Knee extension strength measurements should be considered as part of the comprehensive geriatric assessment

Pathophysiology, epidemiology and therapy of agein

Software engineering techniques for the development of systems of systems

This paper investigates how existing software engineering techniques can be employed, adapted and integrated for the development of systems of systems. Starting from existing system-of-systems (SoS) studies, we identify computing paradigms and techniques that have the potential to help address the challenges associated with SoS development, and propose an SoS development framework that combines these techniques in a novel way. This framework addresses the development of a class of IT systems of systems characterised by high variability in the types of interactions between their component systems, and by relatively small numbers of such interactions. We describe how the framework supports the dynamic, automated generation of the system interfaces required to achieve these interactions, and present a case study illustrating the development of a data-centre SoS using the new framework

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.Acknowledgements: This work was supported by grants from the International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT-2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.); GENMED Labex and JPND PERADES grant; and JPND EADB grant (German Federal Ministry of Education and Research, BMBF: 01ED1619A)

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Altres ajuts: European Alzheimer DNA BioBank, EADB; EU Joint Programme, Neurodegenerative Disease Research (JPND); Neurodegeneration research program of Amsterdam Neuroscience; Stichting Alzheimer Nederland; Stichting VUmc fonds; Stichting Dioraphte; JPco-fuND FP-829-029 (ZonMW projectnumber 733051061); Dutch Federation of University Medical Centers; Dutch Government (from 2007-2011); JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A); German Research Foundation (DFG RA 1971/6-1, RA1971/7-1, RA 1971/8-1); Grifols SA; Fundación bancaria 'La Caixa'; Fundació ACE; CIBERNED; Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'); NIH (P30AG066444, P01AG003991); Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund; Siemens Healthineers; Valdecilla Biobank (PT17/0015/0019); Academy of Finland (338182); German Center for Neurodegenerative Diseases (DZNE); German Federal Ministry of Education and Research (BMBF 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711); ZonMW (#73305095007); Health~Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); Hersenstichting; Edwin Bouw Fonds; Gieskes-Strijbisfonds; NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361); Dementia Foundation (2020-04-13, 2021-04-17); Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681); Swedish Research Council (11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096); Swedish Research Council for Health, Working Life and Welfare (2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496); Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163); Alzheimer's Association Zenith Award (ZEN-01-3151); Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimer's Association (IIRG-03-6168, IIRG-09-131338); Bank of Sweden Tercentenary Foundation; Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALFGBG-771071); Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825); Swedish Research Council (2019-02075); Swedish Research Council (2016-01590); BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012); Swedish Research Council (2018-02532); Swedish State Support for Clinical Research (ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862); UK Dementia Research Institute at UCL; Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA, (#1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614); Chuck Zuckerberg Initiative (CZI).Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch