Publications by authors named "Saud Alhusaini"

27 Publications

  • Page 1 of 1

A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

Neuropathol Appl Neurobiol 2021 Aug 13. Epub 2021 Aug 13.

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Aims: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis.

Methods: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy.

Results: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia.

Conclusions: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
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http://dx.doi.org/10.1111/nan.12758DOI Listing
August 2021

Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study.

Neuroimage Clin 2021 24;31:102765. Epub 2021 Jul 24.

Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany; Institute for Diagnostic and Interventional Radiology, Pediatric and Neuroradiology, University Medical Centre Rostock, Rostock, Germany.

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
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http://dx.doi.org/10.1016/j.nicl.2021.102765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346685PMC
September 2021

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Sci Adv 2020 Nov 18;6(47). Epub 2020 Nov 18.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
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http://dx.doi.org/10.1126/sciadv.abc6457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673818PMC
November 2020

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

Brain 2020 08;143(8):2454-2473

Department of Neurology, Medical University of South Carolina, Charleston 29425 SC, USA.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
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http://dx.doi.org/10.1093/brain/awaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567169PMC
August 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

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

Normal cerebral cortical thickness in first-degree relatives of temporal lobe epilepsy patients.

Neurology 2019 01 26;92(4):e351-e358. Epub 2018 Dec 26.

From the Department of Molecular and Cellular Therapeutics (S.A., G.L.C., N.D.) and FutureNeuro Research Centre (G.L.C., N.D.), the Royal College of Surgeons in Ireland, Dublin; Department of Neurology and Neurosurgery (S.A.), Montreal Neurological Institute and Hospital, Canada; The Florey Institute of Neuroscience and Mental Health (M.A.K., M.K.S., G.D.J.), Austin Campus, Melbourne, Australia; Neuroimaging Laboratory, Department of Neurology (C.L.Y., M.K., M.Z., T.Z., M.H.N., M.K.M.A., V.R.F., I.L.-C., F.C.), University of Campinas, São Paulo, Brazil; Department of Neurology (M.-H.T.), Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Brain Morphometry Laboratory (M.F.) and Division of Neurology (N.D.), Beaumont Hospital; Department of Neurology (C.P.D.), St James's Hospital, Dublin, Ireland; and Department of Neurology (G.D.J.), Austin Health, Melbourne, Australia.

Objective: To examine cerebral cortex thickness in asymptomatic first-degree relatives of patients with mesial temporal lobe epilepsy (MTLE).

Methods: We investigated 127 asymptomatic first-degree relatives of patients with MTLE due to hippocampal sclerosis (HS) (mean age ± SD = 39.4 ± 13 years) and 203 healthy control individuals (mean age ± SD = 36.0 ± 11 years). Participants underwent a comprehensive clinical evaluation and structural brain MRI at 3 study sites. Images were processed simultaneously at each site using a surface-based morphometry method to quantify global brain measures, hippocampal volumes, and cerebral cortical thickness. Differences in brain measures between relatives of patients and controls were examined using generalized models, while controlling for relevant covariates, including age and sex.

Results: None of the asymptomatic first-degree relatives of MTLE + HS patients showed evidence of HS on qualitative image assessments. Compared to the healthy controls, the asymptomatic relatives of patients displayed no significant differences in intracranial volume, average hemispheric surface area, or hippocampal volume. Similarly, no significant cerebral cortical thinning was identified in the relatives of patients. This was consistent across the 3 cohorts.

Conclusion: Lack of cortical thickness changes in the asymptomatic relatives of patients indicates that the previously characterized MTLE + HS-related cortical thinning is not heritable, and is likely driven by disease-related factors. This finding therefore argues for early and aggressive intervention in patients with medically intractable epilepsy.
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http://dx.doi.org/10.1212/WNL.0000000000006834DOI Listing
January 2019

Association between carotid atheroma and cerebral cortex structure at age 73 years.

Ann Neurol 2018 10 5;84(4):576-587. Epub 2018 Oct 5.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Objective: To examine the relationship between carotid atherosclerosis and cerebral cortical thickness and investigate whether cortical thickness mediates the association between carotid atheroma and relative cognitive decline.

Methods: We assessed 554 community-dwelling subjects (male/female: 296/258) from the Lothian Birth Cohort 1936 who underwent brain magnetic resonance imaging and carotid Doppler ultrasound studies at age 73 years. The relationship between carotid atherosclerosis markers (internal carotid artery stenosis, intima-media thickness, velocity, pulsatility, and resistivity indexes) and vertex-wide cerebral cortical thickness was examined cross-sectionally, controlling for gender, extensive vascular risk factors (VRFs), and intelligence quotient at age 11 (IQ-11). We also determined the association between carotid stenosis and a composite measure of fluid intelligence at age 73 years. A mediation model was applied to examine whether cortical thickness mediated the relationship between carotid stenosis and cognitive function.

Results: A widespread negative association was identified between carotid stenosis (median = 15%) and cerebral cortical thickness at age 73 years, independent of the side of carotid stenosis, other carotid measures, VRFs, and IQ-11. This association increased in an almost dose-response relationship from mild to severe degrees of carotid stenosis, across the anterior and posterior circulation territories. A negative association was also noted between carotid stenosis and fluid intelligence (standardized beta coefficient = -0.151, p = 0.001), which appeared partly (approximately 22%) mediated by carotid stenosis-related thinning of the cerebral cortex.

Interpretation: The findings suggest that carotid stenosis represents a marker of processes that accelerate aging of the cerebral cortex and cognition that is in part independent of measurable VRFs. Cortical thinning within the anterior and posterior circulation territories partially mediated the relationship between carotid atheroma and fluid intelligence. Ann Neurol 2018;84:576-587.
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http://dx.doi.org/10.1002/ana.25324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328248PMC
October 2018

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Brain 2018 02;141(2):391-408

Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, USA.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.
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http://dx.doi.org/10.1093/brain/awx341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837616PMC
February 2018

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

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

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

Quantitative magnetic resonance imaging traits as endophenotypes for genetic mapping in epilepsy.

Neuroimage Clin 2016;12:526-534. Epub 2016 Sep 8.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.

Over the last decade, the field of has combined high-throughput genotype data with quantitative magnetic resonance imaging (QMRI) measures to identify genes associated with brain structure, cognition, and several brain-related disorders. Despite its successful application in different psychiatric and neurological disorders, the field has yet to be advanced in epilepsy. In this article we examine the relevance of imaging genomics for future genetic studies in epilepsy from three perspectives. First, we discuss prior genome-wide genetic mapping efforts in epilepsy, considering the possibility that some studies may have been constrained by inherent theoretical and methodological limitations of the genome-wide association study (GWAS) method. Second, we offer a brief overview of the imaging genomics paradigm, from its original inception, to its role in the discovery of important risk genes in a number of brain-related disorders, and its successful application in large-scale multinational research networks. Third, we provide a comprehensive review of past studies that have explored the eligibility of brain QMRI traits as for epilepsy. While the breadth of studies exploring QMRI-derived endophenotypes in epilepsy remains narrow, robust syndrome-specific neuroanatomical QMRI traits have the potential to serve as accessible and relevant intermediate phenotypes for future genetic mapping efforts in epilepsy.
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http://dx.doi.org/10.1016/j.nicl.2016.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030372PMC
September 2016

White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.

Epilepsia 2015 Oct 7;56(10):1551-61. Epub 2015 Aug 7.

Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.

Objective: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy.

Methods: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs).

Results: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset.

Significance: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.
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http://dx.doi.org/10.1111/epi.13103DOI Listing
October 2015

Common genetic variants influence human subcortical brain structures.

Nature 2015 Apr 21;520(7546):224-9. Epub 2015 Jan 21.

1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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http://dx.doi.org/10.1038/nature14101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393366PMC
April 2015

Temporal Cortex Morphology in Mesial Temporal Lobe Epilepsy Patients and Their Asymptomatic Siblings.

Cereb Cortex 2016 Mar 9;26(3):1234-41. Epub 2015 Jan 9.

Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.

Temporal cortex abnormalities are common in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE+HS) and believed to be relevant to the underlying mechanisms. In the present study, we set out to determine the familiarity of temporal cortex morphologic alterations in a cohort of MTLE+HS patients and their asymptomatic siblings. A surface-based morphometry (SBM) method was applied to process MRI data acquired from 140 individuals (50 patients with unilateral MTLE+HS, 50 asymptomatic siblings of patients, and 40 healthy controls). Using a region-of-interest approach, alterations in temporal cortex morphology were determined in patients and their asymptomatic siblings by comparing with the controls. Alterations in temporal cortex morphology were identified in MTLE+HS patients ipsilaterally within the anterio-medial regions, including the entorhinal cortex, parahippocampal gyrus, and temporal pole. Subtle but similar pattern of morphology changes with a medium effect size were also noted in the asymptomatic siblings. These localized alterations were related to volume loss that appeared driven by shared contractions in cerebral cortex surface area. These findings indicate that temporal cortex morphologic alterations are common to patients and their asymptomatic siblings and suggest that such localized traits are possibly heritable.
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http://dx.doi.org/10.1093/cercor/bhu315DOI Listing
March 2016

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

Brain Imaging Behav 2014 Jun;8(2):153-82

Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, 2001 N. Soto Street, Los Angeles, CA, 90033, USA,

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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http://dx.doi.org/10.1007/s11682-013-9269-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008818PMC
June 2014

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Brain 2013 Oct 6;136(Pt 10):3140-50. Epub 2013 Sep 6.

1 NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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http://dx.doi.org/10.1093/brain/awt233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784283PMC
October 2013

Regional increase of cerebral cortex thickness in juvenile myoclonic epilepsy.

Epilepsia 2013 Sep 14;54(9):e138-41. Epub 2013 Aug 14.

Brain Morphometry Laboratory, Epilepsy Programme, Beaumont Hospital, Dublin, Ireland.

The goal of this study was to characterize cerebral cortex thickness patterns in juvenile myoclonic epilepsy (JME). Surface-based morphometry (SBM) was applied to process brain magnetic resonance images acquired from 24 patients with JME and 40 healthy controls and quantify cerebral cortex thickness. Differences in cortical thickness between patients and controls were determined using generalized linear model (covariates: age and gender). In patients with JME, thickness increase was detected bilaterally within localized regions in the orbitofrontal and mesial frontal cortices. Such thickness patterns coexisted with significant bilateral reduction in thalamic volume. These findings confirm that the underlying mechanisms in JME are related to aberrant corticothalamic structure and indicate that frontal cortex abnormalities are possibly linked to regional increase in cerebral cortical thickness.
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http://dx.doi.org/10.1111/epi.12330DOI Listing
September 2013

Heritability of subcortical volumetric traits in mesial temporal lobe epilepsy.

PLoS One 2013 23;8(4):e61880. Epub 2013 Apr 23.

Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.

Objectives: We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE.

Methods: MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated 'sporadic' MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity.

Results: MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population.

Conclusions: The findings indicate that volume deficits for many subcortical structures in 'sporadic' MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633933PMC
November 2013

MRI-based brain structure volumes in temporal lobe epilepsy patients and their unaffected siblings: a preliminary study.

J Neuroimaging 2013 Jan 28;23(1):64-70. Epub 2012 Aug 28.

Brain Morphometry Laboratory, Epilepsy Programme, Beaumont Hospital, Dublin, Ireland.

Introduction: Investigating the heritability of brain structure may be useful in simplifying complicated genetic studies in temporal lobe epilepsy (TLE). A preliminary study is presented to determine if volume deficits of candidate brain structures present at a higher rate in unaffected siblings than controls subjects.

