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1. Intranasal delivery of shRNA to knockdown the 5HT-2A receptor enhances memory and alleviates anxiety

Author: Troy T. Rohn, Dean Radin, Tracy Brandmeyer, Peter G. Seidler, Barry J. Linder, Tom Lytle, John L. Mee, and Fabio Macciardi
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Short-hairpin RNAs (shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. However, whether shRNA constructed molecules can modify neuronal circuits underlying certain behaviors has not been explored. We designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed that the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity. In vivo, intranasal delivery of AAV9 vectors containing shRNA resulted in a decrease in anxiety-like behavior in mice and a significant improvement in memory in both mice (104%) and rats (92%) compared to vehicle-treated animals. Our demonstration of a non-invasive shRNA delivery platform that can bypass the blood–brain barrier has broad implications for treating numerous neurological mental disorders. Specifically, targeting the HTR2A gene presents a novel therapeutic approach for treating chronic anxiety and age-related cognitive decline.
Published: 2024
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2. Evolutionarily recent retrotransposons contribute to schizophrenia

Author: Giorgia Modenini, Paolo Abondio, Guia Guffanti, Alessio Boattini, and Fabio Macciardi
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Transposable elements (TEs) are mobile genetic elements that constitute half of the human genome. Recent studies suggest that polymorphic non-reference TEs (nrTEs) may contribute to cognitive diseases, such as schizophrenia, through a cis-regulatory effect. The aim of this work is to identify sets of nrTEs putatively linked to an increased risk of developing schizophrenia. To do so, we inspected the nrTE content of genomes from the dorsolateral prefrontal cortex of schizophrenic and control individuals and identified 38 nrTEs that possibly contribute to the emergence of this psychiatric disorder, two of them further confirmed with haplotype-based methods. We then performed in silico functional inferences and found that 9 of the 38 nrTEs act as expression/alternative splicing quantitative trait loci (eQTLs/sQTLs) in the brain, suggesting a possible role in shaping the human cognitive genome structure. To our knowledge, this is the first attempt at identifying polymorphic nrTEs that can contribute to the functionality of the brain. Finally, we suggest that a neurodevelopmental genetic mechanism, which involves evolutionarily young nrTEs, can be key to understanding the ethio-pathogenesis of this complex disorder.
Published: 2023
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3. Bioarchaeological and palaeogenomic portrait of two Pompeians that died during the eruption of Vesuvius in 79 AD

Author: Gabriele Scorrano, Serena Viva, Thomaz Pinotti, Pier Francesco Fabbri, Olga Rickards, and Fabio Macciardi
Subjects: Medicine, Science
Abstract: Abstract The archaeological site of Pompeii is one of the 54 UNESCO World Heritage sites in Italy, thanks to its uniqueness: the town was completely destroyed and buried by a Vesuvius’ eruption in 79 AD. In this work, we present a multidisciplinary approach with bioarchaeological and palaeogenomic analyses of two Pompeian human remains from the Casa del Fabbro. We have been able to characterize the genetic profile of the first Pompeian’ genome, which has strong affinities with the surrounding central Italian population from the Roman Imperial Age. Our findings suggest that, despite the extensive connection between Rome and other Mediterranean populations, a noticeable degree of genetic homogeneity exists in the Italian peninsula at that time. Moreover, palaeopathological analyses identified the presence of spinal tuberculosis and we further investigated the presence of ancient DNA from Mycobacterium tuberculosis. In conclusion, our study demonstrates the power of a combined approach to investigate ancient humans and confirms the possibility to retrieve ancient DNA from Pompeii human remains. Our initial findings provide a foundation to promote an intensive and extensive paleogenetic analysis in order to reconstruct the genetic history of population from Pompeii, a unique archaeological site.
Published: 2022
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4. Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome

Author: Mark Mapstone, Thomas J Gross, Fabio Macciardi, Amrita K Cheema, Melissa Petersen, Elizabeth Head, Benjamin L Handen, William E Klunk, Bradley T Christian, Wayne Silverman, Ira T Lott, Nicole Schupf, and for the Alzheimer's Biomarkers Consortium–Down Syndrome (ABC‐DS) Investigators
Subjects: Alzheimer's disease, carbohydrate metabolism, Down syndrome, energy metabolism, fatty acid metabolism, lipid metabolism, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction Disruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD). Methods We examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium–Down Syndrome (ABC‐DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS‐AD), 43 who met criteria for mild cognitive impairment (DS‐MCI), and 211 who were cognitively unaffected and stable (CS). Results We measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate‐corrected q< 0.05. From the DE features, a nine‐feature classifier model classified the CS and DS‐AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two‐feature model classified the DS‐MCI and DS‐AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism. Discussion Our results reveal metabolic alterations in DS‐AD that are similar to those seen in LOAD. The pattern of results in this cross‐sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non‐demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS‐AD.
Published: 2020
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5. Mitochondrial variability in the Mediterranean area: a complex stage for human migrations

Author: Flavio De Angelis, Gabriele Scorrano, Cristina Martínez-Labarga, Giuseppina Scano, Fabio Macciardi, and Olga Rickards
Subjects: mediterranean basin, complete mitochondrial genomes, mediterranean mitochondrial lineages, mtdna human populations, Biology (General), QH301-705.5, Human anatomy, QM1-695, Physiology, QP1-981
Abstract: Context: The Mediterranean area has always played a significant role in human dispersal due to the large number of migratory events contributing to shape the cultural features and the genetic pool of its populations. Objective: This paper aims to review and diachronically describe the mitogenome variability in the Mediterranean population and the main demic diffusions that occurred in this area over time. Methods: Frequency distributions of the leading mitochondrial haplogroups have been geographically and chronologically evaluated. The variability of U5b and K lineages has been focussed to broaden the knowledge of their genetic histories. Results: The mitochondrial genetic makeup of Palaeolithic hunter-gatherers is poorly defined within the extant Mediterranean populations, since only a few traces of their genetic contribution are still detectable. The Neolithic lineages are more represented, suggesting that the Neolithic revolution had a marked effect on the peopling of the Mediterranean area. The largest effect, however, was provided by historical migrations. Conclusion: Although the mitogenome variability has been widely used to try and clarify the evolution of the Mediterranean genetic makeup throughout almost 50 000 years, it is necessary to collect whole genome data on both extinct and extant populations from this area to fully reconstruct and interpret the impact of multiple migratory waves and their cultural and genetic consequences on the structure of the Mediterranean populations.
Published: 2018
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6. Plasma metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls.

Author: Massimo S Fiandaca, Mark Mapstone, Amin Mahmoodi, Thomas Gross, Fabio Macciardi, Amrita K Cheema, Kian Merchant-Borna, Jeffrey Bazarian, and Howard J Federoff
Subjects: Medicine, Science
Abstract: Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and control subjects. A 6-metabolite panel was developed from biomarkers that had their identities confirmed using tandem mass spectrometry (MS/MS) in our Athlete cohort. These biomarkers were defined at ≤6 hours following mTBI and objectively classified mTBI athletes from teammate controls, and provided similar classification of these groups at the 2, 3, and 7 days post-mTBI. The same 6-metabolite panel, when applied to a separate, independent cohort provided statistically similar results despite major differences between the two cohorts. Our confirmed plasma biomarker panel objectively classifies acute mTBI cases from controls within 6 hours of injury in our two independent cohorts. While encouraged by our initial results, we expect future studies to expand on these initial observations.
Published: 2018
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7. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

Author: Lea K Davis, Dongmei Yu, Clare L Keenan, Eric R Gamazon, Anuar I Konkashbaev, Eske M Derks, Benjamin M Neale, Jian Yang, S Hong Lee, Patrick Evans, Cathy L Barr, Laura Bellodi, Fortu Benarroch, Gabriel Bedoya Berrio, Oscar J Bienvenu, Michael H Bloch, Rianne M Blom, Ruth D Bruun, Cathy L Budman, Beatriz Camarena, Desmond Campbell, Carolina Cappi, Julio C Cardona Silgado, Danielle C Cath, Maria C Cavallini, Denise A Chavira, Sylvain Chouinard, David V Conti, Edwin H Cook, Vladimir Coric, Bernadette A Cullen, Dieter Deforce, Richard Delorme, Yves Dion, Christopher K Edlund, Karin Egberts, Peter Falkai, Thomas V Fernandez, Patience J Gallagher, Helena Garrido, Daniel Geller, Simon L Girard, Hans J Grabe, Marco A Grados, Benjamin D Greenberg, Varda Gross-Tsur, Stephen Haddad, Gary A Heiman, Sian M J Hemmings, Ana G Hounie, Cornelia Illmann, Joseph Jankovic, Michael A Jenike, James L Kennedy, Robert A King, Barbara Kremeyer, Roger Kurlan, Nuria Lanzagorta, Marion Leboyer, James F Leckman, Leonhard Lennertz, Chunyu Liu, Christine Lochner, Thomas L Lowe, Fabio Macciardi, James T McCracken, Lauren M McGrath, Sandra C Mesa Restrepo, Rainald Moessner, Jubel Morgan, Heike Muller, Dennis L Murphy, Allan L Naarden, William Cornejo Ochoa, Roel A Ophoff, Lisa Osiecki, Andrew J Pakstis, Michele T Pato, Carlos N Pato, John Piacentini, Christopher Pittenger, Yehuda Pollak, Scott L Rauch, Tobias J Renner, Victor I Reus, Margaret A Richter, Mark A Riddle, Mary M Robertson, Roxana Romero, Maria C Rosàrio, David Rosenberg, Guy A Rouleau, Stephan Ruhrmann, Andres Ruiz-Linares, Aline S Sampaio, Jack Samuels, Paul Sandor, Brooke Sheppard, Harvey S Singer, Jan H Smit, Dan J Stein, E Strengman, Jay A Tischfield, Ana V Valencia Duarte, Homero Vallada, Filip Van Nieuwerburgh, Jeremy Veenstra-Vanderweele, Susanne Walitza, Ying Wang, Jens R Wendland, Herman G M Westenberg, Yin Yao Shugart, Euripedes C Miguel, William McMahon, Michael Wagner, Humberto Nicolini, Danielle Posthuma, Gregory L Hanna, Peter Heutink, Damiaan Denys, Paul D Arnold, Ben A Oostra, Gerald Nestadt, Nelson B Freimer, David L Pauls, Naomi R Wray, S Evelyn Stewart, Carol A Mathews, James A Knowles, Nancy J Cox, and Jeremiah M Scharf
Subjects: Genetics, QH426-470
Abstract: The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Published: 2013
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8. HERVs expression in Autism Spectrum Disorders.

