, M. Arfan Ikram, Tien Yin Wong, Reinhold Schmidt, David A. Bennett, Saima Hilal, Paul M. Thompson, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine, University of Washington [Seattle], Keck School of Medicine [Los Angeles], University of Southern California (USC), National University of Singapore (NUS), Rush University Medical Center [Chicago], Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Los Angeles Biomedical Research Institute (LA BioMed), School of Public Health [Boston], Boston University [Boston] (BU), Columbia University Medical Center (CUMC), Columbia University [New York], University of Glasgow, Leiden University Medical Center (LUMC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Neurology, Clinical Genetics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Universiteit Leiden

Subjects
Pathology, Heredity, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medicine (miscellaneous), Genome-wide association study, Genome-wide association studies, Taugasjúkdómar, 0302 clinical medicine, Parietal Lobe, 2.1 Biological and endogenous factors, Developmental, Aetiology, lcsh:QH301-705.5, 0303 health sciences, Parietal lobe, Gene Expression Regulation, Developmental, Organ Size, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 3. Good health, Phenotype, Mental Health, Neurological, symbols, Occipital Lobe, Erfðarannsóknir, General Agricultural and Biological Sciences, medicine.medical_specialty, Genotype, 1.1 Normal biological development and functioning, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Temporal lobe, 03 medical and health sciences, symbols.namesake, Underpinning research, Genetics, medicine, Humans, Gene, 030304 developmental biology, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Human Genome, Heilinn, Neurosciences, Genetic Variation, United Kingdom, Brain Disorders, Gene Expression Regulation, lcsh:Biology (General), Genetic Loci, Mendelian inheritance, Occipital lobe, Biomarkers, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., 23Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA. 24Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria. 25Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA. 26Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. 27Department of Radiology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. 28Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto M4G 1R8, Canada. 29Departments of Psychology and Psychiatry, University of Toronto, Toronto M5S 1A1, Canada.

Published
2019

24. Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

Author

Leonie Lampe, Peter R. Schofield, Hieab H.H. Adams, Mark A. Logue, Charles DeCarli, Wen Wei, Neda Jahanshad, Jose R. Romero, Anbupalam Thalamuth, Christophe Tzourio, Lloyd T. Elliott, Rui Xia, Meike W. Vernooij, Maria J. Knol, Jeroen van der Grond, Vilmundur Gudnason, Martin Dichigans, Karen A. Mather, Jonathan Marchini, John W Kwok, Jiyang Jain, Bernard Mazoyer, Rebecca F. Gottesman, Edith Hofer, Maragret J Wright, Nicola J. Armstrong, Christine Fennema-Notestine, Joanna M. Wardlaw, Thomas H. Mosley, Stella Trompet, Helena Schmidt, Clinton B. Wright, William S. Kremen, Paul A. Nyquist, Reinhold Schmidt, Stephanie Debbette, Michelle Luciano, Lenore J. Launer, Henry Brodaty, M Afran Ikram, Nicole D Deuker, Rainer Malik, Pauline Maillard, David Ames, J. Wouter Jukema, Cornelia M. van Duijn, Markus Scholz, Lukas Pirpamer, Ralph L. Sacco, Lisa R. Yanek, Julian N. Trollor, Siggi Siggurdsson, Qiong Yang, Muralidharan Sargurupremraj, Mark Jenkinson, Shuo Li, Ludovica Griffanti, Mark E. Bastin, Alexa S. Beiser, Fidel Alfaro-Almagro, David J. Stott, Veronica Witte, Perminder S. Sachdev, Moris Zoe, Asta L Haberg, Paul M. Thompson, Sudha Seshadri, Piyush G Gampwar, Albert V. Smith, Claudia L. Satizabal, Ian J. Deary, Arno Villringer, David C. Liewald, Myriam Fornage, Dina Vojinovic, Clifford R. Jack, Lewis C. Becker, Najaf Amin, Philippe Amouyel, Stephen M. Smith, Brian G. Kral, Gennady V. Roshchupkin, and Matthias L. Schroeter

Subjects
Genetics, White matter, Candidate gene, medicine.anatomical_structure, Genetic variation, Ischemic stroke, Etiology, medicine, Deep white matter hyperintensities, Locus (genetics), Disease, Biology
Abstract

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

Published
2019

25. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Tina Shah, E. C. M. van Leeuwen, Jingjing Liang, Susan M. Ring, Alexander Teumer, P Anugu, Salman M. Tajuddin, Aaron Isaacs, Jorgen Engmann, Marcus Dörr, Kenneth Rice, Anne B. Newman, Sonia Shah, Lenore J. Launer, Diana Kuh, Panos Roussos, P. De Vries, Bo Hedblad, Xiaofeng Zhu, Walter Palmas, John E. Deanfield, Debbie A Lawlor, Ganesh Chauhan, Dennis O. Mook-Kanamori, André G. Uitterlinden, Sudha Seshadri, Ilja M. Nolte, Elmo Mannarino, Daniel H. O'Leary, Susan R. Heckbert, Bogdan Pasaniuc, Solomon K. Musani, Rebecca Hardy, Rainer Malik, Lesca M. Holdt, Lars Lind, Reinhold Schmidt, R. de Mutsert, Aroon D. Hingorani, Riccardo E. Marioni, P. Amouyel, Albert V. Smith, Janne Pott, Eric E. Schadt, Lyytikäinen L-P., Raymond Noordam, Stéphanie Debette, Oscar H. Franco, Vincent Plagnol, Gerardo Heiss, Brenda W.J.H. Penninx, SG Wannamethee, Carl D. Langefeld, Stella Trompet, C.M. van Duijn, Tessel E. Galesloot, Peter K. Joshi, Maryam Kavousi, Juan P. Casas, Joanna M. Wardlaw, P. Giral, Julian Halcox, Björkegren Jlm., U de Faire, Andries J. Smit, Christina L. Wassel, Christopher J. O'Donnell, Matthew Traylor, Uwe Völker, Mika Kivimäki, Jenna Price, Quenna Wong, Chris Finan, Wayne D. Rosamond, Markus Loeffler, Harry Campbell, L Lu, Jerome I. Rotter, Joop Jukema, Karl Gertow, Edith Hofer, Hugh S. Markus, Albert Hofman, Peter H. Whincup, James G. Wilson, Michelle K. Evans, Enzo Grossi, Matthias Sitzer, Martin Dichgans, Oscar L. Rueda-Ochoa, J. C. Bis, Klodian Dhana, Ralph Burkhardt, Harold Snieder, Kiemeney Lalm., Daniel Teupser, A C Morrison, Markus Scholz, Ulf Schminke, Richard W Morris, Meena Kumari, Caroline Dale, Helena Schmidt, Sara Hägg, Niina Pitkänen, Fabrizio Veglia, Donald W. Bowden, Olli T. Raitakari, Joachim Thiery, Anders Hamsten, Muralidharan Sargurupremraj, Hwang S-J., Elena Tremoli, Stela McLachlan, Amanda J. Cox, Kent D. Taylor, Frank Beutner, Henry Völzke, Terho Lehtimäki, Abbas Dehghan, Ruth C. Lovering, Rachael P. Huntley, Mike A. Nalls, Jemma C. Hopewell, Erik Ingelsson, Claudia Giambartolomei, Bruce M. Psaty, Annie Britton, A Seldenrijk, Bengt Sennblad, Olle Melander, J. de Graaf, Adolfo Correa, Fernando Rivadeneira, Oscar Franzén, Laura M. Raffield, Alan B. Zonderman, Rona J. Strawbridge, Thomas W. Winkler, Ian J. Deary, Misa Graff, Wendy S. Post, Andrew Wong, T.B. Harris, Yasaman Saba, Arno Ruusalepp, James F. Wilson, Vilmundur Gudnason, Eric Boerwinkle, Damiano Baldassarre, Cristiano Fava, S.E. Humphries, Sudhir Kurl, Rainer Rauramaa, Christophe Tzourio, Xuejiang Guo, Nora Franceschini, Xiaoling Zhang, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: CARIM - R1.01 - Blood proteins & engineering, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Giambartolomei, Claudia [0000-0003-2786-1225], Huntley, Rachael P [0000-0001-6718-3559], Lovering, Ruth C [0000-0002-9791-0064], Tajuddin, Salman M [0000-0002-7919-8528], Winkler, Thomas W [0000-0003-0292-5421], Nolte, Ilja M [0000-0001-5047-4077], Scholz, Markus [0000-0002-4059-1779], Joshi, Peter K [0000-0002-6361-5059], Isaacs, Aaron [0000-0001-5037-4834], Correa, Adolfo [0000-0002-9501-600X], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Newman, Anne B [0000-0002-0106-1150], Sennblad, Bengt [0000-0002-4360-8003], Baldassarre, Damiano [0000-0002-2766-8882], Kuh, Diana [0000-0001-7386-2857], Schadt, Eric E [0000-0002-7892-8808], Rivadeneira, Fernando [0000-0001-9435-9441], Jukema, J Wouter [0000-0002-3246-8359], Rice, Kenneth [0000-0002-3071-7278], Dhana, Klodian [0000-0002-6397-7009], Dichgans, Martin [0000-0002-0654-387X], Traylor, Matthew [0000-0001-6624-8621], Kivimaki, Mika [0000-0002-4699-5627], Roussos, Panos [0000-0002-4640-6239], Amouyel, Philippe [0000-0001-9088-234X], Burkhardt, Ralph [0000-0003-1924-1202], Morris, Richard W [0000-0001-7240-4563], Hägg, Sara [0000-0002-2452-1500], Lawlor, Deborah A [0000-0002-6793-2262], Wilson, James F [0000-0001-5751-9178], Wardlaw, Joanna M [0000-0002-9812-6642], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Gudnason, Vilmundur [0000-0001-5696-0084], Apollo - University of Cambridge Repository, Psychiatry, APH - Mental Health, APH - Digital Health, Epidemiology, Internal Medicine, and Experimental Immunology

Subjects
0301 basic medicine, Candidate gene, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], General Physics and Astronomy, Genome-wide association study, Coronary Disease, VARIANTS, Carotid Intima-Media Thickness, Coronary artery disease, Protein-Lysine 6-Oxidase, Risk Factors, Medicine, genetics, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, GENE-PRODUCT, cardiovascular genetics, Multidisciplinary, Kardiologi, Plaque, Atherosclerotic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cardiology, cardiovascular system, Medical genetics, CORONARY-ARTERY-DISEASE, HEART, Amino Acid Oxidoreductases, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, MEGASTROKE Consortium, Science, Quantitative Trait Loci, ADAMTS9 Protein, INTEGRATIVE ANALYSIS, Locus (genetics), 610 Medicine & health, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 360 Social problems & social services, Internal medicine, MD Multidisciplinary, Humans, Erfðafræði, intima media thickness, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, Medicinsk genetik, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Intima-media thickness, genome-wide association studies, quantitative trait loci, lcsh:Q, atherosclerosis, Lod Score, hjarta, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans., The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.

Published
2018

26. Validation of 'laboratory-supported' criteria for functional (psychogenic) tremor

Author

Petra Katschnig-Winter, Mark J. Edwards, Petra Schwingenschuh, Kailash P. Bhatia, Edith Hofer, John C. Rothwell, Natasha M. Maurits, Antonella Macerollo, Marina A. J. Tijssen, Stephan Seiler, Sebastian Franthal, Tabish A. Saifee, Mariella Koegl-Wallner, Valeriu Culea, C. Ghadery, Reinhold Schmidt, U. Werner, and Tamara Pendl

Subjects
medicine.medical_specialty, Movement disorders, medicine.diagnostic_test, Prospective data, Test sensitivity, Electromyography, Psychogenic tremor, 03 medical and health sciences, Inter-rater reliability, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Clinical diagnosis, Physical therapy, medicine, Psychogenic disease, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract

BACKGROUND: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity. OBJECTIVES: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty. METHODS: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor. RESULTS: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P