Methods: T1-weighted MR images was acquired for 28 TLE patients, a same-sex unaffected sibling of 12 of these and 28 normal controls. Selected brain structure volumes were measured using an automated whole brain segmentation technique. Candidate brain structure endophenotypes were determined and group differences were investigated between (1) controls and patients and (2) controls and siblings. ICC's were used to measure the quantitative volumetric association within each sibling pair.

Results: TLE patients demonstrated a significantly lower cerebral white matter, bilateral hippocampus, thalamus, and left entorhinal cortex volumes when compared with controls. A significant deficit in cerebral white matter (CWM) was common to patient and nonaffected siblings when compared with controls. Furthermore, a significant correlation was revealed between patients and siblings in CWM and bilateral thalamus.

Conclusion: The findings suggest an overlap in the neurodevelopmental genes responsible for both brain structure and the expression of the disease. Further work is ongoing to confirm these findings.
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http://dx.doi.org/10.1111/j.1552-6569.2012.00736.xDOI Listing
January 2013

Asymmetric cortical surface area and morphology changes in mesial temporal lobe epilepsy with hippocampal sclerosis.

Epilepsia 2012 Jun 17;53(6):995-1003. Epub 2012 Apr 17.

Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.

Purpose: To date, magnetic resonance imaging (MRI)-based studies of the cerebral cortex in mesial temporal lobe epilepsy (MTLE) have focused primarily on investigating cortical volume and thickness. However, volume is a composite of surface area and thickness, each reflecting distinct neurobiologic and genetic processes. The goal of this study was to investigate cerebral cortex (1) surface area, (2) surface geometric distortion, and (3) thickness in MTLE with hippocampal sclerosis (HS).

Methods: Seventy patients with "sporadic" unilateral MTLE + HS and 40 healthy controls underwent T(1) -weighted MRI. Processing MR images using an automated cortical surface reconstruction method (FreeSurfer), we quantified cortical surface area, surface geometric distortion (metric distortion), and thickness at each vertex across the entire cortex. Differences between patients and controls were determined using generalized linear models. Separate linear regression models were employed to assess the relationship between cortical surface area and hippocampal volume as well as a series of important clinical features of the condition.

Key Findings: We detected an asymmetric reduction in cortical surface area, predominantly in ipsilateral mesial and anterior temporal lobe subregions, of patients with MTLE + HS. Changes in surface geometric features were also evident and closely mirrored surface area patterns. In contrast, cortical thinning appeared dispersed across the cortex bilaterally. The regression models revealed that ipsilateral hippocampal volume was a significant predictor of temporal lobe surface area changes.

Significance: Our findings indicate that contraction in surface area, rather than cortical thinning, explains ipsilateral mesial and anterior temporal lobe atrophy in patients with MTLE with HS. Furthermore, the alterations in surface geometry indicate folding abnormality involving the same regions. Cortical surface changes may represent sequelae of the disease or deviant cortical development.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03457.xDOI Listing
June 2012

Identification of common variants associated with human hippocampal and intracranial volumes.

Nat Genet 2012 Apr 15;44(5):552-61. Epub 2012 Apr 15.

Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).
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http://dx.doi.org/10.1038/ng.2250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635491PMC
April 2012

Widespread cortical morphologic changes in juvenile myoclonic epilepsy: evidence from structural MRI.

Epilepsia 2012 Apr 23;53(4):651-8. Epub 2012 Feb 23.

Brain Morphometry Laboratory, Neurophysics Department, Beaumont Hospital, Dublin, Ireland.

Purpose: Atypical morphology of the surface of the cerebral cortex may be related to abnormal cortical folding (gyrification) and therefore may indicate underlying malformations of cortical development (MCDs). Using magnetic resonance imaging (MRI)-based analysis, we examined cortical morphology in patients with juvenile myoclonic epilepsy (JME).

Methods: MRI data was collected for 24 patients with JME and 40 demographically matched healthy controls. FreeSurfer, an automated cortical surface reconstruction method, was applied to compare cortical morphology between patients and controls. Areas of anomalous cortical morphology were defined as regions of interest (ROIs) to contrast regional cortical parameters, such as surface area, average thickness, and mean curvature between patients and controls.