Author: Emanuela Balestrieri, Carla Arpino, Claudia Matteucci, Roberta Sorrentino, Francesca Pica, Riccardo Alessandrelli, Antonella Coniglio, Paolo Curatolo, Giovanni Rezza, Fabio Macciardi, Enrico Garaci, Simona Gaudi, and Paola Sinibaldi-Vallebona
Subjects: Medicine, Science
Abstract: BackgroundAutistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.MethodsThe presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.ResultsThe percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.ConclusionsSpecific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.
Published: 2012
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9. Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample.

Author: Anna Alkelai, Lior Greenbaum, Sara Lupoli, Yoav Kohn, Kyra Sarner-Kanyas, Edna Ben-Asher, Doron Lancet, Fabio Macciardi, and Bernard Lerer
Subjects: Medicine, Science
Abstract: Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10⁻⁶) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10⁻⁶) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.
Published: 2012
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10. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease.

Author: Steven G Potkin, Guia Guffanti, Anita Lakatos, Jessica A Turner, Frithjof Kruggel, James H Fallon, Andrew J Saykin, Alessandro Orro, Sara Lupoli, Erika Salvi, Michael Weiner, Fabio Macciardi, and Alzheimer's Disease Neuroimaging Initiative
Subjects: Medicine, Science
Abstract: BACKGROUND:With the exception of APOE epsilon4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown. METHODS AND FINDINGS:We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of < or =10(-6) (10(-11) for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value < or =10(-6), which can be considered potential "new" candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication. CONCLUSIONS:Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation.
Published: 2009
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11. Genome-Transcriptome-Functional Connectivity-Cognition Link Differentiates Schizophrenia From Bipolar Disorder

Author: Jiayu Chen, Zening Fu, Juan R Bustillo, Nora I Perrone-Bizzozero, Dongdong Lin, Jose Canive, Godfrey D Pearlson, Julia M Stephen, Andrew R Mayer, Steven G Potkin, Theo G M van Erp, Peter Kochunov, L Elliot Hong, Bhim M Adhikari, Ole A Andreassen, Ingrid Agartz, Lars T Westlye, Jing Sui, Yuhui Du, Fabio Macciardi, Faith M Hanlon, Rex E Jung, Jessica A Turner, Jingyu Liu, and Vince D Calhoun
Subjects: Psychiatry and Mental health, Bipolar Disorder, Cognition, Schizophrenia, Humans, Transcriptome, Cognition Disorders
Abstract: Background and Hypothesis Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway. Study Designs Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances. Study Results PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes’ expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains. Conclusions Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.
Published: 2022

12. At the origin of Neanderthals and modern humans - Cerebral complexity and encephalization

Author: Paola Zaio, Mauro Rubini, Claudio Tuniz, Federico Bernardini, Fabio Di Vincenzo, giulia festa, alessandro gozzi, nunzia libianchi, gabriele scorrano, fabio macciardi, james fallon, and Giorgio Manzi
Abstract: The increase of brain dimensions and complexity has characterized the evolution of the genus Homo. According to the available fossil and genetic evidence, a crucial stage came before the divergence of Neanderthals, Denisovans and Homo sapiens, during the Middle Pleistocene. We consider a specimen of about 400 ka, whose phenotype is at the roots of this divergence: Ceprano calvarium (Italy). Here, we show a derived cerebrovascular organization with a mosaic of modern human and primitive features characteristics. Computed microtomography shows vascular variation and ontogenetic defects associated with ventricular and lymphatic involvement while phylogenetic analyzes highlight a dysregulation of the Tet1 gene that shows an accelerated mutation rate between 1.2 Ma and 466 ka, in contrast with the expected neutral evolution of the human genome. These results shed light on the dynamics of cranio-cerebral growth during the encephalization process and on the cerebral vascular and lymphatic system involved in this process. The results of this study could have implications for the research of many of the diseases of the central nervous system that have become predominant in an increasingly structured and long-lived brain system such as that of modern Homo sapiens. One-Sentence Summary: Genetic mutation, anatomical variations and glymphatic system in the process of encephalization towards Homo sapiens.
Published: 2023

13. A System Architecture for Sharing De-Identified, Research-Ready Brain Scans and Health Information Across Clinical Imaging Centers.

Author: Ann L. Chervenak, Theo G. M. van Erp, Carl Kesselman, Mike D'Arcy, Janet Sobell, David B. Keator, Lisa Dahm, Jim Murry, Meng Law, Anton N. Hasso, Joseph Ames, Fabio Macciardi, and Steven G. Potkin
Published: 2012
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14. Infrastructure for sharing standardized clinical brain scans across hospitals.

Author: Theo G. M. van Erp, Ann L. Chervenak, Carl Kesselman, Mike D'Arcy, Janet Sobell, David B. Keator, Lisa Dahm, Jim Murry, Meng Law, Anton N. Hasso, Joseph Ames, Fabio Macciardi, and Steven G. Potkin
Published: 2011
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15. Contributors

Author: Vera Aldeias, Ethel Allué, Markus Bastir, Stefano Benazzi, Ruth Blasco, Hervé Bocherens, Laurence Bourguignon, Aitor Burguet-Coca, Dan Cabanes, Edgard Camarós, Ángel Carrancho, Victor Chabai, M. Gema Chacón, David Cochard, Andre C. Colonese, Rory Connolly, Jean-Philippe Faivre, Joseba Rios Garaizar, Marcos García-Diez, Antonio García-Tabernero, Boris Gasparyan, Phil Glauberman, Brad Gravina, Karen Hardy, David Hérisson, Erella Hovers, Klervia Jaouen, Jacques Jaubert, Kseniya Kolobova, Véronique Laroulandie, Lucia Leierer, Fabio Macciardi, Ariel Malinsky-Buller, Carolina Mallol, Fabio Martini, Bruno Maureille, Jacqueline Meier, Susan Mentzer, Christopher Miller, Kevin Di Modica, Marie-Hélène Moncel, Eugène Morin, Adriana Moroni, Petr Neruda, Marco Peresani, Andrea Picin, William Rendu, Florent Rivals, Francesca Romagnoli, Antonio Rosas, Jordi Rosell, Anna Rufà, María Fernanda Sánchez Goñi, Dennis Sandgathe, Viviane Slon, Mareike Stahlschmidt, Rebecca Wragg Sykes, Sahra Talamo, Laura Tassoni, Isabelle Théry-Parisot, Jessica C. Thompson, Thorsten Uthmeier, Manuel Vaquero, Bence Viola, Marcel Weiss, Frido Welker, and Andrzej Wiśniewski
Published: 2022

16. The Neanderthal brain: Biological and cognitive evolution

Author: Fabio Macciardi and Fabio Martini
Published: 2022

17. A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer's disease

Author: Fabio Macciardi, Maria Giulia Bacalini, Ricardo Miramontes, Alessio Boattini, Cristian Taccioli, Giorgia Modenini, Rond Malhas, Laura Anderlucci, Yuriy Gusev, Thomas J. Gross, Robert M. Padilla, Massimo S. Fiandaca, Elizabeth Head, Guia Guffanti, Howard J. Federoff, Mark Mapstone, Macciardi, Fabio, Giulia Bacalini, Maria, Miramontes, Ricardo, Boattini, Alessio, Taccioli, Cristian, Modenini, Giorgia, Malhas, Rond, Anderlucci, Laura, Gusev, Yuriy, Gross, Thomas J, Padilla, Robert M, Fiandaca, Massimo S, Head, Elizabeth, Guffanti, Guia, Federoff, Howard J, and Mapstone, Mark
Subjects: Aging, Retroelements, Blood biomarker, Neurodegenerative, Alzheimer's Disease, Blood biomarkers, Transposable element, Alzheimer Disease, Machine learning, Acquired Cognitive Impairment, Genetics, Humans, 2.1 Biological and endogenous factors, Retrotransposon, Aetiology, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer disease, Gene expression, Retrotransposons, Transposable elements, Biomarker, Brain Disorders, Neurological, RNA, Dementia, Geriatrics and Gerontology, Biomarkers, Human
Abstract: Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion (phenoconversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value phenoconversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after phenoconversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before phenoconversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.
Published: 2022

18. Genome-wide association study identifies new locus associated with OCD

Author: Danielle Posthuma, Bernie Devlin, Edna Grünblatt, Ying Wang, Daniele Cusi, Stephan Ruhrmann, Steven A. Rasmussen, Michael S. Breen, Julia Klawohn, Ana Gabriela Hounie, Aline S. Sampaio, Cristina Barlassina, Marta Ribasés, Jackson G. Thorp, Cynthia M. Bulik, Marco A. Grados, Dan J. Stein, Abby Fyer, Vladimir Coric, Martha J. Falkenstein, Stephanie Le Hellard, Behrang Mahjani, Nathaniel McGregor, Homero Vallada, Miguel Casas, Laurent F. Thomas, Janice Krasnow, Abraham Reichenberg, Donald W. Black, Gwyneth Zai, Norbert Kathmann, Manuel Mattheisen, Nicholas G. Martin, Jason W. Krompinger, Josep Antoni Ramos-Quiroga, Judith Becker Nissen, Helga Ask, Damiaan Denys, Carolina Cappi, Euripedes Constantino Miguel, O. Joseph Bienvenu, Bengt T. Fundin, Lisa Osiecki, Karin J. H. Verweij, Paul Sandor, Jeremy Veenstra-VanderWeele, Maureen Mulhern, Sarah E. Medland, David M. Hougaard, Lauren Erdman, Jan Haavik, James L. Kennedy, Christopher P. Walker, Jurjen J. Luykx, Tim B. Bigdeli, Ian M. Hickie, Nienke Vulink, Maurizio Turiel, Peter Falkai, Enda M. Byrne, Valentina Ciullo, Daniel A. Geller, Liang Kung-Yee, Miriam A. Schiele, Lambertus Klei, Götz Berberich, Thomas Werge, Brion S. Maher, Christie L. Burton, Julia M. Sealock, Sandra Meier, Bernadette Cullen, Stephan Ripke, Dorothy E. Grice, Richard Delorme, Ted Reichborn-Kjennerud, Dongmei Yu, Danielle C. Cath, Lili Milani, Abdel Abdellaoui, Andres Metspalu, María Soler Artigas, Maria Conceição do Rosário, Ole Mors, Brian P. Brennan, Barbara E. Stranger, Ann E. Pulver, Nora I. Strom, Joseph D. Buxbaum, Hans J. Grabe, Jens R. Wendland, Michael H. Bloch, Srdjan Djurovic, Raquel Rabionet, Angel Carracedo, Carlos N. Pato, Erika L. Nurmi, Janet L. Sobell, Kevin S. O’Connell, Michael Wagner, David R. Rosenberg, Jonathan R. I. Coleman, Jeremiah M. Scharf, Kerry J. Ressler, Jaakko Kaprio, Edwin H. Cook, Scott L. Rauch, Federica Piras, Merete Nordentoft, Christian Rück, Fabrizio Piras, John-Anker Zwart, Jason A. Elias, Christopher Pittenger, Lea K. Davis, Margaret A. Richter, Evonne McArthur, Bendik S. Winsvold, Yin Yao, James J. Crowley, David L. Pauls, Rosa Bosch, Xavier Estivil, Matthew Halvorsen, Adrian Camarena, Nancy L. Pedersen, Pino Alonso, Eric A. Storch, Bjarne Hansen, Helena Brentani, James T. McCracken, Jan Maerten Smit, Donald Hucks, Alexandra Havdahl, Gerome Breen, Christina M. Hultman, Benjamin M. Neale, Gregory L. Hanna, Mikael Landén, Christine Lochner, Dirk J.A. Smit, Fabio Macciardi, Carol A. Mathews, Nuria Lanzagorta, Laura G. Sloofman, Cristina Rodriguez-Fontenla, Michael A. Jenike, Michele T. Pato, Marion Leboyer, Humberto Nicolini, Anders D. Børglum, Maria Cristina Cavallini, Wei Guo, Benjamin D. Greenberg, Maiken Elvestad Gabrielsen, Magdalena Janecka, Mark A. Riddle, Paul S. Nestadt, Beatriz Camarena, Valsamma Eapen, Susanne Walitza, Jack Samuels, Fernando S. Goes, Nicole C.R. McLaughlin, S. Evelyn Stewart, Jennifer Reichert, Sven Sandin, Gerd Kvale, Katharina Domschke, Ole A. Andreassen, Elles de Schipper, Paul D. Arnold, Kristi Krebs, Zachary Gerring, Teemu Palviainen, Kathleen D. Askland, Alfredo Ramirez, James A. Knowles, Laura Bellodi, Kristen Hagen, Julia Boberg, Thomas V. Fernandez, Gerald Nestadt, John Piacentini, Jakob Grove, Eske M. Derks, Preben Bo Mortensen, Elinor K. Karlsson, Gianfranco Spalletta, David Mataix-Cols, Katharina Bey, and Jonas Bybjerg-Grauholm
Subjects: Genetics, business.industry, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Heritability, behavioral disciplines and activities, humanities, Genetic architecture, Anorexia nervosa (differential diagnoses), mental disorders, medicine, Anxiety, SNP, medicine.symptom, business
Abstract: Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.
Published: 2021

19. Genetic polymorphism data support a relationship between schizophrenia and microsatellite variability in PLA2G4A in Northern Europeans not Han Chinese

Author: Craig J. Hudson, Adam M. R. Groh, Fabio Macciardi, and Rhys C. Hudson
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, China, Polymorphism, Genetic, Asian People, Group IV Phospholipases A2, Schizophrenia, Humans, Genetics (clinical), White People, Microsatellite Repeats
Published: 2021

20. Plasma Sphingomyelins in Late-Onset Alzheimer's Disease

Author: Massimo S. Fiandaca, Jie Wu, Howard J. Federoff, Mark Mapstone, Gianna M. Fote, and Fabio Macciardi
Subjects: Oncology, Male, medicine.medical_specialty, Metabolite, Late onset, Disease, Mass Spectrometry, Article, Cohort Studies, chemistry.chemical_compound, Alzheimer Disease, Internal medicine, Lipidomics, medicine, Humans, Metabolomics, Aged, 80 and over, Sphingolipids, business.industry, General Neuroscience, General Medicine, Plasma levels, Sphingolipid, Psychiatry and Mental health, Clinical Psychology, chemistry, Cohort, Asymptomatic Diseases, Female, Geriatrics and Gerontology, business, Sphingomyelin
Abstract: Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer’s disease (AD) and in AD patient plasma samples. Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n = 138). Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. Results: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls. Conclusion: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.
Published: 2021

21. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Author: António Macedo, Patrick F. Sullivan, Pamela Sklar, Diana O. Perkins, David L. Braff, Eric D. Achtyes, Roman Kotov, Eli A. Stahl, Maria Helena Pinto de Azevedo, Colm O'Dushlaine, Elizabeth Bevilacqua, Célia Barreto Carvalho, Marquis P. Vawter, James Nemesh, Edward M. Scolnick, Jacquelyn L. Meyers, Jorge Valderrama, Shaun Purcell, Becky Kinkead, Douglas S. Lehrer, Peter F. Buckley, William Byerley, Humberto Nicolini, Fabio Macciardi, James L. Kennedy, Michael Escamilla, Ruben C. Gur, Dolores Malaspina, Ashley Dumont, Giulio Genovese, Helena Medeiros, Penelope Georgakopoulos, Colony Abbott, Diane Gage, Carlos N. Pato, Brooke M. Sklar, Roseann E. Peterson, Jordan W. Smoller, Steven A. McCarroll, Raquel E. Gur, Ayman H. Fanous, Laura J. Fochtmann, Stephen R. Marder, Sinéad B. Chapman, Mark Hyman Rapaport, James A. Knowles, Michele T. Pato, Janet L. Sobell, Evelyn J. Bromet, Conrad Iyegbe, Lynn E DeLisi, Jeffrey J. Rakofsky, Oleg V. Evgrafov, Jennifer L. Moran, Christopher P. Morley, Tim B. Bigdeli, Richard A. Belliveau, and Mantosh J. Dewan
Subjects: Male, 0301 basic medicine, Linkage disequilibrium, Population, Black People, Genomics, Biology, Polymorphism, Single Nucleotide, Article, European descent, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetics, Humans, Genetic Predisposition to Disease, education, Molecular Biology, Genetic association, education.field_of_study, Genetic variants, Hispanic or Latino, Heritability, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Schizophrenia, Etiology, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography
Abstract: Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P −52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P −58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P −113), further highlighting the advantages of incorporating data from diverse human populations.
Published: 2019

22. Sparse deep neural networks on imaging genetics for schizophrenia case-control classification

Author: Jiayu Chen, Lars T. Westlye, Ole A. Andreassen, Vince D. Calhoun, Shihao Ji, Fabio Macciardi, Jingyu Liu, Ingrid Agartz, Daniel S. O'Leary, Jessica A. Turner, Xiang Li, Theo G.M. van Erp, Judith M. Ford, Lei Wang, Erik G. Jönsson, and Daniel H. Mathalon
Subjects: Adult, Support Vector Machine, Imaging genetics, Computer science, sparse, Word error rate, Feature selection, Neuroimaging, Polymorphism, Single Nucleotide, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Deep Learning, single nucleotide polymorphism, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Generalizability theory, Gray Matter, gray matter volume, Research Articles, Cerebral Cortex, Radiological and Ultrasound Technology, Artificial neural network, business.industry, Deep learning, 05 social sciences, deep neural network, Pattern recognition, Magnetic Resonance Imaging, Support vector machine, schizophrenia, Neurology, Norm (mathematics), Case-Control Studies, Neurology (clinical), Artificial intelligence, Anatomy, business, 030217 neurology & neurosurgery, Research Article
Abstract: Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case–control classification. An L 0‐norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi‐study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools., A sparse deep neural network (DNN) approach is proposed to identify sparse and interpretable biological features with potential for clinical application. Empirical experiments suggest that sparse DNN slightly outperformed ICA + SVM and more effectively fused neuroimaging and genetic features for schizophrenia case‐control classification. The sparse DNN model yielded reasonable interpretation for identified discriminating brain regions, which strongly echoed previous literature.
Published: 2021

23. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author: Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract: EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]
Published: 2021

24. ENIGMA and global neuroscience:A decade of large-scale studies of the brain in health and disease across more than 40 countries

Author: Frank G. Hillary, Esther Walton, Gunter Schumann, Sophia I. Thomopoulos, Patricia J. Conrod, Nic J.A. van der Wee, Daqiang Sun, Charlotte A.M. Cecil, Robin Bülow, Henry Völzke, Rachel M. Brouwer, Yann Chye, Katrina L. Grasby, Ingrid Agartz, Bernhard T. Baune, Josselin Houenou, Simon E. Fisher, Mark S. Shiroishi, Daan van Rooij, Miguel E. Rentería, Yanli Zhang-James, Courtney A. Filippi, Stephen V. Faraone, Sara Bertolín, Elisabeth A. Wilde, Eus J.W. Van Someren, Christopher R.K. Ching, Iliyan Ivanov, Barbara Franke, Derrek P. Hibar, Tiffany C. Ho, Hilleke E. Hulshoff Pol, Norbert Hosten, Ilya M. Veer, Daniel Garijo, Jean-Paul Fouche, Inga K. Koerte, Hans J. Grabe, Carles Soriano-Mas, Lianne Schmaal, Brenda Bartnik-Olson, Amanda K. Tilot, Sinead Kelly, Ysbrand D. van der Werf, Anderson M. Winkler, Henrik Walter, Hugh Garavan, Max A. Laansma, Agnes B. McMahon, Laura K.M. Han, Natalia Shatokhina, Scott Mackey, David F. Tate, Jason L. Stein, Thomas Frodl, Tiril P. Gurholt, Carrie E. Bearden, Katharina Wittfeld, Carrie R. McDonald, Andrew R. Mayer, Yolanda Gil, Jun Soo Kwon, Tomas Hajek, Jan K. Buitelaar, Moji Aghajani, Bhim M. Adhikari, Premika S.W. Boedhoe, Graeme Fairchild, Maria Jalbrzikowski, Alexander Olsen, Carolien G.F. de Kovel, Talia M. Nir, Mojtaba Zarei, Karen Caeyenberghs, Dirk J.A. Smit, Fabio Macciardi, Jeanne Leerssen, Margaret J. Wright, Eduard T. Klapwijk, Elena Pozzi, Lisa T. Eyler, Abraham Nunes, Sanjay M. Sisodiya, Clyde Francks, Emily L. Dennis, Rajendra A. Morey, Pauline Favre, Sophia Frangou, Boris A. Gutman, Merel Postema, Ida E Sønderby, Ian H. Harding, Julio E. Villalon-Reina, Sook-Lei Liew, Peter Kochunov, Celia van der Merwe, Je-Yeon Yun, David C. Glahn, Stefan Ehrlich, George A Karkashadze, Jian Chen, Nils Opel, Tianye Jia, Peristera Paschou, Xiangzhen Kong, Marieke Klein, Leyla Namazova-Baranova, Sylvane Desrivières, Danai Dima, Masoud Tahmasian, Dennis Hernaus, Sven C. Mueller, Gemma Modinos, Guido van Wingen, Ulrike Lueken, Ole A. Andreassen, Jonathan D. Rohrer, Lauren E. Salminen, Laura A. Berner, Eileen Luders, Georg Homuth, Stephane A. De Brito, Martine Hoogman, Federica Piras, Carrie Esopenko, Laura S van Velzen, Janna Marie Bas-Hoogendam, Udo Dannlowski, Mark W. Logue, Willem B Bruin, André Aleman, Sarah E. Medland, Neeltje E.M. van Haren, Theo G.M. van Erp, Sean N. Hatton, Laurena Holleran, Gary Donohoe, Alexander P. Lin, Rebecca C. Knickmeyer, Leonardo Tozzi, Fabrizio Pizzagalli, Kevin Hilbert, Sonja M C de Zwarte, Dick J. Veltman, Gianfranco Spalletta, Daniel S. Pine, Tim Hahn, Pratik Mukherjee, Alexander Teumer, Joanna Bright, Andre Altmann, Neda Jahanshad, James H. Cole, Arielle R. Baskin-Sommers, Odile A. van den Heuvel, Dan J. Stein, Vladimir Zelman, Lei Wang, Ronald A. Cohen, Joseph O' Neill, David Baron, Fabrizio Piras, Robert R. Althoff, Nynke A. Groenewold, Philipp G. Sämann, Christopher D. Whelan, Jessica A. Turner, Janita Bralten, Guohao Zhang, Paul M. Thompson, and Netherlands Institute for Neuroscience (NIN)
Subjects: DISORDER, Scientific community, Review Article, bepress|Life Sciences|Neuroscience and Neurobiology, 0302 clinical medicine, SCHIZOPHRENIA, Medicine and Health Sciences, GENETIC INFLUENCES, ENDOPHENOTYPE CONCEPT, Cervell, VOLUMES, RISK, Psychiatry, 0303 health sciences, 05 social sciences, Brain, Genomics, Magnetic Resonance Imaging, WORKING, 3. Good health, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Eating disorders, Dissociative identity disorder, Biometris, Neurology, Conduct disorder, Schizophrenia, Major depressive disorder, Anxiety, medicine.symptom, Psychology, Neuroinformatics, Neuroimaging, 050105 experimental psychology, 150 000 MR Techniques in Brain Function, lcsh:RC321-571, Neurologia, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, MEGA-ANALYSIS, medicine, Life Science, Humans, 0501 psychology and cognitive sciences, ddc:610, Psiquiatria, Bipolar disorder, diagnostic imaging [Brain], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, bepress|Life Sciences|Neuroscience and Neurobiology|Other Neuroscience and Neurobiology, Biological Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genetics [Depressive Disorder, Major], Reproducibility of Results, OBSESSIVE-COMPULSIVE DISORDER, medicine.disease, PsyArXiv|Neuroscience, PsyArXiv|Neuroscience|Other Neuroscience and Neurobiology, RC0321, HERITABILITY ANALYSIS, Autism, Psychiatric disorders, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract: This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. 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.
Published: 2020

25. Genetic variants for head size share genes and pathways with cancer

Author: Shihua Li, Melissa J. Green, Nagata M, Miyamoto S, Le Grand Q, Pourcain Bs, Grabe Hj, Catherine Helmer, William R. Reay, Nele Friedrich, Mazoyer B, Seshadri S, Per Hoffmann, Simon Haworth, Veronica Witte A, Yang Q, Max Lam, Teunissen Mw, Fang-Chi Hsu, Debette S, Murray J. Cairns, Amod Ar, Setoh K, Windham Bg, Shareefa Dalvie, Georg Homuth, Charlie S. DeCarli, Gennady V. Roshchupkin, Céline S. Reinbold, Mühleisen Tw, Nakahara S, Van der Auwera S, Xueqiu Jian, Cecil Ca, Jean-François Dartigues, Alexa S. Beiser, Stein Jl, Houlden H, Christiane Jockwitz, Moebus S, Claudia L. Satizabal, Tavia E. Evans, Matsuda F, Cora E. Lewis, Wittfeld K, Calhoun Vd, van der Lugt A, Teumer A, Pausova Z, W. T. Longstreth, Aniket Mishra, Tomáš Paus, Vernooij Mw, Medland Se, Palmer Nd, Ahmad R. Hariri, Adrian Preda, Clifford R. Jack, van Erp Tg, Amaia Carrion-Castillo, Werring Dj, Gwénaëlle Catheline, Asta Håberg, Robin Bülow, Sven Cichon, Yann Quidé, Muetzel R, Tabara Y, Sidney S, Cheung C, Brunner Hg, Annchen R. Knodt, Mosley Th, van Dam-Nolen Dh, Hostettler Ic, Jean Shin, Shapland Cy, Reut Avinun, Crivello F, Mäkitie O, Fornage M, Yoshida K, Villringer A, Lim K, Schreiner Pj, Bowden Dw, Thompson Pm, Daniel Bos, Uhlmann A, Enlund-Cerullo M, Schmidt R, Hieab H.H. Adams, Neda Jahanshad, Frauke Beyer, Gloria H.Y. Li, Fabio Macciardi, Lamballais S, Kämpe A, Judith M. Ford, Poot Ra, J. C. Bis, Yoichiro Kamatani, Ami Tsuchida, Markus Scholz, Ikram Ma, Andersson S, Lenore J. Launer, Stein Dj, Koudstaal Pj, Barry I. Freedman, Barbara Franke, Ikram Mk, Sim K, Marie-Gabrielle Duperron, Bryan Rn, Svenja Caspers, Pawlak Ma, Tonya White, Maria J. Knol, Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium
Subjects: Genetics, 0303 health sciences, education.field_of_study, biology, Population, Wnt signaling pathway, Macrocephaly, Cancer, medicine.disease, Biological pathway, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, PTEN, Human height, medicine.symptom, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.
Published: 2020

