- Record: found
- Abstract: found
- Article: found
Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
research-article
Publication date (Electronic):
10 December 2018
Journal:
Nature Communications
Publisher:
Nature Publishing Group UK
Read this article at
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Abstract
Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.
Related collections
Most cited references37
- Record: found
- Abstract: found
- Article: not found
A human phenome-interactome network of protein complexes implicated in genetic disorders.
Kasper Lage, E Olof Karlberg, Zenia Størling … (2007)
We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.
- Record: found
- Abstract: found
- Article: not found
An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome
We report a novel multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation, and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adult individuals that have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation, and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also re-analyze published genome wide association studies (GWAS) using a xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based eQTL resource.
- Record: found
- Abstract: found
- Article: not found
Re-evaluation of SNP heritability in complex human traits
Doug Speed, Na Cai, Michael R Johnson … (2017)
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but the assumptions in current use have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency, linkage disequilibrium and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (standard deviation 3) higher than those obtained from the widely-used software GCTA, and 25% (standard deviation 2) higher than those from the recently-proposed extension GCTA-LDMS. Previously, DNaseI hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model their estimated contribution is only 24%.
Author and article information
Journal
Journal ID (nlm-ta): Nat Commun
Journal ID (iso-abbrev): Nat Commun
Title:
Nature Communications
Publisher:
Nature Publishing Group UK
(London
)
ISSN
(Electronic):
2041-1723
Publication date
(Electronic):
10
December
2018
Publication date PMC-release: 10
December
2018
Publication date Collection: 2018
Volume: 9
Electronic Location Identifier: 5269
Affiliations
[1
]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Vanderbilt University Medical Center, ; Nashville, TN 37232 USA
[2
]ISNI 0000 0004 1936 8470, GRID grid.10025.36, Department of Molecular and Clinical Pharmacology, , University of Liverpool, ; Liverpool, L69 3GL UK
[3
]ISNI 0000 0004 0496 3293, GRID grid.416928.0, The Walton Centre NHS Foundation Trust, ; Liverpool, L9 7LJ UK
[4
]ISNI 0000000121901201, GRID grid.83440.3b, Department of Clinical and Experimental Epilepsy, , UCL Institute of Neurology, Queen Square, ; London, WC1N 3BG UK
[5
]GRID grid.1042.7, Population Health and Immunity Divison, , The Walter and Eliza Hall Institute of Medical Research, ; Parkville, 3052 Australia
[6
]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Department of Biology, , University of Melbourne, ; Parkville, 3010 Australia
[7
]ISNI 0000 0001 2179 088X, GRID grid.1008.9, School of Mathematics and Statistics, , University of Melbourne, ; Parkville, 3010 Australia
[8
]ISNI 0000000121901201, GRID grid.83440.3b, UCL Genetics Institute, , University College London, ; London, WC1E 6BT UK
[9
]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Melbourne Integrative Genomics, , University of Melbourne, ; Parkville, 3052 Australia
[12
]ISNI 0000000121742757, GRID grid.194645.b, Centre for Genomic Sciences, , The University of Hong Kong, ; Hong Kong, Hong Kong
[13
]ISNI 0000 0000 8786 803X, GRID grid.15090.3d, Section for Translational Epilepsy Research, Department of Neuropathology, , University of Bonn Medical Center, ; Bonn, 53105 Germany
[14
]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research,
, University of Tübingen, ; Tübingen, 72076 Germany
[15
]ISNI 0000 0004 1936 9748, GRID grid.6582.9, Department of Neurology, , University of Ulm, ; Ulm, 89081 Germany
[16
]ISNI 0000 0004 0631 9143, GRID grid.419298.f, Stichting Epilepsie Instellingen Nederland (SEIN), ; Zwolle, 8025 BV The Netherlands
[17
]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Epilepsy Research Centre, , University of Melbourne, Austin Health, ; Heidelberg, 3084 Australia
[18