Key Findings: In patients with JME, changes to cortical morphology were detected in several regions. In the left hemisphere, these were in insular and cingulate cortices, occipital pole, and middle temporal and fusiform gyri. In the right hemisphere, changes were detected in insular cortex, inferior temporal gyrus, and precuneus. Further analysis of ROIs revealed that these changes are related to differences in surface area rather than average cortical thickness. In addition, mean curvature abnormalities were detected in the insula bilaterally, the left cingulate cortex, and right inferior temporal gyrus.

Significance: The morphologic findings in this study suggest that structural abnormalities in JME extend beyond mesial frontal lobe regions of the brain. These may be indicative of areas of subtle cortical folding abnormality related to early disruption of cortical development.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03413.xDOI Listing
April 2012

A cross-sectional MRI study of brain regional atrophy and clinical characteristics of temporal lobe epilepsy with hippocampal sclerosis.

Epilepsy Res 2012 Mar 23;99(1-2):156-66. Epub 2011 Dec 23.

Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin 2, Ireland.

Purpose: Applying a cross-sectional design, we set out to further characterize the significance of extrahippocampal brain atrophy in a large sample of 'sporadic' mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). By evaluating the influence of epilepsy chronicity on structural atrophy, this work represents an important step towards the characterization of MRI-based volumetric measurements as genetic endophenotypes for this condition.

Methods: Using an automated brain segmentation technique, MRI-based volume measurements of several brain regions were compared between 75 patients with 'sporadic' MTLE+HS and 50 healthy controls. Applying linear regression models, we examined the relationship between structural atrophy and important clinical features of MTLE+HS, including disease duration, lifetime number of partial and generalized seizures, and history of initial precipitating insults (IPIs).

Results: Significant volume loss was detected in ipsilateral hippocampus, amygdala, thalamus, and cerebral white matter (WM). In addition, contralateral hippocampal and bilateral cerebellar grey matter (GM) volume loss was observed in left MTLE+HS patients. Hippocampal, amygdalar, and cerebral WM volume loss correlated with duration of epilepsy. This correlation was stronger in patients with prior IPIs history. Further, cerebral WM, cerebellar GM, and contralateral hippocampal volume loss correlated with lifetime number of generalized seizures.

Conclusion: Our findings confirm that multiple brain regions beyond the hippocampus are involved in the pathogenesis of MTLE+HS. IPIs are an important factor influencing the rate of regional atrophy but our results also support a role for processes related to epilepsy chronicity. The consequence of epilepsy chronicity on candidate brain regions has important implications on their application as genetic endophenotypes.
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http://dx.doi.org/10.1016/j.eplepsyres.2011.11.005DOI Listing
March 2012

Pharmacogenomics and epilepsy: the road ahead.

Pharmacogenomics 2011 Oct;12(10):1429-47

Molecular & Cellular Therapeutics, the Royal College of Surgeons in Ireland, Dublin, Ireland.

Epilepsy is one of the most common, serious neurological disorders, affecting an estimated 50 million people worldwide. The condition is typically treated using antiepileptic drugs of which there are 16 in widespread use. However, there are many different syndrome and seizure types within epilepsy and information guiding clinicians on the most effective drug and dose for individual patients is lacking. Further, all of the antiepileptic drugs have associated adverse reactions, some of which are severe and life-threatening. Here, we review the pharmacogenomic work to date in the context of these issues and comment on key aspects of study design that are required to speed up the identification of clinically relevant genetic factors.
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http://dx.doi.org/10.2217/pgs.11.85DOI Listing
October 2011

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

N Engl J Med 2011 Mar;364(12):1134-43

Molecular and Cellular Therapeutics, the Royal College of Surgeons in Ireland, Dublin, Ireland.

Background: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.

Methods: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.

Results: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).

Conclusions: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1013297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113609PMC
March 2011

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Brain 2010 Jul 3;133(Pt 7):2136-47. Epub 2010 Jun 3.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
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http://dx.doi.org/10.1093/brain/awq130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892941PMC
July 2010
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