Published
2016

27. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Macé, Carlo Sidore, Stella Trompet, Massimo Mangino, Maria Sabater-Lleal, John P. Kemp, Ali Abbasi, Tim Kacprowski, Niek Verweij, Albert V. Smith, Tao Huang, Carola Marzi, Mary F. Feitosa, Kurt K. Lohman, Marcus E. Kleber, Yuri Milaneschi, Christian Mueller, Mahmudul Huq, Efthymia Vlachopoulou, Leo-Pekka Lyytikäinen, Christopher Oldmeadow, Joris Deelen, Markus Perola, Jing Hua Zhao, Bjarke Feenstra, Marzyeh Amini, Jari Lahti, Katharina E. Schraut, Myriam Fornage, Bhoom Suktitipat, Wei-Min Chen, Xiaohui Li, Teresa Nutile, Giovanni Malerba, Jian’an Luan, Tom Bak, Nicholas Schork, Fabiola Del Greco M., Elisabeth Thiering, Anubha Mahajan, Riccardo E. Marioni, Evelin Mihailov, Joel Eriksson, Ayse Bilge Ozel, Weihua Zhang, Maria Nethander, Yu-Ching Cheng, Stella Aslibekyan, Wei Ang, Ilaria Gandin, Loïc Yengo, Laura Portas, Charles Kooperberg, Edith Hofer, Kumar B. Rajan, Claudia Schurmann, Wouter den Hollander, Tarunveer S. Ahluwalia, Jing Zhao, Harmen H.M. Draisma, Ian Ford, Nicholas Timpson, Alexander Teumer, Hongyan Huang, Simone Wahl, YongMei Liu, Jie Huang, Hae-Won Uh, Frank Geller, Peter K. Joshi, Lisa R. Yanek, Elisabetta Trabetti, Benjamin Lehne, Diego Vozzi, Marie Verbanck, Ginevra Biino, Yasaman Saba, Ingrid Meulenbelt, Jeff R. O’Connell, Markku Laakso, Franco Giulianini, Patrik K.E. Magnusson, Christie M. Ballantyne, Jouke Jan Hottenga, Grant W. Montgomery, Fernando Rivadineira, Rico Rueedi, Maristella Steri, Karl-Heinz Herzig, David J. Stott, Cristina Menni, Mattias Frånberg, Beate St. Pourcain, Stephan B. Felix, Tune H. Pers, Stephan J.L. Bakker, Peter Kraft, Annette Peters, Dhananjay Vaidya, Graciela Delgado, Johannes H. Smit, Vera Großmann, Juha Sinisalo, Ilkka Seppälä, Stephen R. Williams, Elizabeth G. Holliday, Matthijs Moed, Claudia Langenberg, Katri Räikkönen, Jingzhong Ding, Harry Campbell, Michele M. Sale, Yii-Der I. Chen, Alan L. James, Daniela Ruggiero, Nicole Soranzo, Catharina A. Hartman, Erin N. Smith, Gerald S. Berenson, Christian Fuchsberger, Dena Hernandez, Carla M.T. Tiesler, Vilmantas Giedraitis, David Liewald, Krista Fischer, Dan Mellström, Anders Larsson, Yunmei Wang, William R. Scott, Matthias Lorentzon, John Beilby, Kathleen A. Ryan, Craig E. Pennell, Dragana Vuckovic, Beverly Balkau, Maria Pina Concas, Reinhold Schmidt, Carlos F. Mendes de Leon, Erwin P. Bottinger, Margreet Kloppenburg, Lavinia Paternoster, Michael Boehnke, A.W. Musk, Gonneke Willemsen, David M. Evans, Pamela A.F. Madden, Mika Kähönen, Zoltán Kutalik, Magdalena Zoledziewska, Ville Karhunen, Stephen B. Kritchevsky, Naveed Sattar, Genevieve Lachance, Robert Clarke, Tamara B. Harris, Olli T. Raitakari, John R. Attia, Diana van Heemst, Eero Kajantie, Rossella Sorice, Giovanni Gambaro, Robert A. Scott, Andrew A. Hicks, Luigi Ferrucci, Marie Standl, Cecilia M. Lindgren, John M. Starr, Magnus Karlsson, Lars Lind, Jun Z. Li, John C. Chambers, Trevor A. Mori, Eco J.C.N. de Geus, Andrew C. Heath, Nicholas G. Martin, Juha Auvinen, Brendan M. Buckley, Anton J.M. de Craen, Melanie Waldenberger, Konstantin Strauch, Thomas Meitinger, Rodney J. Scott, Mark McEvoy, Marian Beekman, Cristina Bombieri, Paul M. Ridker, Karen L. Mohlke, Nancy L. Pedersen, Alanna C. Morrison, Dorret I. Boomsma, John B. Whitfield, David P. Strachan, Albert Hofman, Peter Vollenweider, Francesco Cucca, Marjo-Riitta Jarvelin, J. Wouter Jukema, Tim D. Spector, Anders Hamsten, Tanja Zeller, André G. Uitterlinden, Matthias Nauck, Vilmundur Gudnason, Lu Qi, Harald Grallert, Ingrid B. Borecki, Jerome I. Rotter, Winfried März, Philipp S. Wild, Marja-Liisa Lokki, Michael Boyle, Veikko Salomaa, Mads Melbye, Johan G. Eriksson, James F. Wilson, Brenda W.J.H. Penninx, Diane M. Becker, Bradford B. Worrall, Greg Gibson, Ronald M. Krauss, Marina Ciullo, Gianluigi Zaza, Nicholas J. Wareham, Albertine J. Oldehinkel, Lyle J. Palmer, Sarah S. Murray, Peter P. Pramstaller, Stefania Bandinelli, Joachim Heinrich, Erik Ingelsson, Ian J. Deary, Reedik Mägi, Liesbeth Vandenput, Pim van der Harst, Karl C. Desch, Jaspal S. Kooner, Claes Ohlsson, Caroline Hayward, Terho Lehtimäki, Alan R. Shuldiner, Donna K. Arnett, Lawrence J. Beilin, Antonietta Robino, Philippe Froguel, Mario Pirastu, Tine Jess, Wolfgang Koenig, Ruth J.F. Loos, Denis A. Evans, Helena Schmidt, George Davey Smith, P. Eline Slagboom, Gudny Eiriksdottir, Andrew P. Morris, Bruce M. Psaty, Russell P. Tracy, Ilja M. Nolte, Eric Boerwinkle, Sophie Visvikis-Siest, Alex P. Reiner, Myron Gross, Joshua C. Bis, Lude Franke, Oscar H. Franco, Emelia J. Benjamin, Daniel I. Chasman, Josée Dupuis, Harold Snieder, Abbas Dehghan, Behrooz Z. Alizadeh, H. Marike Boezen, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Emelia Benjamin, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Josh Bis, Nathan Pankratz, Alex Rainer, James G. Wilson, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Terho Lehtimaki, Yalda Jamshidi, Sophie Siest, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey-Smith, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, J. Rotter, Ken Rice, Leslie Lange, Eco de Geus, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, Eline P. Slagboom, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center Groningen [Groningen] (UMCG), University of Isfahan, University of Tartu, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The University of Texas Health Science Center at Houston (UTHealth), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Split, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Process & Energy Laboratory, Delft University of Technology (TU Delft), Grand Lyon : communauté urbaine de Lyon, Interuniversity Cardiology Institute Netherlands, Department of Twin Research and Genetic Epidemiology, King's College London, London, Huazhong University of Science and Technology [Wuhan] (HUST), Division of Statistical Genomics, Washington University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Institut fuer Theoretische Physik (Institut fuer Theoretische Physik), Universität Heidelberg [Heidelberg] = Heidelberg University, Molecular Epidemiology, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Mahidol University [Bangkok], Northwest A and F University, Laboratoire d'Optimisation des Systèmes Industriels (LOSI), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetics and Biophysics, CNR, Naples, Università degli studi di Verona = University of Verona (UNIVR), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], University of Maryland School of Medicine, University of Maryland System, Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Pop. Genetics, CNR, Sassari, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, IT University of Copenhagen (ITU), Robertson Centre for Biostatistics, University of Glasgow, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, King‘s College London, Jinan University [Guangzhou], Institute of Oceanology [China], School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Shardna life science Pula Cagliari, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Medstar Research Institute, Department of Cardiology, Ernst-Moritz-Arndt University, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Department of Epidemiology, Harvard School of Public Health, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Metacohorts Consortium, INEOS Technologies (SWITZERLAND), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, University of Edinburgh, School of Population Health [Crawley, Western Australia], The University of Western Australia (UWA), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), The Scripps Translational Science Institute and Scripps Health, Tulane Center for Cardiovascular Health, Tulane University Health Sciences Center, Centre for Population Health Sciences, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Luleå University of Technology (LUT), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austrian Institute of Technology [Vienna] (AIT), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC), Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC), Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Virginia, Tampere University Hospital, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Department of Pathological Biochemistry, Royal Infirmary, Oxford University, University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Department of neurology, Institute of Metabolic Science, MRC, The Wellcome Trust Centre for Human Genetics [Oxford], Uppsala Universitet [Uppsala], QIMR Berghofer Medical Research Institute, Institute of Genetic Epidemiology [Neuherberg, Germany], Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Schizophrenia Research Institute [Sydney], Department of Genetics, University of North Carolina System (UNC)-University of North Carolina System (UNC), Vrije Universiteit Brussel (VUB), Population Health Sciences and Education, St George's University of London, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Health Sciences and Biocenter Oulu, University of Oulu, Medizinische Klinik und Poliklinik, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institute of Clinical Chemistry and Laboratory Medicine, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Departments of Epidemiology and Nutrition, Institute of Epidemiology [Neuherberg] (EPI), Medical University Graz, Transplantation Laboratory [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], CLinical Psychology, Genetics and Pathology, Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Center For Narcolepsy, Stanford University, Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, University of Maryland School of Medicine [Baltimore, MD, USA], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Stockholm], Stockholm University, University of Bristol [Bristol], Universiteit Leiden, Department of Epidemiology, University of Washington, University of Washington [Seattle], Department of Epidemiology [Rotterdam], University of Groningen [Groningen], Dutch Initiative on Crohn and Colitis (ICC), Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Physiology and Biophysics [Jackson, MS, USA], University of Southern Mississippi (USM), Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Department of Social Medicine, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Mathematical Institute [Oxford] (MI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, LifeLines Cohort Study, CHARGE Inflammation Working Group, Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L. -P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H. R., Wijmenga, C., Amini, M., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y. -H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W. -M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M. F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y. -C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H. -W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K. -H., Stott, D. J., Menni, C., Franberg, M., S, t. Pourcain B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Grossmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. -D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., Mcevoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M. -R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M. -L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Loos, R. J. F., Evans, D. A., Schmidt, H., Slagboom, P. E., Tracy, R. P., Visvikis-Siest, S., Reiner, A. P., Bis, J. C., Franco, O. H., Benjamin, E. J., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Epidemiology, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), VU University medical center, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Digital Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Universität Heidelberg [Heidelberg], University of Verona (UNIVR), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), IT University of Copenhagen, Technical University of Denmark [Lyngby] (DTU), Consiglio Nazionale delle Ricerche (CNR), University of Virginia [Charlottesville], Université de Lausanne (UNIL), University of Oxford [Oxford], University of Newcastle [Australia] (UoN), Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Helmholtz-Zentrum München (HZM), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Universitätsmedizin der Johannes-Gutenberg Universität Mainz, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Cardiff University-Medical Research Council, University of California-University of California, and DE CARVALHO, Philippe

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Bipolar Disorder, LD SCORE REGRESSION, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, inflammatory disorder, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, ta318, International HapMap Project, Child, Genetics (clinical), 2. Zero hunger, Genetics, Genetics & Heredity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biology, system biology, DEPICT, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, C-reactive protein, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, Adolescent, Adult, Aged, Biomarkers, C-Reactive Protein, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Metabolic Networks and Pathways, Schizophrenia, Young Adult, 3. Good health, [SDV] Life Sciences [q-bio], Medical genetics, Biomarker (medicine), Life Sciences & Biomedicine, Human, medicine.medical_specialty, CHARGE Inflammation Working Group, Biology, IMMUNITY, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, CORONARY-HEART-DISEASE, Mendelian Randomization Analysi, 1000 Genomes Project, METAANALYSIS, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, ta1184, Metabolic Networks and Pathway, Biomarker, INSTRUMENTS, 06 Biological Sciences, 030104 developmental biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, LifeLines Cohort Study
Abstract

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.

Published
2018

28. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author

Charles DeCarli, Vilmundur Gudnason, Debra A. Fleischman, Henning Tiemeier, Rebecca F. Gottesman, William S. Kremen, Xueqiu Jian, Henry Brodaty, Maria del C. Valdés Hernández, Markus Loeffler, Reinhold Schmidt, Shahzad Ahmad, Paul A. Nyquist, Oscar L. Lopez, Anbupalam Thalamuthu, Helena Schmidt, Peter R. Schofield, Tonya White, Edith Hofer, Philip L. De Jager, David Ames, Qiong Yang, Ole A. Andreassen, Cora E. Lewis, Matthias Nauck, David S. Knopman, Anders M. Dale, Sven J. van der Lee, Jeroen van der Grond, Konstantinos Arfanakis, Margaret J. Wright, Jingyun Yang, John B.J. Kwok, Hieab H.H. Adams, Matthew S. Panizzon, Meike W. Vernooij, Yasaman Saba, David A. Bennett, Cornelia M. van Duijn, Tamara B. Harris, Pauline Maillard, Frauke Beyer, M. Arfan Ikram, Jerome I. Rotter, Ryan L. Muetzel, Tomáš Paus, Pamela J. Schreiner, Zdenka Pausova, Katharina Wittfeld, Diane M. Becker, Bruce M. Psaty, Alexander Teumer, Wei Wen, A. Veronica Witte, Karen A. Mather, Hanan El Marroun, William T. Longstreth, Perminder S. Sachdev, Mark E. Bastin, Nathan A. Gillespie, Kenneth Rice, Stella Trompet, Lisa R. Yanek, David J. Stott, Alexa S. Beiser, R. Nick Bryan, Alexander Neumann, Natalie A. Royle, Myriam Fornage, Manon Bernard, Dina Vojinovic, Najaf Amin, Ian J. Deary, Arno Villringer, Georg Homuth, Nicola J. Armstrong, Stephen Sidney, Sudha Seshadri, Joanna M. Wardlaw, Thomas H. Mosley, Hans J. Grabe, Michelle Luciano, Lenore J. Launer, J. Wouter Jukema, Robin Bülow, Markus Scholz, André G. Uitterlinden, Albert V. Smith, Shuo Li, Claudia L. Satizabal, Joshua C. Bis, Epidemiology, Radiology & Nuclear Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Psychology, Internal Medicine, Psychiatry, Neurology, Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands (HÍ), and University of Iceland (UI)

Subjects
0301 basic medicine, Genetics of the nervous system, Cytoskeleton organization, General Physics and Astronomy, Genome-wide association study, Mental disorders, Genome-wide association studies, Genome, Lateral ventricles, 0302 clinical medicine, Lateral Ventricles, Ventricle (lateral), lcsh:Science, Genetics, anatomy & histology [Lateral Ventricles], education.field_of_study, Enlargement, Multidisciplinary, Brain, Organ Size, Middle Aged, Schizophrenia, ddc:500, Science, Population, Elderly people, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Erfðafræði, Humans, Genomes, education, Aged, Genetic association, genetics [Organ Size], Genome, Human, Heilinn, Brain morphometry, Litningarannsóknir, Rannsóknir, General Chemistry, medicine.disease, 030104 developmental biology, Heritable quantitative trait, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein) Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology., See Supplementary Note 2 for information on funding sources.

Published
2018

29. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)

Published
2018

30. Cognitive Deficits and Related Brain Lesions in Patients With Chronic Heart Failure

Author

Laszlo Solymosi, Peter Kraft, Guido Stoll, Ignaz Gunreben, Peter U. Heuschmann, Stefan Störk, Eric Schmid, Caroline Morbach, György A. Homola, Carolin Malsch, Reinhold Schmidt, Anna Frey, Balint Alkonyi, Georg Ertl, Wolfgang Müllges, Roxane Sell, Edith Hofer, and Isabella Colonna

Subjects
Male, medicine.medical_specialty, Intelligence, Diastole, 030204 cardiovascular system & hematology, Neuropsychological Tests, Vocabulary, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Reaction Time, Medicine, Humans, In patient, Cognitive Dysfunction, Aged, Brain Diseases, Heart Failure, Diastolic, Ejection fraction, business.industry, Cognition, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Memory, Short-Term, Stroke prevention, Heart failure, Case-Control Studies, Chronic Disease, Cardiology, Brain lesions, Female, Verbal memory, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, Heart Failure, Systolic
Abstract

This study sought to determine the spectrum of brain lesions seen in heart failure (HF) patients and the extent to which lesion type contributes to cognitive impairment.Cognitive deficits have been reported in patients with HF.A total of 148 systolic and diastolic HF patients (mean age 64 ± 11 years; 16% female; mean left ventricular ejection fraction 43 ± 8%) were extensively evaluated within 2 days by cardiological, neurological, and neuropsychological testing and brain magnetic resonance imaging (MRI). A total of 288 healthy, sex- and age-matched subjects sampled from the Austrian Stroke Prevention Study served as MRI controls.Deficits in reaction times were apparent in 41% of patients and deficits in verbal memory in 46%. On brain MRI, patients showed more advanced medial temporal lobe atrophy (MTA) (Scheltens score) compared to controls (2.1 ± 0.9 vs. 1.0 ± 0.6; p 0.001). The degree of MTA was strongly associated with the severity of cognitive impairment, whereas the extent of white matter hyperintensities was similar in patients and controls. Moreover, patients had a 2.7-fold increased risk for presence of clinically silent lacunes.HF patients exhibit cognitive deficits in the domains of attention and memory. MTA but not white matter lesion load seems to be related to cognitive impairment.

Published
2017

31. Novel genetic loci associated with hippocampal volume

Author

Benjamin S. Aribisala, Marjolein M.J. van Donkelaar, Randy L. Gollub, Rachel M. Brouwer, Norman Delanty, Tomas Axelsson, Oscar L. Lopez, Thomas Espeseth, Alejandro Arias-Vasquez, Kristel R. van Eijk, Tien Yin Wong, Jeroen van der Grond, Georg Homuth, James T. Becker, Sebastian Guelfi, Anton J. M. de Craen, Bruno Vellas, Christopher R.K. Ching, Charles C. DeCarli, Janita Bralten, Lars T. Westlye, Ryota Hashimoto, Sampath Arepalli, Bertram Müller-Myhsok, Loes M. Olde Loohuis, Sudha Seshadri, Simon E. Fisher, K Hegenscheid, Konstantinos Arfanakis, Zdenka Pausova, Robert C. Green, Simone Reppermund, Katie L. McMahon, Ashley Beecham, Daan van Rooij, Marcel P. Zwiers, Karen A. Mather, Randy L. Buckner, Edith Hofer, Marcella Rietschel, Fabrice Crivello, Ronald H. Zielke, G. Bruce Pike, Thomas W. Mühleisen, Myriam Fornage, Kazutaka Ohi, Gareth E. Davies, Chantal Depondt, Gabriel Cuellar-Partida, Iryna O. Fedko, Peter R. Schofield, Steven G. Potkin, Albert Hofman, Paul M. Thompson, Wiro J. Niessen, Deborah Janowitz, Nicholas G. Martin, Li Shen, Mina Ryten, Meike W. Vernooij, Michael E. Weale, Tonya White, Dennis van 't Ent, Sudheer Giddaluru, Nanda Rommelse, Wei Wen, Sven J. van der Lee, Eco J. C. de Geus, Aaron Goldman, Joanne E. Curran, Qiang Chen, Jean Shin, Wayne C. Drevets, Thomas H. Mosley, Matthias Nauck, Massimo Pandolfo, Anders M. Dale, Paul A. Nyquist, Girma Woldehawariat, Francis J. McMahon, Najaf Amin, Emma J. Rose, Norbert Hosten, David J. Stott, Sigurdur Sigursson, Andrew J. Saykin, M. Kamran Ikram, Pieter J. Hoekstra, Neda Jahanshad, Grant W. Montgomery, Michael Weiner, Aad van der Lugt, Esther Walton, Gunter Schumann, Clyde Francks, Narelle K. Hansell, Xinmin Liu, Herve Lemaitre, Cornelia M. van Duijn, Ralph L. Sacco, Clinton B. Wright, Arvin Saremi, Clifford R. Jack, Andre G. Uitterlinden, G. Donohoe, Tomáš Paus, Michael Griswold, Peter T. Fox, Alan B. Zonderman, Lukas Pirpamer, Christiane Wolf, Aiden Corvin, Shannon L. Risacher, Ian Ford, Philippe Amouyel, Henrik Walter, Beng-Choon Ho, William T. Longstreth, M. Arfan Ikram, Hieab H.H. Adams, Colin Smith, Sungeun Kim, Simon Lovestone, Stefan Ehrlich, Benno Pütz, Markus M. Nöthen, Susana Muñoz Maniega, Ian J. Deary, Elena Shumskaya, Susan H. Blanton, Jerome I. Rotter, Neeltje E.M. van Haren, Mar Matarin, I. Kloszewska, Ganesh Chauhan, Anita L. DeStefano, Barbara Franke, Lars Nyberg, Tatiana Foroud, Tianye Jia, Manon Bernard, Unn K. Haukvik, Rebecca F. Gottesman, Srdjan Djurovic, Ching-Yu Cheng, Lachlan T. Strike, Alex P. Zijdenbos, Jouke-Jan Hottenga, Vince D. Calhoun, Yuri Milaneschi, David C. Glahn, Phil Lee, Amelia A. Assareh, Adaikalavan Ramasamy, Emma Sprooten, Debra A. Fleischman, David R. McKay, J. Raphael Gibbs, Bruce M. Psaty, Kazima B. Bulayeva, Bryan J. Traynor, Vilmundur Gudnason, Jessika E. Sussmann, Alexander Teumer, Guillén Fernández, Katharina Wittfeld, Christophe Tzourio, Dennis van der Meer, Wolfgang Hoffmann, Sebastian Mohnke, David C. Liewald, Jordan W. Smoller, Theo G.M. van Erp, Marcel Van Der Brug, Dara M. Cannon, Lenore J. Launer, D. Ames, Juan C. Troncoso, Brenda W.J.H. Penninx, Dhananjay Vaidya, Thomas D. Dyer, Marie-José van Tol, Han G. Brunner, Andrew Singleton, Lavinia Athanasiu, Adam M. Brickman, Eric Westman, P. Mecocci, Sandra Barral, Dick J. Veltman, Catharina A. Hartman, Benedicto Crespo-Facorro, Alexa S. Beiser, Vincent Chouraki, Nhat Trung Doan, Marieke Klein, Jaap Oosterlaan, Natalie A. Royle, John B.J. Kwok, Saud Alhusaini, Ingrid Melle, Roberto Toro, Ravi Duggirala, Allissa Dillman, Reinhold Schmidt, Lisa R. Yanek, Anbupalam Thalamuthu, Helena Schmidt, Derrek P. Hibar, Albert V. Smith, Jean-Luc Martinot, Thomas H. Wassink, Jennifer S. Richards, Oliver Martinez, Joshua L. Roffman, Sylvane Desrivières, Hilkka Soininen, Rene L. Olvera, Ole A. Andreassen, Diana Tordesillas-Gutiérrez, Claudia L. Satizabal, Owen Carmichael, Lianne Schmaal, Bernd Kraemer, Martine Hoogman, Daniah Trabzuni, Oliver Grimm, Andrew M. McIntosh, René S. Kahn, Nazanin Karbalai, Margaret J. Wright, Harald H.H. Göring, Martina Papmeyer, Roberto Roiz-Santiañez, Luigi Ferrucci, David A. Bennett, Kwangsik Nho, Gianpiero L. Cavalleri, Andreas Meyer-Lindenberg, Masashi Ikeda, Avram J. Holmes, Greig I. de Zubicaray, Andreas Heinz, Tatjana Rundek, Maria del C. Valdés Hernández, Dalia Kasperaviciute, Dan L. Longo, Matthew J. Huentelman, Wiepke Cahn, Beverly G. Windham, Michael A. Nalls, Philipp G. Sämann, Stella Trompet, Vidar M. Steen, Marc M. Bohlken, Christopher D. Whelan, Hilleke E. Hulshoff Pol, Susanne Erk, Dorret I. Boomsma, Dirk J. Heslenfeld, Masaki Fukunaga, D. Hoehn, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, M. R. Cookson, C. McDonald, Magda Tsolaki, Badri N. Vardarajan, Jason L. Stein, Jan K. Buitelaar, Erik G. Jönsson, Oliver Gruber, Robert Johnson, Jingyun Yang, Joshua C. Bis, J. Wouter Jukema, Tulio Guadalupe, Nina Romanczuk-Seiferth, Kjetil Nordbø Jørgensen, Henry Brodaty, Diane M. Becker, Anouk den Braber, Allison C. Nugent, Thomas Wolfers, John Hardy, Joanna M. Wardlaw, Michelle Luciano, Christine Macare, Dena G. Hernandez, D. Morris, John Blangero, Andrew J. Schork, Daniel R. Weinberger, Johanna Hass, Andrew Simmons, Micael Andersson, Lucija Abramovic, David S. Knopman, Mark Jenkinson, Roel A. Ophoff, Sanjay M. Sisodiya, Boris A. Gutman, Asta Håberg, Stephanie Le Hellard, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Hans J. Grabe, Henry Völzke, Thomas E. Nichols, Manuel Mattheisen, Sven Cichon, Venkata S. Mattay, Ingrid Agartz, Stefan Ropele, Lorna M. Lopez, Hans van Bokhoven, Philip L. De Jager, Miguel E. Rentería, Laura Almasy, Arthur W. Toga, Michael Czisch, Florian Holsboer, Ryota Kanai, Nic J.A. van der Wee, Peter Kochunov, Perminder S. Sachdev, Andre F. Marquand, Christian Enzinger, Anderson M. Winkler, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Metacohorts Consortium, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, sans affiliation, QIMR Berghofer Medical Research Institute, University of Washington [Seattle], Department of Psychiatry, Donders Centre for Neuroscience, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University Medical Center [Utrecht], Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Sahlgrenska University Hospital [Gothenburg], Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), Assistance Publique - Hôpitaux de Marseille (APHM), University of Oslo (UiO), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), Douglas Mental Health University Institute, McGill University = Université McGill [Montréal, Canada], Université Lille Nord de France (COMUE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Haukeland University Hospital, University of Bergen (UiB), Ames Laboratory [Ames, USA], Iowa State University (ISU)-U.S. Department of Energy [Washington] (DOE), Johns Hopkins University School of Medicine [Baltimore], Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Laboratory of Neuro Imaging [Los Angeles] (LONI), Department of Mathematics [UCLA], Georgia Institute of Technology [Atlanta], Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany, Greifswald University Hospital, Beijing Normal University (BNU), Aalborg University [Denmark] (AAU), UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Imperial College London, Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Department of Neurology, Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Department of Neurology [Austria], Medical University Graz, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [San Diego], Wuhan University [China], Plymouth University, Dpt of Psychiatry [New Haven], Yale University School of Medicine, Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre, Depts of Radiology, Leiden University Medical Center (LUMC), University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), RCMG Ghent, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), National Institutes of Health [Bethesda] (NIH), Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Université de Lille, Department of Clinical Genetics, Department of Experimental Physics, National University of Ireland Maynooth (Maynooth University), Texas Biomedical Research Institute [San Antonio, TX], The University of Texas Health Science Center at Houston (UTHealth), 849 Department of Human Genetics, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], The Mind Research Network, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Northwestern Polytechnical University [Xi'an] (NPU), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], York Structural Biology Laboratory, Department of Chemistry, University of York [York, UK], Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], School of Psychology, University of Queensland, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), École des hautes études en sciences sociales (EHESS), Department of Radiology, Mayo Clinic, Robertson Centre for Biostatistics, University of Glasgow, Human Genetics Center, Department of Medical and Molecular Genetics, Rensselaer Polytechnic Institute (RPI), Department of Physics, Okayama University, Okayama University, University of New Haven [Connecticut], Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., University of Science, VNU-HCM, University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Medical Genetics, HMNC Brain Health, University of Oxford [Oxford], University of Florida [Gainesville] (UF), Göteborgs Universitet (GU), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Brain Centre Rudolf Magnus [Utrecht], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Institute of Cognitive Neuroscience, University College of London [London] (UCL), Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Psychiatry Institute, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, University of Mississippi Medical Center (UMMC), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Department of Statistics [Coventry], University of Warwick [Coventry], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Osaka University [Osaka], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Politecnico di Milano [Milan] (POLIMI), University of Applied Sciences [Munich], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, National Institute of Aging, 3rd Department of Neurology, Aristotle University of Thessaloniki-General Hospital of Thessaloniki George Papanikolaou, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Pretoria [South Africa], University of Missouri [Columbia] (Mizzou), University of Missouri System, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of Southern California (USC), University of California (UC)-University of California (UC), Sans affiliation, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], University of Toronto, Radboud University [Nijmegen], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universität Bonn = University of Bonn, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Universiteit Gent = Ghent University (UGENT), Centre épigénétique et destin cellulaire (EDC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], University of Oxford, University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, University of Eastern Finland, Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Radboud University [Nijmegen]-Radboud University [Nijmegen], School of Medicine / Clinical Medicine, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, Adult Psychiatry, ARD - Amsterdam Reproduction and Development, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], McGill University-McGill University, Sahlgrenska University Hospital, McGill University, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), University of Bergen (UIB), Iowa State University (ISU)-U.S. Department of Energy (DOE), Beijing Normal University, Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Gènes, Synapses et Cognition, Ghent University [Belgium] (UGENT), National University of Ireland Maynooth (NUIM), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], University of Florida [Gainesville], Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Aristotle University of Thessaloniki-G. Papanikolaou Hospital, Humboldt Universität zu Berlin, University of Missouri [Columbia], Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Neurology, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, Cognitive Psychology, IBBA, APH - Personalized Medicine, Amsterdam Neuroscience - Brain Imaging, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, APH - Digital Health, Hal, GIN, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Universidad de Cantabria, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Male, Netherlands Twin Register (NTR), Genome-wide association study, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Spatial memory, 0302 clinical medicine, 610 Medicine & health, Child, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Episodic memory, Aged, 80 and over, Subiculum, 220 Statistical Imaging Neuroscience, COMMON VARIANTS, ALZHEIMERS-DISEASE, ddc:500, Alzheimer's disease, genetics [Methionine Sulfoxide Reductases], Science, Locus (genetics), genetics [Protein-Serine-Threonine Kinases], Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Alzheimer Disease, ASTN2 protein, human, Humans, GENOME-WIDE ASSOCIATION, METAANALYSIS, Aged, Glycoproteins, Dentate gyrus, MEMORY, medicine.disease, R1, 030104 developmental biology, nervous system, Genetic Loci, MSRB3 protein, human, 030217 neurology & neurosurgery, 0301 basic medicine, General Physics and Astronomy, genetics [Alzheimer Disease], Hippocampal formation, Hippocampus, Genome-wide association studies, Taugasjúkdómar, Cohort Studies, DPP4 protein, human, TEMPORAL-LOBE EPILEPSY, BRAIN-REGIONS, genetics [Dipeptidyl Peptidase 4], genetics [Nerve Tissue Proteins], Genetics, Multidisciplinary, Neurodegenerative diseases, BIPOLAR DISORDER, Organ Size, Middle Aged, SUBFIELDS, Protein-Serine-Threonine Kinases, growth & development [Hippocampus], Female, genetics [Glycoproteins], Microtubule-Associated Proteins, Medical Genetics, Neuroinformatics, Adult, genetics [Microtubule-Associated Proteins], Adolescent, SUSCEPTIBILITY LOCI, Dipeptidyl Peptidase 4, genetics [Protein Serine-Threonine Kinases], Nerve Tissue Proteins, Bioinformatik och systembiologi, Protein Serine-Threonine Kinases, Biology, physiopathology [Alzheimer Disease], 150 000 MR Techniques in Brain Function, Young Adult, MAST4 protein, human, medicine, Journal Article, Erfðafræði, Genetic Predisposition to Disease, ddc:610, Medicinsk genetik, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Bioinformatics and Systems Biology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Rannsóknir, General Chemistry, Methionine Sulfoxide Reductases, 150 Psychology, Genome-Wide Association Study
Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness., published version, peerReviewed

Published
2017

32. Strategic white matter tracts for processing speed deficits in age-related small vessel disease

Author

Stefan Ropele, Martin Dichgans, Lukas Pirpamer, Benno Gesierich, Reinhold Schmidt, Stephan Seiler, Edith Hofer, Mariya Gonik, Edouard Duchesnay, Eric Jouvent, Marco Duering, and Hugues Chabriat

Subjects
Male, Trail Making Test, Disease, physiopathology [Brain], computer.software_genre, Brain mapping, blood supply [Brain], Lesion, White matter, methods [Brain Mapping], Leukoencephalopathies, pathology [Brain], Region of interest, Voxel, medicine, Humans, ddc:610, physiopathology [Cerebral Small Vessel Diseases], Aged, physiopathology [Leukoencephalopathies], Brain Mapping, pathology [Leukoencephalopathies], Brain, etiology [Cognition Disorders], Anatomy, instrumentation [Brain Mapping], Middle Aged, Hyperintensity, etiology [Leukoencephalopathies], medicine.anatomical_structure, Cerebral Small Vessel Diseases, complications [Cerebral Small Vessel Diseases], physiopathology [Cognition Disorders], pathology [Cerebral Small Vessel Diseases], pathology [Cognition Disorders], Female, Neurology (clinical), medicine.symptom, Cognition Disorders, Psychology, Neuroscience, computer
Abstract

Objective: Cerebral small vessel disease is the most common cause of vascular cognitive impairment and typically manifests with slowed processing speed. We investigated the impact of lesion location on processing speed in age-related small vessel disease. Methods: A total of 584 community-dwelling elderly underwent brain MRI followed by segmentation of white matter hyperintensities. Processing speed was determined by the timed measure of the Trail Making Test part B. The impact of the location of white matter hyperintensities was assessed by voxel-based lesion-symptom mapping and graph-based statistical models on regional lesion volumes in major white matter tracts. Results: Voxel-based lesion-symptom mapping identified multiple voxel clusters where the presence of white matter hyperintensities was associated with slower performance on the Trail Making Test part B. Clusters were located bilaterally in the forceps minor and anterior thalamic radiation. Region of interest–based Bayesian network analyses on lesion volumes within major white matter tracts depicted the same tracts as direct predictors for an impaired Trail Making Test part B performance. Conclusions: Our findings highlight damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal-subcortical neuronal circuits as a predictor for processing speed performance in age-related small vessel disease.

Published
2014

33. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author

G. Bruce Pike, Marcel P. Zwiers, Andreas Meyer-Lindenberg, Jeroen van der Grond, Randy L. Gollub, Karen A. Mather, Andrew J. Schork, Vidar M. Steen, Marc M. Bohlken, Nhat Trung Doan, Derek W. Morris, John B.J. Kwok, Emma J. Rose, Johanna Hass, Andrew Simmons, Tian Ge, Reinhold Schmidt, Micael Andersson, Ian J. Deary, Christopher Chen, Derrek P. Hibar, Simon E. Fisher, Lucija Abramovic, Marcella Rietschel, Edith Hofer, Simon Lovestone, Clyde Francks, Christopher R.K. Ching, Srdjan Djurovic, Lachlan T. Strike, Lorna M. Lopez, Rene L. Olvera, Owen Carmichael, M. Arfan Ikram, Andre F. Marquand, Christine Macare, W.T. Longstreth, Philippe Amouyel, Aaron L. Goldman, Wolfgang Hoffmann, Philip L. De Jager, David C. Liewald, Harald H H Göring, Aad van der Lugt, David Ames, Neeltje E.M. van Haren, Lars Nyberg, Nina Romanczuk-Seiferth, Lukas Pirpamer, Stefan Ehrlich, Alexa S. Beiser, Lianne Schmaal, Hilkka Soininen, Mark Jenkinson, Kazima B. Bulayeva, Anderson M. Winkler, Mike A. Nalls, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lars T. Westlye, Loes M. Olde Loohuis, Andrew Singleton, Gabriel Cuellar-Partida, Randy L. Buckner, Dorret I. Boomsma, Dena G. Hernandez, Steven G. Potkin, Sudha Seshadri, Bertram Müller-Myhsok, D. Hoehn, Gareth E. Davies, Chantal Depondt, Henrik Walter, Michael E. Weale, Deborah Janowitz, Susanne Erk, Iryna O. Fedko, Daniel R. Weinberger, Nic J A van der Wee, Jean-Luc Martinot, Jessica A. Turner, Marieke Klein, Sandra Barral, Sebastian Mohnke, Albert Hofman, Ingrid Melle, Saud Alhusaini, Vincent Chouraki, Stephen M. Lawrie, Mark E. Bastin, Juan C. Troncoso, Jean Shin, Wiro J. Niessen, Diane M. Becker, Laura Almasy, Anders M. Dale, Benjamin S. Aribisala, Dennis van 't Ent, Marco P. Boks, M. Mallar Chakravarty, Paul M. Thompson, David Reese McKay, Michael Griswold, John Blangero, Narelle K. Hansell, Eco J. C. de Geus, Paul A. Nyquist, Susana Muñoz Maniega, Sampath Arepalli, Tatjana Rundek, Dan L. Longo, Anton J. M. de Craen, Rebekah McWhirter, Nazanin Mirza-Schreiber, Henning Tiemeier, Girma Woldehawariat, Sven Cichon, Irene Pappa, Amelia A. Assareh, Sudheer Giddaluru, Pieter J. Hoekstra, Hieab H.H. Adams, Hilleke E. Hulshoff Pol, Grant W. Montgomery, Roel A. Ophoff, Markus M. Nöthen, Sara Pudas, Sigurdur Sigurdsson, Arthur W. Toga, Tien Yin Wong, Massimo Pandolfo, Corina U. Greven, Esther Walton, Tianye Jia, David J. Stott, Gunter Schumann, Marie-José van Tol, Dalia Kasperaviciute, Thomas Wolfers, Henry Völzke, Ian Ford, Shannon L. Risacher, Jessika E. Sussmann, Nicholas G. Martin, Wei Wen, Daniah Trabzuni, Iwona Kłoszewska, Kwangsik Nho, Gianpiero L. Cavalleri, Adam M. Brickman, Sungeun Kim, Andreas Heinz, Ralph L. Sacco, Neda Jahanshad, Velandai Srikanth, Elena Shumskaya, Susan H. Blanton, Katharina Wittfeld, Badri N. Vardarajan, Joshua C. Bis, Joanne E. Curran, Helena Schmidt, Peter T. Fox, Clifford R. Jack, Jason L. Stein, Laura M. E. Blanken, Thomas Espeseth, Dick J. Veltman, Sebastian Guelfi, Margaret J. Wright, Norman Delanty, Michael Czisch, Martina Papmeyer, Oscar L. Lopez, Marjolein M. J. Van Donkelaar, Bruce M. Psaty, Jan K. Buitelaar, Sven J. van der Lee, David A. Bennett, Beng-Choon Ho, Oliver Martinez, Wiepke Cahn, Li Shen, J. Wouter Jukema, Janita Bralten, Peter Kochunov, Greig I. Zubicaray, Marcel P. van der Brug, Ching-Yu Cheng, Philipp G. Sämann, Stella Trompet, Roberto Roiz-Santiañez, David C. Glahn, Allissa Dillman, Venkata S. Mattay, Dara M. Cannon, Michael W. Weiner, Christopher D. Whelan, Alexander Teumer, Sylvane Desrivières, Ole A. Andreassen, Thomas E. Nichols, Manuel Mattheisen, Matthias Nauck, René S. Kahn, Albert V. Smith, Colin Smith, Vilmundur Gudnason, Denis A. Evans, Anouk den Braber, Katie L. McMahon, Han G. Brunner, Florian Holsboer, Yuri Milaneschi, Andrew J. Saykin, Jiemin Liao, Vince D. Calhoun, Neelum T. Aggarwal, Dennis van der Meer, Hans J. Grabe, Anita L. DeStefano, Claudia L. Satizabal, Alan B. Zonderman, Alex P. Zijdenbos, Tulio Guadalupe, Ingrid Agartz, Jordan W. Smoller, Allison C. Nugent, Alejandro Arias-Vasquez, Masashi Ikeda, Avram J. Holmes, Brenda W.J.H. Penninx, John Hardy, Herve Lemaitre, Charles DeCarli, Patrizia Mecocci, Catharina A. Hartman, Tomas Axelsson, Oliver Grimm, Irina Filippi, Wayne C. Drevets, Hans van Bokhoven, Miguel E. Rentería, Aiden Corvin, Ryota Kanai, Kristel R. van Eijk, Andrew M. McIntosh, Jouke-Jan Hottenga, Roberto Toro, Lavinia Athanasiu, Joanna M. Wardlaw, Thomas H. Mosley, Mina Ryten, Meike W. Vernooij, Michelle Luciano, Joshua L. Roffman, Rebecca F. Gottesman, Dhananjay Vaidya, Ryota Hashimoto, Mar Matarin, Adaikalavan Ramasamy, Jerome I. Rotter, Ryan L. Muetzel, Konstantinos Arfanakis, Theo G.M. van Erp, Ganesh Chauhan, Xinmin Liu, Tomáš Paus, Emma Sprooten, Christiane Wolf, David S. Knopman, Manon Bernard, Zdenka Pausova, Bryan J. Traynor, Maria C. Valdés Hernández, Robert C. Green, Russell Thomson, Ravi Duggirala, Lisa R. Yanek, Luigi Ferrucci, Bing Xu, Thomas D. Dyer, Thomas H. Wassink, Eric Westman, Jennifer S. Richards, Phil H. Lee, Benno Pütz, Mark R. Cookson, Benedicto Crespo-Facorro, Natalie A. Royle, Bernd Kraemer, Katrin Hegenscheid, Francis J. McMahon, Tatiana Foroud, M. Kamran Ikram, Myriam Fornage, Nanda Rommelse, Saima Hilal, Perminder S. Sachdev, Qiang Chen, Najaf Amin, Lenore J. Launer, Norbert Hosten, Guillén Fernández, Simone Reppermund, Ashley Beecham, Dirk J. Heslenfeld, Masaki Fukunaga, Cornelia M. van Duijn, Clinton B. Wright, Erik G. Jönsson, Sanjay M. Sisodiya, Oliver Gruber, Christophe Tzourio, André G. Uitterlinden, Robert Johnson, Jaap Oosterlaan, Bernard Mazoyer, H. Ronald Zielke, Stephanie Le Hellard, Jingyun Yang, Georg Homuth, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Henry Brodaty, Beverly G Windham, Gary Donohoe, Rachel M. Brouwer, James T. Becker, Kumar B. Rajan, Daan van Rooij, Thomas W. Mühleisen, Kazutaka Ohi, Peter R. Schofield, Tonya White, Barbara Franke, Unn K. Haukvik, Debra A. Fleischman, J. Raphael Gibbs, Colm McDonald, Anbupalam Thalamuthu, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Keck School of Medicine [Los Angeles], University of Southern California (USC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Johns Hopkins University (JHU), QIMR Berghofer Medical Research Institute, Leiden University Medical Center (LUMC), Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Miami Leonard M. Miller School of Medicine (UMMSM), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Royal College of Surgeons in Ireland (RCSI), Umeå University, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), University of New South Wales [Sydney] (UNSW), Murdoch University, University of Oslo (UiO), Uppsala University, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Toronto, University of Washington [Seattle], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Columbia University Medical Center (CUMC), Columbia University [New York], Pennington Biomedical Research Center, Louisiana State University (LSU), McGill University = Université McGill [Montréal, Canada], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lieber Institute for Brain Development [Baltimore] (LIBD), University of California [Los Angeles] (UCLA), University of California, Vrije Universiteit Amsterdam [Amsterdam] (VU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Massachusetts General Hospital [Boston], Neuroimagerie en psychiatrie (U1000), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Maison de Solenn [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Bergen (UiB), Haukeland University Hospital, Johns Hopkins University School of Medicine [Baltimore], Universität Heidelberg [Heidelberg], University of Mississippi Medical Center (UMMC), International Max Planck Research School for Language Sciences (IMPRS ), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Language and Genetics Department [Nijmegen], National University of Singapore (NUS), Medical University Graz, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Yale University [New Haven], University College of London [London] (UCL), Imperial College London, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Institute of Human Genetics, University of Bonn, Department of Genomics, Life and Brain Center, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Department of Psychology [Minneapolis], University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Cognitive Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Neurosciences [San Diego], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Queensland Institute of Medical Research, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, King Faisal Specialist Hospital and Research Centre, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Depts of Radiology, University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, National Institutes of Health [Bethesda] (NIH), General Internal Medicine, Johns Hopkins School of Medicine, Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], 849 Department of Human Genetics, Dementia Collaborative Research Centre, Centre for Healthy Brain Ageing, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Université de Lausanne (UNIL), Department of Psychiatry [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Metacohorts Consortium, Division of Medical Genetics, University of Basel (Unibas), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College Dublin-St. James's Hospital, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], VU University Amsterdam, Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), School of Psychology, University of Queensland, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Molecular and Cellular Therapeutics, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Department of Radiology, Mayo Clinic, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Department of Physics, Okayama University, Okayama University, National Institute of Aging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Department of Molecular Neurosciences, Institute of Neurology, UCL, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Tohoku University [Sendai], Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Centre for Allergy Research, Karolinska Institutet [Stockholm], Interuniversity Cardiology Institute Netherlands, Institute of Cognitive Neuroscience, School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Laboratoire de Statistique Théorique et Appliquée (LSTA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Psychiatry Institute, Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Université de Toulon - UFR Lettres et Sciences Humaines (UTLN UFR LSH), Université de Toulon (UTLN), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Warwick Manufacturing Group [Coventry] (WMG), University of Warwick [Coventry], Department of Statistics [Warwick], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Group Health Research Institute, Group Health Cooperative, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Centre for Healthy Brain Ageing [Sydney], The University of Sydney, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Department of Clinical and Experimental Epilepsy, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Department of Epidemiology, Laboratory of Neuro Imaging [Los Angeles] (LONI), University of York [York, UK], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Departments of Radiology and of Epidemiology [Rotterdam], Psychiatry and Leiden Institute for Brain and Cognition, Department of Neurology [Rotterdam], Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Physics [Hong Kong University of Science and Technology], Hong Kong University of Science and Technology (HKUST), Department of Neurobiology, Care Sciences and Society, Research Laboratory for Archaeology & the History of Art, Singapore Eye Research Institute, Singapore National Eye Centre, School of Life Sciences, Arizona State University [Tempe] (ASU), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], University of Missouri [Columbia] (Mizzou), University of Missouri System, Göttingen Zentrum Geowissenschaften, Georg-August-University [Göttingen], Human Genetics Center, Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, Klinische Genetica, MUMC+: DA Klinische Genetica (5), RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Universidad de Cantabria, Universiteit Leiden, Radboud University [Nijmegen], University of California (UC), Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Bonn = University of Bonn, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), University of California (UC)-University of California (UC), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Radboud University [Nijmegen]-Radboud University [Nijmegen], Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Harvard University-Massachusetts Institute of Technology (MIT), University of Eastern Finland, Humboldt University Of Berlin, Georg-August-University = Georg-August-Universität Göttingen, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Epidemiology, Child and Adolescent Psychiatry / Psychology, Ophthalmology, Radiology & Nuclear Medicine, Internal Medicine, Neurosciences, Obstetrics & Gynecology, Neurology, EMGO+ - Mental Health, Biological Psychology, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), McGill University-McGill University, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), McGill University, Technische Universität Dresden (TUD), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Minnesota [Twin Cities], Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge], University of Tasmania (UTAS), Humboldt Universität zu Berlin, Department of Physics [Kowloon], University of Missouri [Columbia], Georg-August-Universität Göttingen, and the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genome-wide association study, Disease, methods [Genome-Wide Association Study], Genome-wide association studies, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, pathology [Brain], genetics [Parkinson Disease], 610 Medicine & health, General Neuroscience, growth & development [Brain], physiology [Cognition], 220 Statistical Imaging Neuroscience, COMMON VARIANTS, Brain, Parkinson Disease, Phenotype, 17Q21.31 MICRODELETION, IGF-I, genetics [Oncogene Protein v-akt], Oncogene Protein v-akt, ALZHEIMERS-DISEASE, HEAD CIRCUMFERENCE, Brain size, genetics [Polymorphism, Single Nucleotide], Medical genetics, GROWTH, Neuroinformatics, medicine.medical_specialty, Neuroscience(all), European Continental Ancestry Group, genetics [Genetic Loci], Biology, Genetic correlation, Polymorphism, Single Nucleotide, 150 000 MR Techniques in Brain Function, Article, White People, 03 medical and health sciences, Image processing, SDG 3 - Good Health and Well-being, ddc:570, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Height, [SCCO.NEUR]Cognitive science/Neuroscience, CONSORTIUM, Development of the nervous system, 1702 Cognitive Science, 030104 developmental biology, Genetic Loci, Human genome, BRAIN SIZE, 1109 Neurosciences, genetics [Phosphatidylinositol 3-Kinases], Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 165723pub.pdf (Publisher’s version ) (Closed access) Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rhogenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Published
2016