]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Center for Applied Genomics, The Children’s Hospital of Philadelphia, ; Philadelphia, PA 19104 USA
[20
]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, MD 20892 USA
[21
]GRID grid.411897.2, Department of Biomedical Sciences, , Cooper Medical School of Rowan University Camden, ; Camden, NJ 08103 USA
[22
]ISNI 0000 0004 0442 8581, GRID grid.412726.4, Department of Neurology, , Thomas Jefferson University Hospital, ; Philadelphia, PA 19107 USA
[23
]ISNI 0000 0000 9565 2378, GRID grid.412915.a, Belfast Health and Social Care Trust, ; Belfast, BT9 7AB UK
[24
]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Division of Epilepsy, Department of Neurology, Mayo Clinic, ; Rochester, MN 55902 USA
[25
]ISNI 0000 0004 0488 7120, GRID grid.4912.e, Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in
Ireland, ; Dublin 2, Ireland
[27
]ISNI 0000000121742757, GRID grid.194645.b, Department of Psychiatry, , The University of Hong Kong, ; Hong Kong, Hong Kong
[28
]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Department of Epidemiology and Preventive Medicine, , School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, ; Tel Aviv, 6997801 Israel
[29
]ISNI 0000 0004 0606 5382, GRID grid.10306.34, The Wellcome Trust Sanger Institute, Hinxton, ; Cambridge, CB10 1SA UK
[31
]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Neuroscience, , Reproductive and Odontostomatological Sciences, University Federico II, ; Naples, 80138 Italy
[32
]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Laboratory of Neurogenetics and Neurosciences, Institute G. Gaslini, ; Genova, 16148 Italy
[33
]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Neurosciences, , University of Montreal, ; Montreal, CA 26758 Canada
[34
]ISNI 0000 0004 0399 1866, GRID grid.416232.0, Department of Neurology, , Royal Victoria Hospital, Belfast Health and Social Care Trust, ; Grosvenor Road, Belfast, BT12 6BA UK
[35
]ISNI 0000 0004 0631 9143, GRID grid.419298.f, Stichting Epilepsie Instellingen Nederland (SEIN), ; Heemstede, 2103 SW The Netherlands
[36
]ISNI 0000 0001 0790 3681, GRID grid.5284.b, Neurogenetics Group, Center for Molecular Neurology, VIB and Laboratory of Neurogenetics,
Institute Born-Bunge, , University of Antwerp, ; Antwerp, 2610 Belgium
[37
]ISNI 0000 0004 0626 3418, GRID grid.411414.5, Department of Neurology, , Antwerp University Hospital, ; Edegem, 2650 Belgium
[38
]ISNI 0000000090126352, GRID grid.7692.a, Department of Genetics, University Medical Center Utrecht, ; Utrecht, 3584 CX The Netherlands
[39
]ISNI 0000 0004 0617 6058, GRID grid.414315.6, Division of Neurology, Beaumont Hospital, ; Dublin, D09 FT51 Ireland
[41
]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Comprehensive Epilepsy Center, , New York University School of Medicine, ; New York, NY 10016 USA
[42
]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Department of Neurology, , The Children’s Hospital of Philadelphia, ; Philadelphia, PA 19104 USA
[43
]ISNI 0000 0004 0617 8280, GRID grid.416409.e, Neurology Department, St. James’s Hospital, ; Dublin, D03 VX82 Ireland
[44
]ISNI 0000 0000 8786 803X, GRID grid.15090.3d, Department of Epileptology, , University of Bonn Medical Centre, ; Bonn, 53127 Germany
[45
]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of General Practice and Primary Health Care, , University of Helsinki and Helsinki University Hospital, ; Helsinki, 0014 Finland
[46
]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Pharmacology and Psychiatry, , University of Pennsylvania Perlman School of Medicine, ; Philadelphia, PA 19104 USA
[47
]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Pediatrics and Neonatology, , Medical University of Vienna, ; Vienna, 1090 Austria
[48
]ISNI 0000 0004 1936 8470, GRID grid.10025.36, Department of Biostatistics, , University of Liverpool, ; Liverpool, L69 3GL UK
[49
]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, University
Hospital Schleswig Holstein, Kiel, 24105 Germany
[50
]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Department of Neurology, , NYU School of Medicine, ; New York City, NY 10003 USA
[51
]GRID grid.418434.e, Department of Neurology, , Charité Universitaetsmedizin Berlin, Campus Virchow-Clinic, ; Berlin, 13353 Germany
[53
]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research
Center for Environmental Health, ; Neuherberg, D-85764 Germany
[54
]Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for
Environmental Health, Neuherberg, D-85764 Germany
[55
]ISNI 0000 0000 9025 8099, GRID grid.239573.9, Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children’s Hospital
Medical Center, ; Cincinnati, OH 45229 USA
[56
]ISNI 0000000086837370, GRID grid.214458.e, Department of Neurology, University of Michigan, ; Ann Arbor, MI 48109 USA
[57
]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Center for Human Genome Variation, , Duke University School of Medicine, ; Durham, NC 27710 USA
[58
]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Institute for Genomic Medicine, , Columbia University Medical Center, ; New York, NY 10032 USA
[59
]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine,
, University of Pennsylvania, ; Philadelphia, PA 19104 USA
[60
]ISNI 0000 0000 8786 803X, GRID grid.15090.3d, Life and Brain Center, , University of Bonn Medical Center, ; Bonn, 53127 Germany
[62
]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Department of Neuropediatrics, , University Medical Center Schleswig-Holstein (UKSH), ; Kiel, 24105 Germany
[64
]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Institute of Regional Health Services Research, , University of Southern Denmark, ; Odense, 5000 Denmark
[65
]ISNI 0000 0004 0618 6889, GRID grid.421812.c, deCODE genetics, Inc., ; Reykjavik, IS-101 Iceland
[66
]ISNI 0000 0004 1936 8868, GRID grid.4563.4, Department of Psychiatry and Applied Psychology, , Institute of Mental Health University of Nottingham, ; Nottingham, NG7 2TU UK
[67
]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Faculty of Medicine, , Imperial College London, ; London, SW7 2AZ UK
[68
]ISNI 0000 0004 0628 207X, GRID grid.410705.7, Kuopio Epilepsy Center, , Neurocenter, Kuopio University Hospital, ; Kuopio, 70029 Finland
[69
]ISNI 0000 0001 0726 2490, GRID grid.9668.1, Institute of Clinical Medicine, , University of Eastern Finland, ; Kuopio, 70029 Finland
[70
]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Neurology, , University of California, ; San Francisco, CA 94143 USA
[71
]ISNI 0000000106344187, GRID grid.265892.2, University of Alabama Birmingham, Department of Neurology, ; Birmingham, AL 35233 USA
[72
]ISNI 0000 0001 2295 9843, GRID grid.16008.3f, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, ; Esch-sur-Alzette, L-4362 Luxembourg
[73
]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Neurology, , Medical University of Vienna, ; Vienna, 1090 Austria
[74
]ISNI 0000 0001 2284 9943, GRID grid.257060.6, Department of Neurology, , Zucker-Hofstra Northwell School of Medicine, ; New York, NY 10075 USA
[75
]Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville,
VIC 3050 Australia
[76
]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Neuroscience, , Central Clinical School, Monash University, ; Melbourne, VIC 3004 Australia
[77
]GRID grid.66859.34, Stanley Center for Psychiatric Research, , Broad Institute of Harvard and M.I.T, ; Cambridge, MA 02142 USA
[78
]ISNI 0000000121742757, GRID grid.194645.b, Department of Paediatrics and Adolescent Medicine, , The University of Hong Kong, ; Hong Kong, Hong Kong
[79
]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Folkhälsan Research Center and Medical Faculty, , University of Helsinki, ; Helsinki, 00290 Finland
[80
]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Genomic Medicine Institute, , Lerner Research Institute, Cleveland Clinic, ; Cleveland, OH 44195 USA
[81
]ISNI 0000 0001 2153 9986, GRID grid.9764.c, Institut für Epidemiologie Christian-Albrechts-Universität zu Kiel, ; Kiel, 24105 Germany
[82
]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Pediatrics and Neurology, , Ohio State University and Nationwide Children’s Hospital, ; Columbus, OH 43205 USA
[83
]ISNI 0000 0001 0723 2494, GRID grid.411087.b, Department of Medical Genetics, School of Medical Sciences, , University of Campinas (UNICAMP), ; Campinas, 13083-887 SP Brazil
[84
]Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP 13083-970
Brazil
[87
]ISNI 0000 0000 9635 8082, GRID grid.420089.7, Division of Intramural Population Health Research, Eunice Kennedy Shriver National
Institute of Child Health and Human Development, National Institutes of Health, ; Bethesda, MD 20892 USA
[89
]ISNI 0000 0004 1936 9705, GRID grid.8217.c, School of Medicine, Trinity College Dublin, ; Dublin 2, Ireland
[91