26. The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

Author: Dan Liang, Barbara E. Stranger, Simon E. Fisher, Jodie N. Painter, Amanda K. Tilot, Siyao Liu, Lucía Colodro-Conde, Paul M. Thompson, Sarah E. Medland, Ekaterina A. Khramtsova, Lea K. Davis, Jason L. Stein, Penelope A. Lind, Fabio Macciardi, Janita Bralten, Katrina L. Grasby, Derrek P. Hibar, Sarah M Brotman, and Neda Jahanshad
Subjects: Neuroinformatics, Multifactorial Inheritance, Lineage (genetic), Cognitive Neuroscience, Quantitative Trait Loci, Genome-wide association study, cortical surface area, Biology, Genome, Visual processing, Cellular and Molecular Neuroscience, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Cortex (anatomy), medicine, Psychology, Humans, Genetic Testing, AcademicSubjects/MED00385, Gene, 030304 developmental biology, Cerebral Cortex, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genome-wide association study, AcademicSubjects/SCI01870, Neurosciences, Genetic Variation, Experimental Psychology, Cognition, Human brain, Organ Size, Biological Evolution, Magnetic Resonance Imaging, polygenic selection, medicine.anatomical_structure, Evolutionary biology, Homo sapiens, Cognitive Sciences, Original Article, AcademicSubjects/MED00310, human gained enhancers, 030217 neurology & neurosurgery, Genetic screen, Neuroanatomy
Abstract: Contains fulltext : 231711.pdf (Publisher’s version ) (Open Access) Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000-3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.
Published: 2020

27. Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia

Author: James T. Voyvodic, Daniel S. O'Leary, Bryon A. Mueller, Judith M. Ford, Daniel H. Mathalon, Jatin G. Vaidya, Kelvin O. Lim, Theo G.M. van Erp, Sarah McEwen, Sarah E. Medland, Aysenil Belger, Jessica A. Turner, Vince D. Calhoun, Fabio Macciardi, Guia Guffanti, Steven G. Potkin, Juan R. Bustillo, and Soichiro Nakahara
Subjects: Male, 0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, PRS, Medical and Health Sciences, 0302 clinical medicine, GWAS, 2.1 Biological and endogenous factors, Aetiology, media_common, Psychiatry, Neuropsychology, Cognition, Serious Mental Illness, Psychiatry and Mental health, Mental Health, Schizophrenic Psychology, Female, Psychology, Biotechnology, Clinical psychology, Vigilance (psychology), Adult, media_common.quotation_subject, MCCB, Genomics, Article, 03 medical and health sciences, Behavioral and Social Science, Genetics, Humans, Genetic Predisposition to Disease, Cognitive Dysfunction, Gene, Biological Psychiatry, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, 030104 developmental biology, Genetic Loci, Schizophrenia, Verbal memory, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia.
Published: 2018

28. Functional impairment of cortical AMPA receptors in schizophrenia

Author: Tommaso Zeppillo, William E. Bunney, Melanie Föcking, David Cotter, Agenor Limon, Anton Schulmann, Brooke E. Hjelm, Ilaria Guella, P. Adolfo Sequeira, Marquis P. Vawter, and Fabio Macciardi
Subjects: Agonist, Proteomics, medicine.drug_class, Kainate receptor, AMPA receptor, Synaptic Transmission, Article, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, medicine, Humans, Receptors, AMPA, Biological Psychiatry, Kainic Acid, Chemistry, musculoskeletal, neural, and ocular physiology, Glutamate receptor, 030227 psychiatry, Dorsolateral prefrontal cortex, Psychiatry and Mental health, Electrophysiology, medicine.anatomical_structure, nervous system, Excitatory postsynaptic potential, Schizophrenia, Neuroscience, 030217 neurology & neurosurgery
Abstract: Clinical and preclinical studies suggest that some of the behavioral alterations observed in schizophrenia (SZ) may be mechanistically linked to synaptic dysfunction of glutamatergic signaling. Recent genetic and proteomic studies suggest alterations of cortical glutamate receptors of the AMPA-type (AMPARs), which are the predominant ligand-gated ionic channels of fast transmission at excitatory synapses. The impact of gene and protein alterations on the electrophysiological activity of AMPARs is not known in SZ. In this proof of principle work, using human postmortem brain synaptic membranes isolated from the dorsolateral prefrontal cortex (DLPFC), we combined electrophysiological analysis from microtransplanted synaptic membranes (MSM) with transcriptomic (RNA-Seq) and label-free proteomics data in 10 control and 10 subjects diagnosed with SZ. We observed in SZ a reduction in the amplitude of AMPARs currents elicited by kainate, an agonist of AMPARs that blocks the desensitization of the receptor. This reduction was not associated with protein abundance but with a reduction in kainate’s potency to activate AMPARs. Electrophysiologically-anchored dataset analysis (EDA) was used to identify synaptosomal proteins that linearly correlate with the amplitude of the AMPARs responses, gene ontology functional annotations were then used to determine protein-protein interactions. Protein modules associated with positive AMPARs current increases were down-regulated in SZ, while protein modules that were up-regulated in SZ were associated with decreased AMPARs currents. Our results indicate that transcriptomic and proteomic alterations, frequently observed in the DLPFC in SZ, converge at the synaptic level producing a functional electrophysiological impairment of AMPARs.
Published: 2019

29. A method for building a genome-connectome bipartite graph model

Author: Bryon A. Mueller, Judith M. Ford, Daniel H. Mathalon, Jatin G. Vaidya, Vince D. Calhoun, Jessica A. Turner, Fabio Macciardi, Adrian Preda, Godfrey D. Pearlson, Yuhui Du, Sarah McEwen, Theo G.M. van Erp, Jing Sui, Qingbao Yu, Eswar Damaraju, Aysenil Belger, and Jiayu Chen
Subjects: 0301 basic medicine, Male, Genome, 0302 clinical medicine, Models, 2.1 Biological and endogenous factors, Psychology, Aetiology, Bipartite graph, Degree (graph theory), General Neuroscience, fMRI, Brain, Single Nucleotide, Middle Aged, Serious Mental Illness, Magnetic Resonance Imaging, Mental Health, Neurological, Connectome, Biomedical Imaging, Female, Cognitive Sciences, Human, SNPs, Adult, Schizophrenia (object-oriented programming), Single-nucleotide polymorphism, Computational biology, Biology, Models, Biological, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Clinical Research, Genetics, SNP, Humans, Polymorphism, General linear model, Neurology & Neurosurgery, Genome, Human, Human Genome, Neurosciences, Biological, Brain Disorders, 030104 developmental biology, Good Health and Well Being, FNC, Schizophrenia, 030217 neurology & neurosurgery
Abstract: It has been widely shown that genomic factors influence both risk for schizophrenia and variation in functional brain connectivity. Moreover, schizophrenia is characterized by disrupted brain connectivity. In this work, we proposed a genome-connectome bipartite graph model to perform imaging genomic analysis. Functional network connectivity (FNC) was estimated after decomposing resting state functional magnetic resonance imaging data from both healthy controls (HC) and patients with schizophrenia (SZ) into spatial brain components using group independent component analysis (G-ICA). Then 83 FNC connections showing a group difference (HC vs SZ) were selected as fMRI nodes, and eighty-one schizophrenia-related single nucleotide polymorphisms (SNPs) were selected as genetic nodes respectively in the bipartite graph. Edges connecting pairs of genetic and fMRI nodes were defined based on the SNP-FNC associations across subjects evaluated by a general linear model. Results show that some SNP nodes in the bipartite graph have a high degree implying they are influential in modulating brain connectivity and may be more strongly associated with the risk of schizophrenia than other SNPs. A bi-clustering analysis detected a cluster with 15 SNPs interacting with 38 FNC connections, most of which were within or between somato-motor and visual brain areas. This suggests that the activity of these brain regions may be related to common SNPs and provides insights into the pathology of schizophrenia. The findings suggest that the SNP-FNC bipartite graph approach is a novel model to investigate genetic influences on functional brain connectivity in mental illness.
Published: 2019

30. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Published: 2019

31. Epigenetic mechanisms and associated brain circuits in the regulation of positive emotions: A role for transposable elements

Author: Fabio Macciardi, Simona Gaudi, Guia Guffanti, and James H. Fallon
Subjects: 0301 basic medicine, Somatic cell, General Neuroscience, Cellular differentiation, Genomics, Biology, Genome, Germline, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Epigenetics, Reprogramming, Gene, Neuroscience, 030217 neurology & neurosurgery
Abstract: Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how genomic and epigenetic mechanisms can modify and potentially alter our emotional (limbic) brain and affect our social interactions. J. Comp. Neurol. 524:2944-2954, 2016. © 2016 Wiley Periodicals, Inc.
Published: 2016

32. LINE1 insertions as a genomic risk factor for schizophrenia: Preliminary evidence from an affected family

Author: Guia Guffanti, Carlos N. Pato, Fabio Macciardi, James H. Fallon, Harry Mangalam, Simona Gaudi, Michele T. Pato, Claudia Klengel, Ravi Madduri, Janet L. Sobell, Paula DeCrescenzo, Kerry J. Ressler, Emily Glovienka, Torsten Klengel, and Alex Rodriguez
Subjects: Adult, Male, 0301 basic medicine, Subfamily, Genomics, Retrotransposon, Biology, Genome, DNA sequencing, Open Reading Frames, 03 medical and health sciences, Cellular and Molecular Neuroscience, symbols.namesake, 0302 clinical medicine, Risk Factors, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Genetics, Polymorphism, Genetic, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Middle Aged, Pedigree, Mutagenesis, Insertional, Psychiatry and Mental health, Long Interspersed Nucleotide Elements, 030104 developmental biology, Schizophrenia, Mendelian inheritance, symbols, Female, Human genome, 030217 neurology & neurosurgery
Abstract: Recent studies show that human-specific LINE1s (L1HS) play a key role in the development of the central nervous system (CNS) and its disorders, and that their transpositions within the human genome are more common than previously thought. Many polymorphic L1HS, that is, present or absent across individuals, are not annotated in the current release of the genome and are customarily termed "non-reference L1s." We developed an analytical workflow to identify L1 polymorphic insertions with next-generation sequencing (NGS) using data from a family in which SZ segregates. Our workflow exploits two independent algorithms to detect non-reference L1 insertions, performs local de novo alignment of the regions harboring predicted L1 insertions and resolves the L1 subfamily designation from the de novo assembled sequence. We found 110 non-reference L1 polymorphic loci exhibiting Mendelian inheritance, the vast majority of which are already reported in dbRIP and/or euL1db, thus, confirming their status as non-reference L1 polymorphic insertions. Four previously undetected L1 polymorphic loci were confirmed by PCR amplification and direct sequencing of the insert. A large fraction of our non-reference L1s is located within the open reading frame of protein-coding genes that belong to pathways already implicated in the pathogenesis of schizophrenia. The finding of these polymorphic variants among SZ offsprings is intriguing and suggestive of putative pathogenic role. Our data show the utility of NGS to uncover L1 polymorphic insertions, a neglected type of genetic variants with the potential to influence the risk to develop schizophrenia like SNVs and CNVs. © 2016 Wiley Periodicals, Inc.
Published: 2016

33. Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences

Author: Federica Torri, Filippo Spreafico, Daniela Perotti, Beatrice Gamba, Monica Terenziani, Fabio Macciardi, Paolo Radice, Sara Ciceri, and Paola Collini
Subjects: Male, Ribonuclease III, SIX1, 0301 basic medicine, recurrence, Real-Time Polymerase Chain Reaction, Bioinformatics, medicine.disease_cause, Wilms Tumor, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Tumor, medicine, Humans, SNP, RNA, Messenger, chromosomal anomalies, Child, Survival rate, Drosha, Neoplasm Staging, Chromosome Aberrations, Homeodomain Proteins, Mutation, Reverse Transcriptase Polymerase Chain Reaction, business.industry, High-Throughput Nucleotide Sequencing, Infant, Wilms' tumor, Prognosis, medicine.disease, Kidney Neoplasms, Survival Rate, 030104 developmental biology, Oncology, Chromosome 3, Chromosomes, Human, Pair 1, miRNA processor genes, Tumor progression, Child, Preschool, 030220 oncology & carcinogenesis, Genomic Profile, Female, Chromosomes, Human, Pair 3, Neoplasm Recurrence, Local, business, Chromosomes, Human, Pair 16, Research Paper
Abstract: Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures. Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.
Published: 2016

34. Reply to:New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Author: Theo G.M. van Erp, Esther Walton, Derrek P. Hibar, Lianne Schmaal, Wenhao Jiang, David C. Glahn, Godfrey D. Pearlson, Nailin Yao, Masaki Fukunaga, Ryota Hashimoto, Naohiro Okada, Hidenaga Yamamori, Vincent P. Clark, Bryon A. Mueller, Sonja M.C. de Zwarte, Roel A. Ophoff, Neeltje E.M. van Haren, Ole A. Andreassen, Tiril P. Gurholt, Oliver Gruber, Bernd Kraemer, Anja Richter, Vince D. Calhoun, Benedicto Crespo-Facorro, Roberto Roiz-Santiañez, Diana Tordesillas-Gutiérrez, Carmel Loughland, Stanley Catts, Janice M. Fullerton, Melissa J. Green, Frans Henskens, Assen Jablensky, Bryan J. Mowry, Christos Pantelis, Yann Quidé, Ulrich Schall, Rodney J. Scott, Murray J. Cairns, Marc Seal, Paul A. Tooney, Paul E. Rasser, Gavin Cooper, Cynthia Shannon Weickert, Thomas W. Weickert, Elliot Hong, Peter Kochunov, Raquel E. Gur, Ruben C. Gur, Judith M. Ford, Fabio Macciardi, Daniel H. Mathalon, Steven G. Potkin, Adrian Preda, Fengmei Fan, Stefan Ehrlich, Margaret D. King, Lieuwe De Haan, Dick J. Veltman, Francesca Assogna, Nerisa Banaj, Pietro de Rossi, Mariangela Iorio, Fabrizio Piras, Gianfranco Spalletta, Edith Pomarol-Clotet, Sinead Kelly, Simone Ciufolini, Joaquim Radua, Robin Murray, Tiago Reis Marques, Andrew Simmons, Stefan Borgwardt, Fabienne Schönborn-Harrisberger, Anita Riecher-Rössler, Renata Smieskova, Kathryn I. Alpert, Alessandro Bertolino, Aurora Bonvino, Annabella Di Giorgio, Emma Neilson, Andrew R. Mayer, Je-Yeon Yun, Dara M. Cannon, Irina Lebedeva, Alexander S. Tomyshev, Tolibjohn Akhadov, Vasily Kaleda, Helena Fatouros-Bergman, Lena Flyckt, Pedro G.P. Rosa, Mauricio H. Serpa, Marcus V. Zanetti, Cyril Hoschl, Antonin Skoch, Filip Spaniel, David Tomecek, Andrew M. McIntosh, Heather C. Whalley, Christian Knöchel, Viola Oertel-Knöchel, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Anne Uhlmann, Carlos Lopez-Jaramillo, Danai Dima, Joshua I. Faskowitz, Boris A. Gutman, Neda Jahanshad, Paul M. Thompson, Jessica A. Turner, Lars Farde, Simon Cervenka, Ingrid Agartz, Karin Collste, Pauliina Victorsson, Göran Engberg, Sophie Erhardt, Lilly Schwieler, Anna Malmqvist, Mikael Hedberg, Funda Orhan, Fredrik Piehl, APH - Mental Health, Adult Psychiatry, Universidad de Cantabria, Child and Adolescent Psychiatry / Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Schizophrenia (object-oriented programming), Prefrontal Cortex, BF, Neuroimaging, Mega, Severity of Illness Index, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Medical imaging, Humans, Medical physics, Disease process, Age of Onset, Child, Biological Psychiatry, Aged, Brain Diseases, medicine.diagnostic_test, Brain, Magnetic resonance imaging, Middle Aged, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 030104 developmental biology, Case-Control Studies, Linear Models, Schizophrenia, RC0321, Female, Biological psychiatry, Psychology, 030217 neurology & neurosurgery
Abstract: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
Published: 2018

35. Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex

Author: Claudia Klengel, Andrew A. Bartlett, Gennadi V. Glinsky, Torsten Klengel, Richard G. Hunter, Guia Guffanti, Fabio Macciardi, and Arkhipova, Irina
Subjects: 0301 basic medicine, Male, comparative genomics, Genome, Transcriptome, 0302 clinical medicine, dorsolateral prefrontal cortex, Middle Aged, medicine.anatomical_structure, transcription factor binding sites, Female, transposable elements, Human, Primates, Adult, 1.1 Normal biological development and functioning, Prefrontal Cortex, Rodentia, Biology, 03 medical and health sciences, Underpinning research, medicine, Genetics, Animals, Humans, Epigenetics, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Discoveries, Aged, Evolutionary Biology, Genome, Human, Gene Expression Profiling, Human Genome, Intron, Computational Biology, Rats, RNA-mediated epigenetics and RNA-seq, Dorsolateral prefrontal cortex, DNA binding site, Gene expression profiling, schizophrenia, 030104 developmental biology, Evolutionary biology, Case-Control Studies, DNA Transposable Elements, Generic health relevance, Biochemistry and Cell Biology, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Expression of transposable elements (TE) is transiently activated during human preimplantation embryogenesis in a developmental stage- and cell type-specific manner and TE-mediated epigenetic regulation is intrinsically wired in developmental genetic networks in human embryos and embryonic stem cells. However, there are no systematic studies devoted to a comprehensive analysis of the TE transcriptome in human adult organs and tissues, including human neural tissues. To investigate TE expression in the human Dorsolateral Prefrontal Cortex (DLPFC), we developed and validated a straightforward analytical approach to chart quantitative genome-wide expression profiles of all annotated TE loci based on unambiguous mapping of discrete TE-encoded transcripts using a de novo assembly strategy. To initially evaluate the potential regulatory impact of DLPFC-expressed TE, we adopted a comparative evolutionary genomics approach across humans, primates, and rodents to document conservation patterns, lineage-specificity, and colocalizations with transcription factor binding sites mapped within primate- and human-specific TE. We identified 654,665 transcripts expressed from 477,507 distinct loci of different TE classes and families, the majority of which appear to have originated from primate-specific sequences. We discovered 4,687 human-specific and transcriptionally active TEs in DLPFC, of which the prominent majority (80.2%) appears spliced. Our analyses revealed significant associations of DLPFC-expressed TE with primate- and human-specific transcription factor binding sites, suggesting potential cross-talks of concordant regulatory functions. We identified 1,689 TEs differentially expressed in the DLPFC of Schizophrenia patients, a majority of which is located within introns of 1,137 protein-coding genes. Our findings imply that identified DLPFC-expressed TEs may affect human brain structures and functions following different evolutionary trajectories. On one side, hundreds of thousands of TEs maintained a remarkably high conservation for ∼8 My of primates’ evolution, suggesting that they are likely conveying evolutionary-constrained primate-specific regulatory functions. In parallel, thousands of transcriptionally active human-specific TE loci emerged more recently, suggesting that they could be relevant for human-specific behavioral or cognitive functions.
Published: 2018