34. Genetic variants linked to education predict longevity

Author

Chris Power, Gail Davies, Ilaria Gandin, Panagiotis Deloukas, Jennifer E. Huffman, Pascal Timshel, Albert V. Smith, A. Kong, Paul Lichtenstein, Joseph K. Pickrell, Philipp Koellinger, P. L. De Jager, Reedik Mägi, G. B. Chen, Neil Pendleton, B. V. Halldórsson, George Dedoussis, Antti-Pekka Sarin, Natalia Pervjakova, Veikko Salomaa, Simona Vaccargiu, Ozren Polasek, K. H. Jöckel, Elisabeth Steinhagen-Thiessen, Y. Milaneschi, Jessica D. Faul, Patricia A. Boyle, Patrik K. E. Magnusson, Igor Rudan, Christopher P. Nelson, Vilmundur Gudnason, John Attia, Jürgen Wellmann, Kristi Läll, Konstantin Strauch, Stuart J. Ritchie, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, R. de Vlaming, Liisa Keltigangas-Jarvinen, Thomas Meitinger, Riccardo E. Marioni, Anu Loukola, Barbera Franke, Reinhold Schmidt, Maël Lebreton, Sven Oskarsson, E. Mihailov, Harm-Jan Westra, David R. Weir, Aldi T. Kraja, Niek Verweij, Peter M. Visscher, Hans-Jörgen Grabe, Johannes H. Brandsma, Mark Adams, R. J. Scott, G. Thorleifsson, Tõnu Esko, Mika Kähönen, Saskia P. Hagenaars, Patrick Turley, Johannes Waage, Peter Lichtner, Dragana Vuckovic, Antonietta Robino, Henry Völzke, Lydia Quaye, C. de Leeuw, Marika Kaakinen, Wei Zhao, Abdel Abdellaoui, Reka Nagy, Pedro Marques-Vidal, Johan G. Eriksson, Alan F. Wright, Andres Metspalu, Lavinia Paternoster, Momoko Horikoshi, Jan A. Staessen, Tarunveer S. Ahluwalia, Tian Liu, Martin Kroh, Aldo Rustichini, Giorgia Girotto, Cristina Venturini, Lili Milani, Jennifer A. Smith, Ginevra Biino, Tessel E. Galesloot, Michael A. Horan, Gerardus A. Meddens, James F. Wilson, Francesco Cucca, Peter Vollenweider, Erika Salvi, P. J. van der Most, Jari Lahti, Campbell A, David Laibson, Andrew Bakshi, Wolfgang Hoffmann, Tomi Mäki-Opas, Andreas J. Forstner, C M van Duijn, Nicholas G. Martin, Jonathan Marten, Ute Bültmann, Olli T. Raitakari, David A. Bennett, A.G. Uitterlinden, J. E. De Neve, Ingrid B. Borecki, WD Hill, Bo Jacobsson, Antti Latvala, Katri Räikkönen, Michael B. Miller, Jonathan P. Beauchamp, S. J. van der Lee, Ilja Demuth, Stavroula Kanoni, Veronique Vitart, Elina Hyppönen, N. Eklund, Francesco P. Cappuccio, Robert F. Krueger, Maria Pina Concas, Jaime Derringer, F. J.A. Van Rooij, Helena Schmidt, Patrick J. F. Groenen, Valur Emilsson, Rico Rueedi, Aysu Okbay, Georg Homuth, Edith Hofer, W. E. R. Ollier, Hannah Campbell, Paolo Gasparini, Mark Alan Fontana, Magnus Johannesson, Seppo Koskinen, Christopher F. Chabris, Jouke-Jan Hottenga, Christine Meisinger, Kari Stefansson, Jun Ding, Tia Sorensen, Brenda W.J.H. Penninx, Michelle N. Meyer, James J. Lee, Diego Vozzi, Gonneke Willemsen, K. Petrovic, Sarah E. Medland, Mary F. Feitosa, Henning Tiemeier, L. J. Launer, William G. Iacono, Massimo Mangino, Tune H. Pers, S. E. Baumeister, Christopher Oldmeadow, Grant W. Montgomery, Marjo-Riitta Järvelin, Jaakko Kaprio, Catharine R. Gale, S.F.W. Meddens, Kevin Thom, Klaus Berger, Pablo V. Gejman, Lude Franke, Gyda Bjornsdottir, Daniel J. Benjamin, Steven F. Lehrer, Krista Fischer, Alan R. Sanders, S. Ulivi, Katharina E. Schraut, Tim D. Spector, Amy Hofman, Matt McGue, Terho Lehtimäki, D. C. Liewald, Hans Bisgaard, L. Eisele, Astanand Jugessur, George Davey Smith, T.B. Harris, A.R. Thurik, Cornelius A. Rietveld, David Schlessinger, Z. Kutalik, David J. Porteous, Lynne J. Hocking, N J Timpson, A. Palotie, Lambertus A. Kiemeney, Ian J. Deary, Sharon L.R. Kardia, Peter K. Joshi, Nilesh J. Samani, Michael A. Province, Börge Schmidt, Richa Gupta, Carmen Amador, Erin B. Ware, Joyce Y. Tung, Ioanna-Panagiota Kalafati, Lars Bertram, Caroline Hayward, P. van der Harst, Penelope A. Lind, Kadri Kaasik, N.A. Furlotte, Sarah E. Harris, B. St Pourcain, Susan M. Ring, Zhihong Zhu, Alexander Teumer, Behrooz Z. Alizadeh, Judith M. Vonk, Blair H. Smith, A Payton, Wouter J. Peyrot, Jacob Gratten, Douglas F. Levinson, C Gieger, Leanne M. Hall, Andrew Heath, Mario Pirastu, Peter Eibich, Nancy L. Pedersen, Ronny Myhre, Antonio Terracciano, David M. Evans, Raymond A. Poot, Uwe Völker, Dorret I. Boomsma, Clemens Baumbach, Unnur Thorsteinsdottir, Ivana Kolcic, Jia-Shu Yang, Dalton Conley, A. A. Vinkhuyzen, Danielle Posthuma, Karl-Oskar Lindgren, Olga Rostapshova, Jonas Bacelis, Daniele Cusi, Yong Qian, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Pamela A. F. Madden, David A. Hinds, David Cesarini, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Applied Economics, Epidemiology, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Aletta Jacobs School of Public Health, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO - Mental health, Complex Trait Genetics, Biological Psychology, Marioni, RE, Ritchie, SJ, Joshi, PK, Hagenaars, SP, Hypponen, E, Benjamin, DJ, Social Science Genetic Association Consortium, Marioni, Re, Ritchie, Sj, Joshi, Pk, Hagenaars, Sp, Okbay, A, Fischer, K, Adams, Mj, Hill, Wd, Davies, G, Nagy, R, Amador, C, Läll, K, Metspalu, A, Liewald, Dc, Campbell, A, Wilson, Jf, Hayward, C, Esko, T, Porteous, Dj, Gale, Cr, Deary, Ij, Beauchamp, Jp, Fontana, Ma, Lee, Jj, Pers, Th, Rietveld, Ca, Turley, P, Chen, Gb, Emilsson, V, Meddens, Sf, Oskarsson, S, Pickrell, Jk, Thom, K, Timshel, P, de Vlaming, R, Abdellaoui, A, Ahluwalia, T, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Jh, Concas, MARIA PINA, Derringer, J, Furlotte, Na, Galesloot, Te, Girotto, Giorgia, Gupta, R, Hall, Lm, Harris, Se, Hofer, E, Horikoshi, M, Huffman, Je, Kaasik, K, Kalafati, Ip, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sj, de Leeuw, C, Lind, Pa, Lindgren, Ko, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, Mb, van der Most, Pj, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, Wj, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, Ke, Shi, J, Smith, Av, Poot, Ra, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, Dragana, Wellmann, J, Westra, Hj, Yang, J, Zhao, W, Zhu, Z, Alizadeh, Bz, Amin, N, Bakshi, A, Baumeister, Se, Biino, G, Bønnelykke, K, Boyle, Pa, Campbell, H, Cappuccio, Fp, De Neve, Je, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, Dm, Faul, Jd, Feitosa, Mf, Forstner, Aj, Gandin, Ilaria, Gunnarsson, B, Halldórsson, Bv, Harris, Tb, Heath, Ac, Hocking, Lj, Holliday, Eg, Homuth, G, Horan, Ma, Hottenga, Jj, de Jager, Pl, Jugessur, A, Kaakinen, Ma, Kähönen, M, Kanoni, S, Keltigangas Järvinen, L, Kiemeney, La, Kolcic, I, Koskinen, S, Kraja, At, Kroh, M, Kutalik, Z, Latvala, A, Launer, Lj, Lebreton, Mp, Levinson, Df, Lichtenstein, P, Lichtner, P, Loukola, A, Madden, Pa, Mägi, R, Mäki Opas, T, Marques Vidal, P, Meddens, Ga, Mcmahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, Gw, Myhre, R, Nelson, Cp, Nyholt, Dr, Ollier, We, Palotie, A, Paternoster, L, Pedersen, Nl, Petrovic, Ke, Räikkönen, K, Ring, Sm, Robino, Antonietta, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, Ar, Sarin, Ap, Schmidt, H, Scott, Rj, Smith, Bh, Smith, Ja, Staessen, Ja, Steinhagen Thiessen, E, Strauch, K, Terracciano, A, Tobin, Md, Ulivi, Sheila, Vaccargiu, S, Quaye, L, van Rooij, Fj, Venturini, C, Vinkhuyzen, Aa, Völker, U, Völzke, H, Vonk, Jm, Vozzi, Diego, Waage, J, Ware, Eb, Willemsen, G, Attia, Jr, Bennett, Da, Berger, K, Bertram, L, Bisgaard, H, Boomsma, Di, Borecki, Ib, Bultmann, U, Chabris, Cf, Cucca, F, Cusi, D, Dedoussis, Gv, van Duijn, Cm, Eriksson, Jg, Franke, B, Franke, L, Gasparini, Paolo, Gejman, Pv, Gieger, C, Grabe, Hj, Gratten, J, Groenen, Pj, Gudnason, V, van der Harst, P, Hinds, Da, Hoffmann, W, Iacono, Wg, Jacobsson, B, Järvelin, Mr, Jöckel, Kh, Kaprio, J, Kardia, Sl, Lehtimäki, T, Lehrer, Sf, Magnusson, Pk, Martin, Ng, Mcgue, M, Pendleton, N, Penninx, Bw, Perola, M, Pirastu, Nicola, Pirastu, M, Polasek, O, Posthuma, D, Power, C, Province, Ma, Samani, Nj, Schlessinger, D, Schmidt, R, Sørensen, Ti, Spector, Td, Stefansson, K, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tiemeier, H, Tung, Jy, Uitterlinden, Ag, Vitart, V, Vollenweider, P, Weir, Dr, Wright, Af, Conley, Dc, Krueger, Rf, Smith, Gd, Hofman, A, Laibson, Di, Medland, Se, Meyer, Mn, Johannesson, M, Visscher, Pm, Koellinger, Pd, Cesarini, D, and Benjamin, Dj

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Male, Parents, education: longevity: prediction: polygenic score [genetics], Multifactorial Inheritance, polygenic, Lebenserwartung, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Medicine, genetics, polygenic score, longevity, education, gene, Soziales und Gesundheit, media_common, Aged, 80 and over, education, Multidisciplinary, Longevity, Middle Aged, Biobank, humanities, 3. Good health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, Educational Status, Female, Cohort study, Estonia, education, longevity, polygenic, Offspring, media_common.quotation_subject, Kultursektor, Prognose, Lernen, Lower risk, Education, 03 medical and health sciences, longevity, SDG 3 - Good Health and Well-being, Commentaries, Polygenic score, Journal Article, Genetics, Humans, Non-Profit-Sektor, Genetic Association Studies, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, ta1184, Genetic Variation, prediction, Educational attainment, United Kingdom, Gesundheitsstatistik, 030104 developmental biology, Genetic epidemiology, Scotland, Gesundheitszustand, Genetische Forschung, business, Prediction, Bildung, 030217 neurology & neurosurgery, Demography
Abstract

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed

Published
2016

35. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Author

John C. Chambers, J. Wouter Jukema, Rajesh Rawal, Alanna C. Morrison, Paul M. Ridker, Pamela A. F. Madden, Jaakko Kaprio, Gunter Schumann, John M. Starr, Claudia Langenberg, Caterina Barbieri, Cristina Venturini, Leo-Pekka Lyytikäinen, Kenneth J. Mukamal, Dragana Vuckovic, Vilmundur Gudnason, David J. Stott, Evangelos Evangelou, Philippe Froguel, Jaana Laitinen, Christian P. Müller, Paul F. O'Reilly, Christopher P. Nelson, Katharina E. Schraut, Sylvane Desrivières, Lynda M. Rose, Massimo Mangino, Pedro Marques-Vidal, Toniolo Daniela, Hans J. Grabe, Parkyong Song, Anu Loukola, Jenni Hällfors, Nicola Pirastu, Jian'an Luan, Toni-Kim Clarke, Albert V. Smith, Cornelia M. van Duijn, Tianye Jia, Cinzia Sala, Oscar H. Franco, Yongmei Liu, Peter K. Joshi, Robert A. Scott, Helena Schmidt, Marjo-Riitta Järvelin, Sarah R. Preis, Peter Vollenweider, Krista Fischer, Jerome I. Rotter, Alexander Teumer, Ulf Gyllensten, Ani Manichaikul, Brenda W.J.H. Penninx, Stefan Enroth, Alireza Moayyeri, John Whitfield, Anne-Claire Vergnaud, Georgy Bakalkin, Steven A. Kliewer, Niek Verweij, Jaspal S. Kooner, Daniel I. Chasman, Bruce H W Wolffenbuttel, Rozenn N. Lemaitre, Tim D. Spector, Jing Hua Zhao, Weihua Zhang, Zoltán Kutalik, Kenneth Rice, Veronique Vitart, Bing Xu, Anna-Liisa Hartikainen, Niina E. Kaartinen, David J. Mangelsdorf, Jouke-Jan Hottenga, Bing Yu, Loic Yengo, Stella Trompet, Ioanna Tzoulaki, He Gao, Edith Hofer, Nicholas J. Wareham, Takashi Satoh, Nilesh J. Samani, Albert Hofman, Najaf Amin, Hamdi Mbarek, Christian Gieger, Nicholas G. Martin, Yun Liu, Jennifer A. Nettleton, Bruce M. Psaty, Sarah E. Harris, Richard J. Rose, Johan G. Eriksson, Dorret I. Boomsma, Eco J. C. de Geus, André G. Uitterlinden, Andrew C. Heath, Olli T. Raitakari, Chunyu Liu, Terho Lehtimäki, Ian J. Deary, Paul Elliott, Pim van der Harst, Shizuo Akira, Åsa Johansson, Tõnu Esko, Marcelo P. Segura Lepe, Antonietta Robino, Sebastian E. Baumeister, Jari Lahti, James G. Wilson, Saskia Hieber, Barbara Ruggeri, Juho Wedenoja, Eemil Partinen, Reinhold Schmidt, Stéphane Cauchi, Yuri Milaneschi, Tamara B. Harris, Cornelia Huth, Lynne J. Hocking, Daniel Levy, Volker Eulenburg, David P. Strachan, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), Gastroenterology & Hepatology, Epidemiology, Internal Medicine, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
Male, 0301 basic medicine, Gerontology, Netherlands Twin Register (NTR), LIVER, FGF21, Emotions, Alcohol, Genome-wide association study, Disease, DISEASE, SWEET, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, β-Klotho, DEPENDENCE, Mice, Knockout, Multidisciplinary, Behavior, Animal, Brain, Biological Sciences, 3. Good health, HEART, Female, medicine.medical_specialty, Mice, 129 Strain, Alcohol Drinking, alcohol consumption, mouse model, Polymorphism, Single Nucleotide, Gene product, 03 medical and health sciences, Internal medicine, MD Multidisciplinary, medicine, Animals, Humans, Endocrine system, ddc:610, human, GENOME-WIDE ASSOCIATION, Klotho Proteins, business.industry, ta1184, Membrane Proteins, CONSUMPTION, Beta-Klotho, beta-Klotho, ta3121, Fibroblast Growth Factors, Mice, Inbred C57BL, MICE, 030104 developmental biology, Endocrinology, chemistry, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Hormone
Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific beta-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Published
2016

36. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Author

Ozren Polasek, Bo Jacobsson, Eleonora Porcu, Vinicius Tragante, Joel Eriksson, Jie Yao, Mika Kähönen, Mark Alan Fontana, Stefania Cappellani, J. Viikari, Rick Jansen, Crysovalanto Mamasoula, Linda Broer, Tamara B. Harris, Ellen A. Nohr, Genevieve Lachance, Johan G. Eriksson, Nicholas Eriksson, Rico Rueedi, Francesco Cucca, Jaakko Kaprio, Nicholas J. Timpson, George Dedoussis, Matt McGue, Per Magnus, Klaus Berger, Olli T. Raitakari, Cornelia M. van Duijn, Brenda W.J.H. Penninx, Jing Hua Zhao, Peter Eibich, Sheila Ulivi, Hugoline G. de Haan, Ronny Myhre, Ruth McQuillan, Florian Kronenberg, Markus Perola, Klaus Bønnelykke, Robert Karlsson, Martina La Bianca, Paul Mitchell, Ian J. Deary, Melinda Mills, Teresa Nutile, Patrick J. F. Groenen, Stacey A. Missmer, Nicholas G. Martin, Panos Deloukas, Mario Pirastu, Lindsay K. Matteson, Robert Luben, Veikko Salomaa, Renée de Mutsert, Chris Power, Nir Barzilai, Annette Kifley, Hamdi Mbarek, Denis A. Evans, Erica P. Gunderson, Tim D. Spector, Anke Tönjes, Michela Traglia, Claire Monnereau, Karin Halina Greiser, Sharon L.R. Kardia, John M. Starr, Peter K. Joshi, Sandra Lai, Doris Stöckl, James J. Lee, Heather J. Cordell, Andrew Bakshi, Nicholas J. Wareham, David C. Liewald, P Koponen, Paul M. Ridker, Joyce Y. Tung, Ilaria Gandin, Kauko Heikkilä, Johannes Haerting, Gonneke Willemsen, Janet W. Rich-Edwards, Andrew C. Heath, Astanand Jugessur, John L. Hopper, Stefan Kiechl, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Dan Mellström, Simon R. Cox, Yasaman Saba, Magnus Johannesson, Ginevra Biino, David Schlessinger, Kirsi Auro, Dennis O. Mook-Kanamori, Christa Meisinger, Igor Rudan, Audrey J. Gaskins, Lars Bertram, Roy Thurik, Laura M. Yerges-Armstrong, Caterina Barbieri, Katri Räikkönen, Lawrence F. Bielak, Aviv Bergman, Philipp Koellinger, Ronald de Vlaming, Tian Liu, Johannes W. A. Smit, Peter Kovacs, Vincent W. V. Jaddoe, Jennifer A. Smith, Sven Bergmann, Inga Prokopenko, Xiuqing Guo, Marina Ciullo, Krina T. Zondervan, Marcel den Hoed, Daniel J. Benjamin, Kathryn Roll, Alan F. Wright, Helena Schmidt, William G. Iacono, Jie Jin Wang, Harold Snieder, Juho Wedenoja, Tarunveer S. Ahluwalia, David R. Weir, Ken K. Ong, Daniela Toniolo, Ruifang Li-Gao, Evelin Mihailov, Edith Hofer, Leslie J. Raffel, Daniel I. Chasman, Alexander Kluttig, Bernard Keavney, Eco J. C. de Geus, Kathleen A. Ryan, Kristin L. Ayers, Lude Franke, S. Fleur W. Meddens, Alison Pattie, Jornt J. Mandemakers, Eva Albrecht, David Cesarini, Beverley Balkau, Grant W. Montgomery, Michael Stumvoll, Ahmad Vaez, Michael B. Miller, Najaf Amin, Gyda Bjornsdottir, Cecile Lecoeur, Enes Makalic, Marc Jan Bonder, Terho Lehtimäki, Albert Hofman, Loic Yengo, Lynda M. Rose, Lisette Stolk, Juergen Wellmann, Gail Davies, Eero Kajantie, Nicole Schupf, Hans Bisgaard, Unnur Thorsteinsdottir, Konstantin Strauch, Ivana Kolcic, Lili Milani, Chunyan He, Claes Ohlsson, Yongmei Liu, Gil Atzmon, Janine F. Felix, Christian Gieger, Mike A. Nalls, Riitta Luoto, Nicola Barban, Philippe Froguel, Daniel F. Schmidt, Dorret I. Boomsma, Harry Campbell, Xia Shen, Vasiliki Lagou, Danny Ben-Avraham, Veronique Vitart, Ioanna P. Kalafati, Kari Stefansson, Daria V. Zhernakova, Constance Turman, Julie E. Buring, Johannes Waage, James F. Wilson, Maria Pina Concas, Zoltán Kutalik, Peter Willeit, Jørn Olsen, Dan Rujescu, Caroline Hayward, Penelope A. Lind, George McMahon, Elizabeth G. Holliday, Ilja M. Nolte, Fahimeh Falahi, Minh Bui, Gudmar Thorleifsson, Patrick F. McArdle, Cinzia Sala, Alana Cavadino, Rossella Sorice, Wei Zhao, Andres Metspalu, Sander W. van der Laan, Stavroula Kanoni, Elina Hyppönen, Morris A. Swertz, Simona Vaccargiu, Felix C. Tropf, Michael Lucht, Susan M. Ring, Elizabeth A. Streeten, Reinhold Schmidt, Augustine Kong, Johann Willeit, Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Tõnu Esko, Antonietta Robino, Lavinia Paternoster, Peter J. van der Most, Kumar B. Rajan, George Davey-Smith, Dragana Vuckovic, Hans J. Grabe, Jari Lahti, Giorgia Girotto, Jorge E. Chavarro, Robert F. Krueger, Hongyan Huang, Georg Homuth, Paolo Gasparini, Sarah E. Medland, Gert G. Wagner, Peter Kraft, André G. Uitterlinden, Cornelius A. Rietveld, Howard Andrews, Cecilia M. Lindgren, Peter Vollenweider, Perry, John [0000-0001-6483-3771], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, BARBAN N, Rick Jansen, Ronald de Vlaming, Ahmad Vaez, Jornt J Mandemaker, Felix C Tropf, Xia Shen, James F Wilson, Daniel I Chasman, Ilja M Nolte, Vinicius Tragante, Sander W van der Laan, John R B Perry, Augustine Kong, BIOS Consortium, Tarunveer S Ahluwalia, Eva Albrecht, Laura Yerges-Armstrong, Gil Atzmon, Kirsi Auro, Kristin Ayer, Andrew Bakshi, Danny Ben-Avraham, Klaus Berger, Aviv Bergman, Lars Bertram, Lawrence F Bielak, Gyda Bjornsdottir, Marc Jan Bonder, Linda Broer, Minh Bui, Caterina Barbieri, Alana Cavadino, Jorge E Chavarro, Constance Turman, Maria Pina Conca, Heather J Cordell, Gail Davie, Peter Eibich, Nicholas Eriksson, Tõnu Esko, Joel Eriksson, Fahimeh Falahi, Janine F Felix, Mark Alan Fontana, Lude Franke, Ilaria Gandin, Audrey J Gaskin, Christian Gieger, Erica P Gunderson, Xiuqing Guo, Caroline Hayward, Chunyan He, Edith Hofer, Hongyan Huang, Peter K Joshi, Stavroula Kanoni, Robert Karlsson, Stefan Kiechl, Annette Kifley, Alexander Kluttig, Peter Kraft, Vasiliki Lagou, Cecile Lecoeur, Jari Lahti, Ruifang Li-Gao, Penelope A Lind, Tian Liu, Enes Makalic, Crysovalanto Mamasoula, Lindsay Matteson, Hamdi Mbarek, Patrick F McArdle, George McMahon, S Fleur W Medden, Evelin Mihailov, Mike Miller, Stacey A Missmer, Claire Monnereau, Peter J van der Most, Ronny Myhre, Mike A Nall, Teresa Nutile, Ioanna Panagiota Kalafati, Eleonora Porcu, Inga Prokopenko, Kumar B Rajan, Janet Rich-Edward, Cornelius A Rietveld, Antonietta Robino, Lynda M Rose, Rico Rueedi, Kathleen A Ryan, Yasaman Saba, Daniel Schmidt, Jennifer A Smith, Lisette Stolk, Elizabeth Streeten, Anke Tönje, Gudmar Thorleifsson, Sheila Ulivi, Juho Wedenoja, Juergen Wellmann, Peter Willeit, Jie Yao, Loic Yengo, Jing Hua Zhao, Wei Zhao, Daria V Zhernakova, Najaf Amin, Howard Andrew, Beverley Balkau, Nir Barzilai, Sven Bergmann, Ginevra Biino, Hans Bisgaard, Klaus Bønnelykke, Dorret I Boomsma, Julie E Buring, Harry Campbell, Stefania Cappellani, Marina Ciullo, Simon R Cox, Francesco Cucca, Daniela Toniolo, George Davey-Smith, Ian J Deary, George Dedoussi, Panos Delouka, Cornelia M van Duijn, Eco J C de Geu, Johan G Eriksson, Denis A Evan, Jessica D Faul, Cinzia Felicita Sala, Philippe Froguel, Paolo Gasparini, Giorgia Girotto, Hans-Jörgen Grabe, Karin Halina Greiser, Patrick J F Groenen, Hugoline G de Haan, Johannes Haerting, Tamara B Harri, Andrew C Heath, Kauko Heikkilä, Albert Hofman, Georg Homuth, Elizabeth G Holliday, John Hopper, Elina Hyppönen, Bo Jacobsson, Vincent W V Jaddoe, Magnus Johannesson, Astanand Jugessur, Mika Kähönen, Eero Kajantie, Sharon L R Kardia, Bernard Keavney, Ivana Kolcic, Päivikki Koponen, Peter Kovac, Florian Kronenberg, Zoltan Kutalik, Martina La Bianca, Genevieve Lachance, William G Iacono, Sandra Lai, Terho Lehtimäki, David C Liewald, LifeLines Cohort Study, Cecilia M Lindgren, Yongmei Liu, Robert Luben, Michael Lucht, Riitta Luoto, Per Magnu, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Ruth McQuillan, Sarah E Medland, Christa Meisinger, Dan Mellström, Andres Metspalu, Michela Traglia, Lili Milani, Paul Mitchell, Grant W Montgomery, Dennis Mook-Kanamori, Renée de Mutsert, Ellen A Nohr, Claes Ohlsson, Jørn Olsen, Ken K Ong, Lavinia Paternoster, Alison Pattie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Mario Pirastu, Ozren Polasek, Chris Power, Jaakko Kaprio, Leslie J Raffel, Katri Räikkönen, Olli Raitakari, Paul M Ridker, Susan M Ring, Kathryn Roll, Igor Rudan, Daniela Ruggiero, Dan Rujescu, Veikko Salomaa, David Schlessinger, Helena Schmidt, Reinhold Schmidt, Nicole Schupf, Johannes Smit, Rossella Sorice, Tim D Spector, John M Starr, Doris Stöckl, Konstantin Strauch, Michael Stumvoll, Morris A Swertz, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Joyce Y Tung, André G Uitterlinden, Simona Vaccargiu, Jorma Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Dragana Vuckovic, Johannes Waage, Gert G Wagner, Jie Jin Wang, Nicholas J Wareham, David R Weir, Gonneke Willemsen, Johann Willeit, Alan F Wright, Krina T Zondervan, Kari Stefansson, Robert F Krueger, James J Lee, Daniel J Benjamin, David Cesarini, Philipp D Koellinger, Marcel den Hoed, Harold Snieder & Melinda C Mills, Barban, N, Jansen, R, de Vlaming, R, Vaez, A, Mandemakers, Jj, Tropf, Fc, Shen, X, Wilson, Jf, Chasman, Di, Nolte, Im, Tragante, V, van der Laan, Sw, Perry, Jr, Kong, A, Ahluwalia, T, Albrecht, E, Yerges Armstrong, L, Atzmon, G, Auro, K, Ayers, K, Bakshi, A, Ben Avraham, D, Berger, K, Bergman, A, Bertram, L, Bielak, Lf, Bjornsdottir, G, Bonder, Mj, Broer, L, Bui, M, Barbieri, CATERINA MARIA, Cavadino, A, Chavarro, Je, Turman, C, Concas, MARIA PINA, Cordell, Hj, Davies, G, Eibich, P, Eriksson, N, Esko, T, Eriksson, J, Falahi, F, Felix, Jf, Fontana, Ma, Franke, L, Gandin, Ilaria, Gaskins, Aj, Gieger, C, Gunderson, Ep, Guo, X, Hayward, C, He, C, Hofer, E, Huang, H, Joshi, Pk, Kanoni, S, Karlsson, R, Kiechl, S, Kifley, A, Kluttig, A, Kraft, P, Lagou, V, Lecoeur, C, Lahti, J, Li Gao, R, Lind, Pa, Liu, T, Makalic, E, Mamasoula, C, Matteson, L, Mbarek, H, Mcardle, Pf, Mcmahon, G, Meddens, Sf, Mihailov, E, Miller, M, Missmer, Sa, Monnereau, C, van der Most, Pj, Myhre, R, Nalls, Ma, Nutile, T, Kalafati, Ip, Porcu, E, Prokopenko, I, Rajan, Kb, Rich Edwards, J, Rietveld, Ca, Robino, Antonietta, Rose, Lm, Rueedi, R, Ryan, Ka, Saba, Y, Schmidt, D, Smith, Ja, Stolk, L, Streeten, E, Tönjes, A, Thorleifsson, G, Ulivi, Sheila, Wedenoja, J, Wellmann, J, Willeit, P, Yao, J, Yengo, L, Zhao, Jh, Zhao, W, Zhernakova, Dv, Amin, N, Andrews, H, Balkau, B, Barzilai, N, Bergmann, S, Biino, G, Bisgaard, H, Bønnelykke, K, Boomsma, Di, Buring, Je, Campbell, H, Cappellani, Stefania, Ciullo, M, Cox, Sr, Cucca, F, Toniolo, D, Davey Smith, G, Deary, Ij, Dedoussis, G, Deloukas, P, van Duijn, Cm, de Geus, Ej, Eriksson, Jg, Evans, Da, Faul, Jd, Sala, Cf, Froguel, P, Gasparini, Paolo, Girotto, Giorgia, Grabe, Hj, Greiser, Kh, Groenen, Pj, de Haan, Hg, Haerting, J, Harris, Tb, Heath, Ac, Heikkilä, K, Hofman, A, Homuth, G, Holliday, Eg, Hopper, J, Hyppönen, E, Jacobsson, B, Jaddoe, Vw, Johannesson, M, Jugessur, A, Kähönen, M, Kajantie, E, Kardia, Sl, Keavney, B, Kolcic, I, Koponen, P, Kovacs, P, Kronenberg, F, Kutalik, Z, LA BIANCA, Martina, Lachance, G, Iacono, Wg, Lai, S, Lehtimäki, T, Liewald, Dc, Lindgren, Cm, Liu, Y, Luben, R, Lucht, M, Luoto, R, Magnus, P, Magnusson, Pk, Martin, Ng, Mcgue, M, Mcquillan, R, Medland, Se, Meisinger, C, Mellström, D, Metspalu, A, Traglia, Michela, Milani, L, Mitchell, P, Montgomery, Gw, Mook Kanamori, D, de Mutsert, R, Nohr, Ea, Ohlsson, C, Olsen, J, Ong, Kk, Paternoster, L, Pattie, A, Penninx, Bw, Perola, M, Peyser, Pa, Pirastu, M, Polasek, O, Power, C, Kaprio, J, Raffel, Lj, Räikkönen, K, Raitakari, O, Ridker, Pm, Ring, Sm, Roll, K, Rudan, I, Ruggiero, D, Rujescu, D, Salomaa, V, Schlessinger, D, Schmidt, H, Schmidt, R, Schupf, N, Smit, J, Sorice, R, Spector, Td, Starr, Jm, Stöckl, D, Strauch, K, Stumvoll, M, Swertz, Ma, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tung, Jy, Uitterlinden, Ag, Vaccargiu, S, Viikari, J, Vitart, V, Völzke, H, Vollenweider, P, Vuckovic, Dragana, Waage, J, Wagner, Gg, Wang, Jj, Wareham, Nj, Weir, Dr, Willemsen, G, Willeit, J, Wright, Af, Zondervan, Kt, Stefansson, K, Krueger, Rf, Lee, Jj, Benjamin, Dj, Cesarini, D, Koellinger, Pd, den Hoed, M, Snieder, H, Mills, Mc, Sociology/ICS, Life Course Epidemiology (LCE), Isotope Research, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Barban, Nicola, Jansen, Rick, De Vlaming, Ronald, Vaez, Ahmad, Hyppönen, Elina, Mills, Melinda C, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, EMGO - Mental health, Applied Economics, Public Health, Internal Medicine, Erasmus MC other, Epidemiology, Econometrics, Pediatrics, EMGO+ - Lifestyle, Overweight and Diabetes, Complex Trait Genetics, and Biological Psychology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), PROTEIN, WASS, Genome-wide association study, Reproductive Behavior, MOUSE, Genome-wide association studies, GWAS, reproductive behavior, fertility, 0302 clinical medicine, G1 PHASE, Pregnancy, Genetics & Heredity, Genetics, HUMAN-DISEASES, Reproduction, Human Reproduction, 11 Medical And Health Sciences, ASSOCIATION, Genome-Wide, POLYCYSTIC-OVARY-SYNDROME, Sociologie van Consumptie en Huishoudens, Parity, Phenotype, Behavioural genetics, Medical genetics, Female, BIOS Consortium, FOS: Medical biotechnology, Life Sciences & Biomedicine, Maternal Age, Infertility, medicine.medical_specialty, GENE PRIORITIZATION, Quantitative Trait Loci, Sociology of Consumption and Households, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, AGE, QUALITY-CONTROL, medicine, Journal Article, Life Science, SNP, Humans, gene, reproductive, behaviour, Science & Technology, ta1184, 06 Biological Sciences, medicine.disease, Genetic architecture, human reproductive behavior, 030104 developmental biology, Fertility, Human genome, Birth Order, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis, Genome-Wide Association Study
Abstract

Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC.

Published
2016

37. Determinants of iron accumulation in the normal aging brain

Author

Edith Hofer, Eric Jouvent, Martin Dichgans, Lukas Pirpamer, Benno Gesierich, François De Guio, Marco Duering, Stephan Seiler, Edouard Duchesnay, Reinhold Schmidt, Paul Freudenberger, and Stefan Ropele

Subjects
0301 basic medicine, Adult, Male, Postmortem studies, Relaxometry, Pathology, medicine.medical_specialty, Aging, Iron, Physiology, Single-nucleotide polymorphism, Temporal lobe, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Aged, Aged, 80 and over, Neocortex, medicine.diagnostic_test, General Neuroscience, Smoking, Brain, Magnetic resonance imaging, Middle Aged, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Brain size, Female, Neurology (clinical), Geriatrics and Gerontology, Psychology, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
Abstract

In a recent postmortem study, R-2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82 years. Quantitative magnetic resonance imaging was performed on 3T and included R-2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R-2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R-2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (p = 0.0091), medial temporal lobe (p = 0.0002), and hippocampus (p

Published
2015

38. White matter lesion progression: A genome-wide search for genetic influences

Author

Sudha Seshadri, Wiro J. Niessen, David J. Stott, Albert V. Smith, Claudia L. Satizabal, Rudi G. J. Westendorp, Cornelia M. van Duijn, Richard Beare, Vilmundur Gudnason, Sigurdur Sigurdsson, Qiong Yang, Christophe Tzourio, Thomas Lumley, M. Arfan Ikram, Carole Dufouil, Brendan M. Buckley, Bernard Mazoyer, Reinhold Schmidt, Michele L. Callisaya, Alexa S. Beiser, Ian Ford, Myriam Fornage, Anton J. M. de Craen, Thanh G. Phan, W. T. Longstreth, Naveed Sattar, Edith Hofer, P. Eline Slagboom, Lenore J. Launer, Stella Trompet, Jing Wang, Gerardo Heiss, Charles DeCarli, Hieab H.H. Adams, B. Gwen Windham, Velandai Srikanth, Kent D. Taylor, Chris Moran, Thomas H. Mosley, Albert Hofman, Margherita Cavalieri, Rebecca F. Gottesman, Christiane Wolf, Alex P. Zijdenbos, Benjamin F.J. Verhaaren, Mark A. van Buchem, Ganesh Chauhan, Oliver Martinez, J. Wouter Jukema, Meike W. Vernooij, Sabrina Schilling, Paul Freudenberger, Stéphanie Debette, Dean Shibata, Helena Schmidt, Anna Maria Töglhofer, Joshua C. Bis, Bruce M. Psaty, Russell Thomson, Philippe Amouyel, Epidemiology, Radiology & Nuclear Medicine, and Medical Informatics

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Pathology, Genome-wide association study, Article, Cohort Studies, Framingham Heart Study, Leukoencephalopathies, Internal medicine, Epidemiology, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Cognitive decline, Prospective cohort study, Genetic association, Aged, Advanced and Specialized Nursing, business.industry, Middle Aged, White Matter, Hyperintensity, Disease Progression, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Cohort study, Genome-Wide Association Study
Abstract

Background and Purpose— White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods— Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results— A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance ( P −8 ). Four loci were suggestive ( P −5 ) of an association with WML progression: 10q24.32 (rs10883817, P =1.46×10 −6 ); 12q13.13 (rs4761974, P =8.71×10 −7 ); 20p12.1 (rs6135309, P =3.69×10 −6 ); and 4p15.31 (rs7664442, P =2.26×10 −6 ). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions— Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Published
2015

39. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author

Susan H. Blanton, Ashley Beecham, Pamela J. Schreiner, Ralph L. Sacco, Stéphanie Debette, Ben A. Oostra, Marian Beekman, M. Arfan Ikram, Edith Hofer, Anna Maria Töglhofer, Alexander Teumer, Ganesh Chauhan, Clinton B. Wright, Meike W. Vernooij, Wiro J. Niessen, Aad van der Lugt, Cornelia M. van Duijn, Christophe Tzourio, Matthias Nauck, Bernard Mazoyer, Bettina von Sarnowski, Alexa S. Beiser, Susan R. Heckbert, André G. Uitterlinden, Alex P. Zijdenbos, David S. Knopman, Paul Freudenberger, Myriam Fornage, Maaike Schuur, Stephen Turner, Matthew Traylor, Qiong Yang, Fabrice Crivello, P. Eline Slagboom, Ian J. Deary, Sharon L.R. Kardia, Cora E. Lewis, Stella Trompet, Mike A. Nalls, Jennifer A. Smith, Katrin Hegenscheid, Hans J. Grabe, Lenore J. Launer, Reinhold Schmidt, Albert V. Smith, M. Kamran Ikram, Kumar B. Rajan, Mariza de Andrade, Sudha Seshadri, Lorna M. Lopez, Philip L. De Jager, Albert Hofman, Joshua C. Bis, Gerardo Heiss, Neelum T. Aggarwal, Elizabeth J. Atkinson, Carla A. Ibrahim-Verbaas, David C. Liewald, Anton J. M. de Craen, Jing Wang, David J. Stott, Sandra Barral, Adam M. Brickman, Mohamad Habes, Eric Boerwinkle, Katharina Wittfeld, Jerome I. Rotter, Saima Hilal, R. Nick Bryan, Charles C. DeCarli, Mark A. van Buchem, Mitchell S.V. Elkind, Rebecca F. Gottesman, Christiane Wolf, Vincent Chouraki, Jeroen van der Grond, Jiemin Liao, Joris Deelen, Stephen Sidney, Kenneth Rice, Vilmundur Guðnason, Hieab H.H. Adams, Benjamin F.J. Verhaaren, Tien Yin Wong, Oliver Martinez, Denis A. Evans, Helena Schmidt, W. T. Longstreth, J. Wouter Jukema, Richard Mayeux, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Sigurdur Sigurdsson, Carole Dufouil, Christopher Chen, Philippe Amouyel, Wei Zhao, John C. van Swieten, Bruce M. Psaty, Hae-Won Uh, B. Gwen Windham, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM U897, University of Bordeaux, France, University of Washington [Seattle], University of Michigan [Ann Arbor], University of Michigan System, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Rush University Medical Center [Chicago], University of Edinburgh, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, Depts of Radiology, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Materials Science and Metallurgy [Cambridge University] (DMSM), University of Cambridge [UK] (CAM), JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Greifswald University Hospital, Division of Biomedical Statistics and Informatics, Mayo Clinic, Division of Biomedical Statistics and Informatics, Mayo Clinic, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Genetics, The University of Texas Health Science Center at Houston (UTHealth), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University [New York], Perelman School of Medicine, University of Pennsylvania, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE), Department of neurology, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dept of Psychology, Molecular Epidemiology, Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Columbia Mailman School of Public Health, Laboratoire pharmaceutique Lilly France [Neuilly-sur-Seine], Institute of Molecular Biology & Biochemistry, Johns Hopkins University School of Medicine [Baltimore], Faculty of Medicine, University of Iceland [Reykjavik], The Icelandic Heart Association, Kopavogur, Iceland, Institutes for Community Medicine, Department of Epidemiology, University of Washington, Group Health Research Institute, Group Health Cooperative, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National University of Singapore (NUS), Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication (UGA UFR LLASIC SIC), Mayo Clinic [Rochester], Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, East China University of Science and Technology, Medstar Research Institute, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Bioinformatics, GlaxoSmithKline, National Institutes of Health [Bethesda] (NIH), Institute of Clinical Chemistry and Laboratory Medicine, Universität Greifswald - University of Greifswald, Delft University of Technology (TU Delft), Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington, Department of Health Services, University of Washington, Department of Biostatistics, University of Washington, Cedars-Sinai Medical Center, Dept of Neurology, Univ Medicine of Greifswald, Germany, Department of Physics [Stockholm], Stockholm University, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Kaiser Permanente, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Uppsala University, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, King‘s College London, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria, Research Centre for Stroke & Dementia, St George 's Univ of London, Interuniversity Cardiology Institute Netherlands, SAC, Bush Estate, School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Singapore Eye Research Institute, Singapore National Eye Centre, University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Dundee Technopole, CXR Biosciences Ltd, Department of Atmospheric, Oceanic, and Space Sciences [Ann Arbor] (AOSS), University of Michigan System-University of Michigan System, University of Miami [Coral Gables], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biospective [Montréal], Dept of Epidemiology & Public Health Sciences, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Mississippi Medical Center (UMMC), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Austrian Institute of Technology [Vienna] (AIT), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Human Genetics Center, University of Pennsylvania [Philadelphia], Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Memory Aging & Cognition Centre, National Univ of Singapore, Singapore, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Dept of Ophthalmology, National Univ of Singapore & National Univ Health System, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California-University of California, Radboud university [Nijmegen], Epidemiology, Radiology & Nuclear Medicine, General Practice, Neurology, Medical Informatics, Clinical Genetics, Internal Medicine, Human genetics, NCA - neurodegeneration, Hal, GIN, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and HESAM Université (HESAM)-HESAM Université (HESAM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, Male, single nucleotide, Pathology, Genome-wide association study, leukoencephalopathies, polymorphisms, single nucleotide, Chromosomes, Human, Genetics (clinical), Aged, 80 and over, education.field_of_study, Continental Population Groups, cerebrovascular disorders, Middle Aged, White Matter, 3. Good health, Stroke, genetics [Stroke], Female, cerebral small vessel diseases, Alzheimer's disease, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, hypertension, Population, genetics [Chromosomes, Human], Article, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Dementia, Humans, ddc:610, 1000 Genomes Project, education, Genetic association, Aged, Intracerebral hemorrhage, genome-wide association study, Models, Genetic, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Racial Groups, medicine.disease, ethnology [Stroke], Hyperintensity, Genetic Loci, pathology [Stroke], business, polymorphisms, Genome-Wide Association Study
Abstract

Background— The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results— We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 ( P =2.7×10 −19 ) and identified novel loci on chr10q24 ( P =1.6×10 −9 ) and chr2p21 ( P =4.4×10 −8 ). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 ( P =2.0×10 −8 ) and chr2p16 ( P =1.5×10 −8 ). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions— We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Published
2015

40. EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease

Author

Tormod Fladby, Dorota Religa, Reinhold Schmidt, Jakub Hort, José Luis Molinuevo, Sandro Sorbi, Michael T. Heneka, Edith Hofer, John T. O'Brien, Jonathan M. Schott, Jan Laczó, Femke H. Bouwman, Philip Scheltens, Jean Georges, Charlotte Cordonnier, Daniela Galimberti, Katharina Buerger, Neurology, and NCA - neurodegeneration

Subjects
medicine.medical_specialty, therapeutic use [Memantine], Placebo-controlled study, therapeutic use [Excitatory Amino Acid Antagonists], law.invention, Randomized controlled trial, therapeutic use [Cholinesterase Inhibitors], law, Alzheimer Disease, Memantine, Internal medicine, medicine, Dementia, drug therapy [Alzheimer Disease], Humans, ddc:610, Psychiatry, business.industry, Guideline, medicine.disease, Neurology, Tolerability, Strictly standardized mean difference, Meta-analysis, Practice Guidelines as Topic, Drug Therapy, Combination, Neurology (clinical), Cholinesterase Inhibitors, business, Excitatory Amino Acid Antagonists, medicine.drug
Abstract

Background and purpose Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). Methods A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) −0.20; 95% confidence interval (CI) −0.31; −0.09], cognitive functioning (SMD −0.27, 95% CI −0.37; −0.17) and behaviour (SMD −0.19; 95% CI −0.31; −0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. Conclusions We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.

Published
2015

41. R2* mapping for brain iron: associations with cognition in normal aging

Author

Reinhold Schmidt, Marisa Loitfelder, Lukas Pirpamer, Katja Petrovic, Martin Dichgans, Edith Hofer, Franz Fazekas, Eric Jouvent, Hugues Chabriat, Stefan Ropele, Jean-François Mangin, Petra Schwingenschuh, Helena Schmidt, Marco Duering, C. Ghadery, Stephan Seiler, and Christian Langkammer

Subjects
Male, Aging, Iron, Brain mapping, Basal Ganglia, Cohort Studies, Cognition, Basal ganglia, medicine, Humans, Effects of sleep deprivation on cognitive performance, Aged, Psychomotor learning, Brain Mapping, Neocortex, General Neuroscience, Brain, Neurodegenerative Diseases, Middle Aged, Magnetic Resonance Imaging, Globus pallidus, medicine.anatomical_structure, Brain size, Female, Neurology (clinical), Geriatrics and Gerontology, Psychology, Neuroscience, Developmental Biology
Abstract

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.

Published
2014

42. The impact of neurological disorders on the risk for falls in the community dwelling elderly: a case-controlled study

Author

Theresa Griedl, Gerd Ivanic, Edith Hofer, Franz Fazekas, C. N. Homann, Marion Grundner, Barbara Homann, Annemarie Plaschg, and Alice Haubenhofer

Subjects
medicine.medical_specialty, Pediatrics, Neurology, fall risk, neurological disorders, Disease, elderly, medicine, Dementia, Stroke, Geriatrics, business.industry, Incidence (epidemiology), Research, Case-control study, community dwelling, General Medicine, medicine.disease, Physical therapy, Falls, medicine.symptom, business, Tinnitus
Abstract

Objectives Owing to a lack of data, our aim was to evaluate and compare the impact of various common neurological diseases on the risk for falls in independent community dwelling senior citizens. Design Prospective case-controlled study. Setting General hospital. Participants Of 298 consecutive patients and 214 controls enrolled, 228 patients (aged 74.5±7.8; 61% women) and 193 controls (aged 71.4±6.8; 63% women) were included. The exclusion criteria were as follows: for patients, severe disability, disabling general condition or severe cognitive impairment; for controls, any history of neurological disorders or disabling medical conditions; and for both, age below 60 years. A matching process led to 171 age-matched and gender-matched pairs of neurological patients and healthy controls. Main outcome measures A 1-year incidence of falls based on patients' 12-month recall; motor and non-motor function tests to detect additional risk factors. Results 46% of patients and 16% of controls fell at least once a year. Patients with stroke (89%), Parkinson’s disease (77%), dementia (60%) or epilepsy (57%) had a particularly high proportion of fallers, but even subgroups of patients with the least fall-associated neurological diseases like tinnitus (30%) and headache (28%) had a higher proportion of fallers than the control group. Neuropathies, peripheral nerve lesions and Parkinson's disease were predisposing to recurrent falls. A higher number of neurological comorbidities (p

Published
2013

43. Anticardiolipin antibodies are associated with cognitive dysfunction in stroke-free individuals

Author

Nina Homayoon, Petra Schwingenschuh, Edith Hofer, Petra Katschnig-Winter, and Reinhold Schmidt

Subjects
Male, medicine.medical_specialty, Pathology, Cardiolipins, Immunoglobulins, Statistics, Nonparametric, Cohort Studies, Risk Factors, Internal medicine, medicine, Humans, Risk factor, Stroke, Aged, Mini–Mental State Examination, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Chorea, Middle Aged, musculoskeletal system, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, surgical procedures, operative, Neurology, Austria, Cohort, Linear Models, Female, Neurology (clinical), medicine.symptom, business, Cognition Disorders, Mental Status Schedule, human activities, Cohort study
Abstract

Background and purpose The presence of anticardiolipin antibodies (aCLs) has been associated with vascular occlusive events. The role of aCLs as a risk factor for stroke has been a matter of debate, and scarce information exists on the relationship between aCLs and other cerebral disorders. Reports exist for seizures, chorea and subtle cognitive dysfunction. The association between aCLs and cognition was further explored and the relationship between aCL titres and brain magnetic resonance imaging (MRI) findings was evaluated in a large cohort of community-dwelling individuals. Methods The study cohort was drawn from the Austrian Stroke Prevention Study. A total of 1895 subjects had a complete risk factor assessment and measurement of aCL titres in serum. Participants were classified as aCL positive if either the immunoglobulin G (IgG) or IgM aCL titres were elevated (IgG > 21 U/ml, IgM > 12 U/ml). All subjects were also categorized based on the quartile distribution of IgG and IgM isotype titres. All underwent cognitive testing by the Mini Mental State Examination (MMSE) and a random sample of 947 participants also underwent brain MRI. Results aCL positive participants performed worse on the MMSE. IgG but not IgM isotype titres related to worse performance on the MMSE. No significant association existed with vascular brain abnormalities including lacunes, cortical infarcts and white matter lesions. Conclusions These data support the view that in normal elderly persons increasing IgG aCL titres relate to global cognitive dysfunction. It is unlikely that structural brain lesions are responsible for this finding.

Published
2013

44. Anticardiolipin antibodies, cognition, and brain magnetic resonance imaging

Author

Marisa Loitfelder, K. Petrovic, Reinhold Schmidt, Helena Schmidt, Edith Hofer, and N. Homayoon

Subjects
Nuclear magnetic resonance, Neurology, business.industry, Medicine, Anticardiolipin antibodies, Cognition, Brain magnetic resonance imaging, Neurology (clinical), business
Published
2013

45. Impaired conditional discrimination learning in schizophrenia

Author

Edith Hofer, Peter Anderer, K. Dantendorfer, and Dagmar Doby

Subjects
Adult, Male, medicine.medical_specialty, Psychosis, Conditioning, Classical, Conditional discrimination, Audiology, Stimulus (physiology), Developmental psychology, Discrimination Learning, Discriminative model, medicine, Humans, Biological Psychiatry, Psychiatric Status Rating Scales, Analysis of Variance, Cognition, medicine.disease, Conditioning, Eyelid, Psychiatry and Mental health, Schizophrenia, Conditioning, Female, Schizophrenic Psychology, Analysis of variance, Age of onset, Psychology
Abstract

Learning deficits have repeatedly been found in patients with schizophrenia. Eyelid conditional discrimination learning (ECDL) is a test of discriminative aversive conditioning and places minimal demands on motivation. An ECDL task was used to examine residual and paranoid type individuals with schizophrenia and age- and gender-equivalent healthy controls. In the experiment two differently colored light stimuli were randomly presented. Only one of the stimuli (in reinforced trials) was followed by an aversive airpuff to the cornea, as opposed to unreinforced trials where the stimulus was not followed by an aversive airpuff. Conditioned responses develop to both trial types during the course of the experiment. These conditioned responses consist of reflectory eyelid closures already upon light presentation. The patients showed significantly impaired conditional discrimination learning abilities. There was no significant difference between the results in the two schizophrenia subtypes. Patients failed to increase response frequencies on reinforced trials during the course of the experiment, while controls showed appropriate conditional discrimination ability. Thus the results show an impairment of adequate behavior modification in an aversive conditioning task in individuals with schizophrenia. It is concluded that ECDL might be a trait marker for schizophrenia.

Published
2001

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