Publications by authors named "Stéphanie Debette"

173 Publications

Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study.

Front Neurol 2021 20;12:675244. Epub 2021 May 20.

UMR1219 Bordeaux Population Health Center (Team VINTAGE), INSERM-University of Bordeaux, Bordeaux, France.

Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral ( = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.
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http://dx.doi.org/10.3389/fneur.2021.675244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173138PMC
May 2021

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

Int J Stroke 2021 Apr 26:17474930211007288. Epub 2021 Apr 26.

Stroke Pharmacogenomics and Genetics Group, Sant Pau Biomedical Research Institute, Barcelona, Spain.

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.
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http://dx.doi.org/10.1177/17474930211007288DOI Listing
April 2021

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Blood 2021 Apr;137(17):2394-2402

Aix Marseille University, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), Centre de Recherche en CardioVasculaire et Nutrition, Marseille, France.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
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http://dx.doi.org/10.1182/blood.2020008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085481PMC
April 2021

A Mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.

Blood 2020 12;136(26):3062-3069

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
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http://dx.doi.org/10.1182/blood.2019004781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770565PMC
December 2020

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Extracellular matrix protein signature in cervical artery dissection: The key differentiator?

Neurology 2020 10 4;95(15):663-664. Epub 2020 Sep 4.

From the Department of Neurology and Stroke Center (C.T.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T.), University Department of Geriatric Medicine Felix Platter, Basel, Switzerland; Department of Neurology (S.D.), Bordeaux University Hospital; and University of Bordeaux and Inserm U1219 (S.D.), Bordeaux, France.

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http://dx.doi.org/10.1212/WNL.0000000000010750DOI Listing
October 2020

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

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 (), 10q23.1 (), and 10q24.33 ( 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 () 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: (2q32.1), (3q27.1), (5q27.1), and (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.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study.

Front Psychiatry 2020 4;11:342. Epub 2020 May 4.

Institute of Neurodegenerative Diseases (IMN), CNRS, CEA, Bordeaux, France.

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process.
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http://dx.doi.org/10.3389/fpsyt.2020.00342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212692PMC
May 2020

Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke.

Nat Rev Neurol 2020 May 22;16(5):247-264. Epub 2020 Apr 22.

Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain.

Despite many years of research, no biomarkers for stroke are available to use in clinical practice. Progress in high-throughput technologies has provided new opportunities to understand the pathophysiology of this complex disease, and these studies have generated large amounts of data and information at different molecular levels. The integration of these multi-omics data means that thousands of proteins (proteomics), genes (genomics), RNAs (transcriptomics) and metabolites (metabolomics) can be studied simultaneously, revealing interaction networks between the molecular levels. Integrated analysis of multi-omics data will provide useful insight into stroke pathogenesis, identification of therapeutic targets and biomarker discovery. In this Review, we detail current knowledge on the pathology of stroke and the current status of biomarker research in stroke. We summarize how proteomics, metabolomics, transcriptomics and genomics are all contributing to the identification of new candidate biomarkers that could be developed and used in clinical stroke management.
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http://dx.doi.org/10.1038/s41582-020-0350-6DOI Listing
May 2020

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

Cereb Cortex 2020 06;30(7):4121-4139

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04109 Leipzig, Germany.

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.
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http://dx.doi.org/10.1093/cercor/bhaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947185PMC
June 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Risk of Intracranial Aneurysm and Dissection and Fluoroquinolone Use: A Case-Time-Control Study.

Stroke 2020 03 22;51(3):994-997. Epub 2020 Jan 22.

From the Team Pharmacoepidemiology (S.M.-R., Y.M., A.P.), Bordeaux Population Health Research Center, Inserm U1219, University of Bordeaux, France.

Background and Purpose- Fluoroquinolone use is associated with an increased risk of aortic aneurysm and dissection. We investigated this risk of arterial wall injury on intracranial arteries, given the similar pathophysiological mechanisms for aneurysm and dissection in both types of arteries. Methods- A case-time-control study was conducted using French National Insurance databases covering >60 million inhabitants. Cases were aged ≥18 years with first ruptured intracranial aneurysm and dissection between 2010 and 2015. For each case, fluoroquinolone use was compared between the exposure-risk window (day 30-day 1 before the outcome) and matched control windows (day 120-day 91, day 150-day 121, and day 180-day 151) and adjusted for time-varying confounders; potential time-trend for exposure was controlled using an age- and sex-matched reference group. Amoxicillin use was studied similarly for indication bias controlling. The potential excess of risk conveyed by fluoroquinolones was assessed by the ratio of OR for fluoroquinolones to that for amoxicillin. Results- Of the 7443 identified cases, 75 had been exposed to fluoroquinolones in the prior 180 days, including 16 in the 30-day at-risk window (385/97 cases exposed to amoxicillin, respectively). The adjusted OR for fluoroquinolones was 1.26 (95%CI, 0.65-2.41) and that for amoxicillin of 1.36 (95% CI, 1.05-1.78). Ratio of OR for fluoroquinolones to that for amoxicillin was estimated at 0.92 (95% CI, 0.46-1.86). Result was similar when extending outcome definition to unruptured events (ratio of OR for fluoroquinolones to that for amoxicillin, 0.97 [95% CI, 0.61-1.53]). Conclusions- This study did not evidence an excess of risk of intracranial aneurysm or dissection with fluoroquinolone use.
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http://dx.doi.org/10.1161/STROKEAHA.119.028490DOI Listing
March 2020

Vascular contributions to cognitive impairment and dementia: Research consortia that focus on etiology and treatable targets to lessen the burden of dementia worldwide.

Alzheimers Dement (N Y) 2019 19;5:789-796. Epub 2019 Nov 19.

Department of Neurology, G03.232, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.

The research into vascular contributions to cognitive impairment and dementia (VCID) aims to understand the importance of cerebrovascular biology in cognitive decline. Prevention and treatment of VCID is poised to have major impact on dementia-related disease burden and is thus a critical emerging objective in dementia research. This article presents VCID consortia focused on multidisciplinary approaches to identify key pathologic targets and develop diagnostic tools with the goal of bridging the divide between basic research and clinical trials. Members of these multi-institute, multidisciplinary consortia provide a prospective on the history and emerging science of VCID and how VCID consortia can address some of the more complex questions in VCID and drive the field forward. These consortia, and others like them, are uniquely suited to tackle some of the most difficult obstacles in translating research to the clinic.
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http://dx.doi.org/10.1016/j.trci.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944727PMC
November 2019

Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia.

Obes Rev 2020 04 3;21(4):e12989. Epub 2020 Jan 3.

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.
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http://dx.doi.org/10.1111/obr.12989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079047PMC
April 2020

Association Between Cerebral Small Vessel Disease With Antidepressant Use and Depression: 3C Dijon Magnetic Resonance Imaging Study.

Stroke 2020 02 12;51(2):402-408. Epub 2019 Dec 12.

From the Inserm, Bordeaux Population Health Research Center, UMR 1219 (P.J.T., A.A., A.S., S.D., C.T.), University of Bordeaux, France.

Background and Purpose- Evidence links antidepressant use with cerebral small vessel disease; however, it remains unclear whether people with depression face comparable risk. This study aims to determine the association between antidepressant drug use and depression with markers of cerebral small vessel disease. Methods- One thousand nine hundred five participants (mean age, 72.5 years; 60% women) without stroke or dementia history underwent brain magnetic resonance imaging at baseline, and 1402 individuals underwent a second magnetic resonance imaging at 4 years. Outcomes were lacunes 3 to 15 mm and white matter hyperintensity volume (cm) at baseline and follow-up. Exposure to antidepressants was grouped as (1) selective serotonin reuptake inhibitors (n=68), (2) tricyclics (n=40), (3) atypicals (n=24), (4) depressed nonusers (n=303), and (5) nondepressed/nonuser group (reference group, n=1470). Statistical analyses adjusted for propensity scores due to the nonrandomized exposure to antidepressant drugs. Results- There was an association between use of atypical antidepressants with lacunes at baseline (adjusted rate ratio, 2.59 [95% CI, 1.14-5.88]; =0.023) and follow-up (adjusted rate ratio, 3.05 [95% CI, 1.25-7.43]; =0.014). Lacunes at baseline were also associated with depressed nonusers (adjusted rate ratio, 1.53 [95% CI, 1.06-2.21]; =0.023). Selective serotonin reuptake inhibitor users and depressed nonusers displayed higher total, periventricular, and deep white matter hyperintensity volumes at baseline. Selective serotonin reuptake inhibitor users had higher deep white matter hyperintensity volumes at follow-up. Conclusions- Users of atypical antidepressants, selective serotonin reuptake inhibitors, and depressed people without any antidepressant exposure all displayed markers of cerebral small vessel disease higher than the nondepressed/nonuser group. The findings suggest that cerebral small vessel disease is associated with depression and exposure to antidepressants.
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http://dx.doi.org/10.1161/STROKEAHA.119.026712DOI Listing
February 2020

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

Neurology 2020 01 22;94(2):e170-e180. Epub 2019 Nov 22.

From the Department of Neurology and Stroke Center (C.T., G.M.D.M., A. Polymeris, H.G., L.H.B., S.T.E., P.L.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T., H.G., S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland; Departments of Neurology (C.G.-G., M.K.) and Vascular and Endovascular Surgery (C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (B.G.S., U.F., H.S., M.A.), University Hospital Bern; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; University of Bordeaux (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.Pezzini.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (A.M.S., B.B.W.), University of Virginia Health System, Charlottesville; Univ-Lille (D.L.), Inserm U1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Dijon Bourgogne (Y.B.), EA7460, Pathophysiology and Epidemiology of Cardio-Cerebro-Vascular Diseases, University of Burgundy, Dijon, France; Department of Neurology (H.S.), University Hospital of Zurich, Switzerland; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Cerebrovascular Unit Fondazione IRCCS Istituto Neurologico Carlo Besta (A.B.), Milan, Italy; Swiss National Accident Insurance Institution (T.B.), Lucerne, Switzerland; Normandie Université (E.T.), Université Caen Normandie, Inserm U1037, Department of Neurology, CHU Caen Normandie; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (H.C.), Lariboisière Hospital, Paris, France; Department of Neurology (T.T.), Sahlgrenska University Hospital; and Department of Clinical Neuroscience Institute for Neuroscience and Physiology (T.T.), Sahlgrenska Academy at University of Gothenburg, Sweden.

Objective: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).

Methods: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.

Results: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, = 0.059).

Conclusion: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000008654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988986PMC
January 2020

Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis.

BMJ Open 2019 11 14;9(11):e031144. Epub 2019 Nov 14.

Neurology Department, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.

Methods And Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.

Ethics And Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
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http://dx.doi.org/10.1136/bmjopen-2019-031144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887075PMC
November 2019

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

Lancet Neurol 2020 01 6;19(1):61-70. Epub 2019 Nov 6.

Intramural Research Program, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address:

Background: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia.

Methods: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses.

Results: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease.

Interpretation: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia.

Funding: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.
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http://dx.doi.org/10.1016/S1474-4422(19)30393-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391421PMC
January 2020

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Nat Genet 2019 11 28;51(11):1580-1587. Epub 2019 Oct 28.

National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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http://dx.doi.org/10.1038/s41588-019-0514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858575PMC
November 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

High dilated perivascular space burden: a new MRI marker for risk of intracerebral hemorrhage.

Neurobiol Aging 2019 12 10;84:158-165. Epub 2019 Sep 10.

Univ. Bordeaux, Inserm U1219, Bordeaux Population Health Research Center, Bordeaux, France; CHU de Bordeaux, Department of Neurology, Bordeaux, France. Electronic address:

Commonly observed in older community persons, dilated perivascular spaces (dPVSs) are thought to represent an emerging MRI marker of cerebral small vessel disease, but their clinical significance is uncertain. We examined the longitudinal relationship of dPVS burden with risk of incident stroke, ischemic stroke, and intracerebral hemorrhage (ICH) in the 3C-Dijon population-based study (N = 1678 participants, mean age 72.7 ± 4.1 years) using Cox regression. dPVS burden was studied as a global score and according to dPVS location (basal ganglia, white matter, hippocampus, brainstem) at the baseline. During a mean follow-up of 9.1 ± 2.6 years, 66 participants suffered an incident stroke. Increasing global dPVS burden was associated with a higher risk of any incident stroke (hazard ratio [HR], 1.24; 95% CI, [1.06-1.45]) and of incident ICH (HR, 3.12 [1.78-5.47]), adjusting for sex and intracranial volume. Association with ICH remained significant after additionally adjusting for vascular risk factors and for other cerebral small vessel disease MRI markers. High dPVS burden in basal ganglia and hippocampus, but not in white matter or brainstem, were associated with higher risk of any stroke and ICH.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.031DOI Listing
December 2019

Genome-wide association study of cerebral small vessel disease reveals established and novel loci.

Brain 2019 10;142(10):3176-3189

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.
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http://dx.doi.org/10.1093/brain/awz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763741PMC
October 2019

A plasma proteogenomic signature for fibromuscular dysplasia.

Cardiovasc Res 2020 01;116(1):63-77

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.

Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.

Methods And Results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios  = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.

Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
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http://dx.doi.org/10.1093/cvr/cvz219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918065PMC
January 2020

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

Commun Biol 2019 2;2:285. Epub 2019 Aug 2.

17Department of Biomedical Data Sciences, Statistical Genetics, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.

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 ( and ), or close to genes causing Mendelian brain-related diseases ( and ). 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.
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http://dx.doi.org/10.1038/s42003-019-0537-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677735PMC
April 2020