]ISNI 0000 0004 1771 3082, GRID grid.417037.6, United Christian Hospital, ; Hong Kong, Hong Kong
[93
]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Cologne Center for Genomics, University of Cologne, ; Cologne, 50931 Germany
[94
]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, ; Helsinki, 0014 Finland
[96
]ISNI 0000 0004 5929 4381, GRID grid.417815.e, AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech
Unit, AstraZeneca, ; Cambridge, CB2 0AA UK
[97
]Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston,
MA 02115 USA
[98
]ISNI 0000 0000 9881 9161, GRID grid.413561.4, Department of Neurology, Neuroscience Institute, , University of Cincinnati Medical Center, ; Cincinnati, OH 45220 USA
[99
]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Department of Neurology, , Duke University School of Medicine, ; Durham, NC 27710 USA
[100
]ISNI 0000 0000 8584 9230, GRID grid.411067.5, Epilepsy-Center Hessen, Department of Neurology, University Medical Center Giessen
and Marburg, Marburg, Germany and Philipps-University Marburg, ; Marburg, 35043 Germany
[101
]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe
University Frankfurt, ; Frankfurt, 60528 Germany
[102
]ISNI 0000 0004 0386 7187, GRID grid.452379.e, Chalfont Centre for Epilepsy, Chalfont-St-Peter, ; Buckinghamshire, SL9 0RJ UK
[103
]ISNI 0000 0004 0435 0884, GRID grid.411115.1, Department of Endocrinology, , Hospital of The University of Pennsylvania, ; Philadelphia, PA 19104 USA
[104
]Departments of Neurology, Beth Israel Deaconess Medical Center, Massachusetts General
Hospital, and Harvard Medical School, Boston, MA 02215 USA
[105
]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Department of Neurology, Inselspital, Bern University Hospital, , University of Bern, ; Bern, 3010 Switzerland
[106
]ISNI 0000 0004 0614 0346, GRID grid.416107.5, Department of Neurology, , Royal Children’s Hospital, ; Parkville, VIC 3052 Australia
[107
]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Neurosciences, , University of California, San Diego, ; La Jolla, CA 92037 USA
[108
]ISNI 0000 0004 0488 7120, GRID grid.4912.e, The Royal College of Surgeons in Ireland, ; Dublin, D02 YN77 Ireland
[109
]ISNI 0000 0001 0705 3621, GRID grid.240684.c, Rush University Medical Center, ; Chicago, 60612 IL USA
[110
]ISNI 0000 0001 0169 7725, GRID grid.241103.5, Department of Neurology, Alan Richens Epilepsy Unit, , University Hospital of Wales, ; Cardiff, CF14 4XW UK
[111
]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Aarhus Institute of Advanced Studies (AIAS), , Aarhus University, ; Aarhus, 8000 Denmark
[112
]ISNI 0000 0001 2166 5843, GRID grid.265008.9, Department of Neurology and Comprehensive Epilepsy Center, , Thomas Jefferson University, ; Philadelphia, PA 19107 USA
[113
]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center
for Environmental Health, Neuherberg, ; Neuherberg, D-85764 Germany
[114
]ISNI 0000 0004 1936 973X, GRID grid.5252.0, IBE, Faculty of Medicine, LMU Munich, ; Munich, 80539 Germany
[115
]ISNI 0000 0001 2151 3065, GRID grid.5606.5, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation,
Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, , University of Genoa, ; Genova, 16148 Italy
[116
]ISNI 0000 0004 0444 9008, GRID grid.413327.0, CWZ Hospital, ; Nijmegen, 6532 SZ The Netherlands
[117
]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Neurology, , Washington University School of Medicine, ; St. Louis, MO 63110 USA
[118
]ISNI 0000 0004 1936 7486, GRID grid.6572.6, Institute for Applied Health Research, , University of Birmingham, ; Birmingham, B15 2TT UK
[120
]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Departments of Neurology and Pediatrics, , The Johns Hopkins University School of Medicine, ; Baltimore, MD 21287 USA
[122
]ISNI 0000000100241216, GRID grid.189509.c, Division of Medical Genetics, Department of Pediatrics, , Duke University Medical Center, ; Durham, NC 27710 USA
Article
Publisher ID: 7524DOI: 10.1038/s41467-018-07524-z
PMC ID: 6288131
PubMed ID: 30531953
SO-VID: bb7e1580-48bd-4086-a051-a49e146d6705
Copyright © © The Author(s) 2018
License:
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
History
Date
received
: 21
May
2018
Date
accepted
: 30
October
2018
Categories
Subject:
Article
Custom metadata
issue-copyright-statement © The Author(s) 2018
ScienceOpen disciplines: Uncategorized
Data availability:
ScienceOpen disciplines: Uncategorized