36. Toward Reproducible Results from Targeted Metabolomic Studies: Perspectives for Data Pre-processing and a Basis for Analytic Pipeline Development

Author: Ricardo Miramontes, Thomas J. Gross, Mark Mapstone, Massimo S. Fiandaca, Robert M. Padilla, Fabio Macciardi, Amrita K. Cheema, and Howard J. Federoff
Subjects: 0301 basic medicine, Computer science, Reproducibility of Results, Sample (statistics), General Medicine, Data science, Pipeline (software), 03 medical and health sciences, Exploratory data analysis, 030104 developmental biology, Metabolomics, Workflow, Phenotype, Drug Discovery, Humans, Data pre-processing, Biomarker discovery, Raw data, Biomarkers
Abstract: Contemporary metabolomics experiments generate a rich array of complex high-dimensional data. Consequently, there have been concurrent efforts to develop methodological standards and analytical workflows to streamline the generation of meaningful biochemical and clinical inferences from raw data generated using an analytical platform like mass spectrometry. While such considerations have been frequently addressed in untargeted metabolomics (i.e., the broad survey of all distinguishable metabolites within a sample of interest), this methodological scrutiny has seldom been applied to data generated using commercial, targeted metabolomics kits. We suggest that this may, in part, account for past and more recent incomplete replications of previously specified biomarker panels. Herein, we identify common impediments challenging the analysis of raw, targeted metabolomic abundance data from a commercial kit and review methods to remedy these issues. In doing so, we propose an analytical pipeline suitable for the pre-processing of data for downstream biomarker discovery. Operational and statistical considerations for integrating targeted data sets across experimental sites and analytical batches are discussed, as are best practices for developing predictive models relating pre-processed metabolomic data to associated phenotypic information.
Published: 2018

37. Mitochondrial variability in the Mediterranean area: a complex stage for human migrations

Author: G. Scano, Gabriele Scorrano, Cristina Martínez-Labarga, Fabio Macciardi, Flavio De Angelis, and Olga Rickards
Subjects: 0301 basic medicine, Mediterranean climate, Aging, Physiology, Epidemiology, Human Migration, Population, Settore BIO/08, Mediterranean Basin, Haplogroup, mtDNA human populations, 03 medical and health sciences, Middle East, Africa, Northern, Stage (stratigraphy), Genetics, Humans, Northern, education, education.field_of_study, Genome, Human migration, business.industry, Ecology, Genome, Human, Mediterranean Region, Public Health, Environmental and Occupational Health, Genetic Variation, complete mitochondrial genomes, Mediterranean mitochondrial lineages, Anatomy & Morphology, Mitochondrial, 030104 developmental biology, Geography, Genome, Mitochondrial, Africa, Biological dispersal, Gene pool, Biochemistry and Cell Biology, business, Human
Abstract: The Mediterranean area has always played a significant role in human dispersal due to the large number of migratory events contributing to shape the cultural features and the genetic pool of its populations.This paper aims to review and diachronically describe the mitogenome variability in the Mediterranean population and the main demic diffusions that occurred in this area over time.Frequency distributions of the leading mitochondrial haplogroups have been geographically and chronologically evaluated. The variability of U5b and K lineages has been focussed to broaden the knowledge of their genetic histories.The mitochondrial genetic makeup of Palaeolithic hunter-gatherers is poorly defined within the extant Mediterranean populations, since only a few traces of their genetic contribution are still detectable. The Neolithic lineages are more represented, suggesting that the Neolithic revolution had a marked effect on the peopling of the Mediterranean area. The largest effect, however, was provided by historical migrations.Although the mitogenome variability has been widely used to try and clarify the evolution of the Mediterranean genetic makeup throughout almost 50 000 years, it is necessary to collect whole genome data on both extinct and extant populations from this area to fully reconstruct and interpret the impact of multiple migratory waves and their cultural and genetic consequences on the structure of the Mediterranean populations.
Published: 2018

38. Systems healthcare: a holistic paradigm for tomorrow

Author: Shaista Malik, Howard J. Federoff, Massimo S. Fiandaca, Mireille Jacobson, Mark Mapstone, Elenora Connors, Fabio Macciardi, and Edwin S. Monuki
Subjects: 0301 basic medicine, Knowledge management, Systems biology, media_common.quotation_subject, Review, Health administration, 03 medical and health sciences, Presentation, 0302 clinical medicine, Structural Biology, Alzheimer Disease, Intervention (counseling), Health care, Humans, Molecular Biology, lcsh:QH301-705.5, Health policy, media_common, business.industry, Applied Mathematics, Health Policy, Systems Biology, Computer Science Applications, Systems medicine, 030104 developmental biology, lcsh:Biology (General), Cardiovascular Diseases, Modeling and Simulation, Costs and Cost Analysis, business, Psychology, Delivery of Health Care, 030217 neurology & neurosurgery, Biological network
Abstract: Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer’s and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0521-2) contains supplementary material, which is available to authorized users.
Published: 2017

39. Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

Author: Wei Dai, Angelo Demuro, Emily M. Sontag, Asa Hatami, John M. Ringman, William E. Bunney, Jane S. Paulsen, Fabio Macciardi, Wah Chiu, Shichun Ling, T.G.M. van Erp, Ricardo Albay, Leslie M. Thompson, K. T. Potkin, Jeffrey D. Long, Steven G. Potkin, Ian Parker, Michelle A. Digman, Julia Overman, Zhiqun Tan, and Charles G. Glabe
Subjects: Male, Huntington's Disease, Pathology, Huntingtin, Mutant, Neurodegenerative, medicine.disease_cause, Medical and Health Sciences, Transgenic, 0302 clinical medicine, Cerebrospinal fluid, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, Psychiatry, Microscopy, Huntingtin Protein, 0303 health sciences, Mutation, Cultured, Transfection, Biological Sciences, 3. Good health, Cell biology, Psychiatry and Mental health, Huntington Disease, Neurological, Female, Rats, Transgenic, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Cells, Nerve Tissue Proteins, Biology, Protein Aggregation, Pathological, Electron, 03 medical and health sciences, Cellular and Molecular Neuroscience, Rare Diseases, Huntington's disease, Pathological, mental disorders, medicine, Animals, Humans, Dementia, Molecular Biology, 030304 developmental biology, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Protein Aggregation, Rats, Brain Disorders, nervous system diseases, Microscopy, Electron, Orphan Drug, Immediate Communication, Peptides, 030217 neurology & neurosurgery
Abstract: Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.
Published: 2015

40. Schizophrenia miR-137 Locus Risk Genotype Is Associated with Dorsolateral Prefrontal Cortex Hyperactivation

Author: Ilaria Guella, Kelvin O. Lim, Fabio Macciardi, Douglas N. Greve, Dana Nguyen, Aysenil Belger, Gary H. Glover, Gregory G. Brown, Steven G. Potkin, Adrian Preda, Michele T. Diaz, Judith M. Ford, Vince D. Calhoun, Theo G.M. van Erp, Marquis P. Vawter, Juan R. Bustillo, Gregory McCarthy, Jessica A. Turner, and Daniel H. Mathalon
Subjects: Oncology, medicine.medical_specialty, medicine.diagnostic_test, Working memory, Single-nucleotide polymorphism, behavioral disciplines and activities, Dorsolateral prefrontal cortex, Exact test, medicine.anatomical_structure, Internal medicine, mental disorders, Genotype, medicine, Psychiatry, Psychology, Functional magnetic resonance imaging, Prefrontal cortex, Allele frequency, Biological Psychiatry
Abstract: Background miR-137 dysregulation has been implicated in the etiology of schizophrenia, but its functional role remains to be determined. Methods Functional magnetic resonance imaging scans were acquired on 48 schizophrenia patients and 63 healthy volunteers (total sample size N = 111 subjects), with similar mean age and sex distribution, while subjects performed a Sternberg Item Response Paradigm with memory loads of one, three, and five numbers. Dorsolateral prefrontal cortex (DLPFC) retrieval activation for the working memory load of three numbers, for which hyperactivation had been shown in schizophrenia patients compared with control subjects, was extracted. The genome-wide association study confirmed schizophrenia risk single nucleotide polymorphism rs1625579 (miR-137 locus) was genotyped (schizophrenia: GG n = 0, GT n = 9, TT n = 39; healthy volunteers: GG=2, GT n = 15, and TT n = 46). Fisher's exact test examined the effect of diagnosis on rs1625579 allele frequency distribution ( p = nonsignificant). Mixed model regression analyses examined the effects of diagnosis and genotype on working memory performance measures and DLPFC activation. Results Patients showed significantly higher left DLPFC retrieval activation on working memory load 3, lower working memory performance, and longer response times compared with controls. There was no effect of genotype on working memory performance or response times in either group. However, individuals with the rs1625579 TT genotype had significantly higher left DLPFC activation than those with the GG/GT genotypes. Conclusions Our study suggests that the rs1625579 TT (miR-137 locus) schizophrenia risk genotype is associated with the schizophrenia risk phenotype DLPFC hyperactivation commonly considered a measure of brain inefficiency.
Published: 2014

41. Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

Author: Svante Pääbo, Philipp Gunz, Han G. Brunner, Katharina Wittfeld, Uwe Völker, Simon E. Fisher, Beate St Pourcain, Janet Kelso, Barbara Franke, Fabio Macciardi, Tulio Guadalupe, Amanda K. Tilot, Fabio Di Vincenzo, Chin Yang Shapland, Giorgio Manzi, Antonio Profico, Guillén Fernández, Hans J. Grabe, Jean-Jacques Hublin, Norbert Hosten, Theo G.M. van Erp, James H. Fallon, Benjamin Vernot, Wolfgang Enard, Michael Dannemann, Alexander Teumer, Simon Neubauer, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: brain shape, Male, 0301 basic medicine, genetic association, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Brain tissue, Language in Interaction, BASAL GANGLIA, 0302 clinical medicine, SCHIZOPHRENIA, magnetic resonance imaging, anatomy & histology [Skull], Neanderthals, Netherlands, Aged, 80 and over, 0303 health sciences, Fossils, Brain, myelination, Hominidae, ASSOCIATION, Middle Aged, Biological Evolution, GENOME, Phenotype, medicine.anatomical_structure, basal ganglia, Female, General Agricultural and Biological Sciences, cerebellum, evolution, gene expression, homo sapiens, Neandertal, Neuroinformatics, Adult, HOMO, Adolescent, Introgression, Genomics, Biology, SEQUENCE, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Globular shape, ddc:570, Endocranium, medicine, Animals, Humans, PHLPP, 030304 developmental biology, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], AKT, Skull, EVOLUTION, anatomy & histology [Neanderthals], 030104 developmental biology, Homo sapiens, Evolutionary biology, Hybridization, Genetic, MYELINATION, 030217 neurology & neurosurgery, Endocast
Abstract: SUMMARY One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1–4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape., In Brief Gunz, Tilot et al. combine paleoanthropology, archaic genomics, neuroimaging, and gene expression to study biological foundations of the characteristic modern human endocranial shape. They find introgressed Neandertal alleles that associate with reduced endocranial globularity and affect expression of genes linked to neurogenesis and myelination.
Published: 2019

42. Genome-wide association study of obsessive-compulsive disorder

Author: Helena Garrido, Richard O'Brien, Michael H. Bloch, David L. Pauls, M. Van Der Brug, Anna Tikhomirov, Andrew B. Singleton, Susanne Walitza, Benjamin M. Neale, Patrick Evans, Rianne M. Blom, Mina Ryten, James L. Kennedy, Christopher Pittenger, C. Illman, Amin Azzam, Stephen A. Haddad, Gregory L. Hanna, Michele T. Pato, D. Rosenberg, Maurizio Turiel, Stephan Ruhrmann, Peter Falkai, Nuria Lanzagorta, Richard Delorme, D. G. Hernandez, Leonhard Lennertz, Abby J. Fyer, M Conceição do Rosário, Euripedes Constantino Miguel, John Hardy, Carlos N. Pato, Francesca Frau, Hans-Jörgen Grabe, Daniele Cusi, Alan B. Zonderman, Dieter Deforce, Peter Heutink, Brooke Sheppard, Jacquelyn Crane, Dongmei Yu, Danielle C. Cath, Rainald Moessner, Nancy J. Cox, Shaun Purcell, James A. Knowles, Daniel B. Mirel, Aline S. Sampaio, D. L. Murphy, R. Johnson, Jens R. Wendland, David V. Conti, Carolina Cappi, Paula Umaña, Marco A. Grados, Dan J. Stein, J. R. Gibbs, Humberto Nicolini, Anna Pluzhnikov, Denise A. Chavira, F. Van Nieuwerburgh, Valsamma Eapen, Lisa Osiecki, Christine Lochner, Juan C. Troncoso, Jeremy Veenstra-VanderWeele, Mark A. Riddle, Michael Wagner, Jeremiah M. Scharf, Beatriz Camarena, Edwin H. Cook, Ana Gabriela Hounie, Daniah Trabzuni, Donald W. Black, Scott L. Rauch, Marion Leboyer, Andrew Crenshaw, S. E. Stewart, Roel A. Ophoff, Dianne M. Hezel, Damiaan Denys, Gerald Nestadt, Melissa Parkin, Karin Egberts, Colin Smith, Anuar Konkashbaev, Danielle Posthuma, Vladimir Coric, James F. Leckman, Eric Strengman, Jack Samuels, Tobias J. Renner, Michael E. Weale, L. Ferrucci, Mark R. Cookson, Laura Bellodi, Oscar J. Bienvenu, C. Mayerfeld, Christopher K. Edlund, Youfa Wang, Robert Walker, Dan L. Longo, Maria Cristina Cavallini, James T. McCracken, Jesen Fagerness, H. R. Zielke, Homero Vallada, Chunyu Liu, Bernadette Cullen, Carol A. Mathews, Sian M. J. Hemmings, Allissa Dillman, E. Voyiaziakis, Fabio Macciardi, Eduardo Fournier, Benjamin D. Greenberg, Eric R. Gamazon, S. Arepalli, Margaret A. Richter, Bryan J. Traynor, Michael A. Jenike, J.H. Smit, M. A. Nalls, Lauren M. McGrath, Paul D. Arnold, H.G.M. Westenberg, W. Maier, Other departments, ANS - Amsterdam Neuroscience, Adult Psychiatry, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Netherlands Institute for Neuroscience (NIN), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
Subjects: Parents, Obsessive-Compulsive Disorder, OCD COLLABORATIVE GENETICS, SLC1A1, Genome-wide association study, genomic, 0302 clinical medicine, Polymorphism (computer science), TRANSPORTER GENE, GWAS, SNPS, Genetics, QUANTITATIVE TRAIT LOCI, 0303 health sciences, biology, Frontal Lobe, obsessive-compulsive disorder, Psychiatry and Mental health, EXPRESSION, Quantitative Trait Loci, TWIN, Nerve Tissue Proteins, Single-nucleotide polymorphism, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 17 - Partnerships for the Goals, DLGAP, Genetic variation, mental disorders, LINKAGE, Humans, SNP, Genetic Predisposition to Disease, Molecular Biology, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Biology and Life Sciences, neurodevelopmental disorder, SAP90-PSD95 Associated Proteins, Case-Control Studies, REPLICATION, Expression quantitative trait loci, biology.protein, genetic, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P = 2.49 x 10(-6) and P = 3.44 x 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value = 3.84 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P < 0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P = 0.001) was observed within the top-ranked SNPs (P < 0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
Published: 2013

43. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author: Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.
Subjects: Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Published: 2016

44. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2016

45. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

Author: Daniel H. Wolf, Ingrid Agartz, Catherine Bois, Hilleke E. Hulshoff Pol, Roel A. Ophoff, T.G.M. van Erp, Lars T. Westlye, Stephen M. Lawrie, Gary Donohoe, Sinead Kelly, Ingrid Melle, HJ Bockholt, Jessica A. Turner, David C. Glahn, R.E. Gur, Benedicto Crespo-Facorro, Godfrey D. Pearlson, Vince D. Calhoun, Andrew M. McIntosh, Theodore D. Satterthwaite, Johanna Hass, Steven G. Potkin, Esther Walton, Cecilie B. Hartberg, René S. Kahn, Bernd Kraemer, Jerod M. Rasmussen, Ole A. Andreassen, Derrek P. Hibar, N.E.M. van Haren, Adrian Preda, Erik G. Jönsson, Unn K. Haukvik, L. de Haan, Scott R. Sponheim, Oliver Gruber, Laura Koenders, Stefan Ehrlich, Anders M. Dale, Lei Wang, Dara M. Cannon, Kathryn I. Alpert, Bryon A. Mueller, Dick J. Veltman, Aiden Corvin, Paul M. Thompson, Colm McDonald, Daniel H. Mathalon, Marise W. J. Machielsen, Rali Dimitrova, Fabio Macciardi, Roberto Roiz-Santiañez, David Zilles, R.C. Gur, Jody M. Shoemaker, Ryota Hashimoto, Heather C. Whalley, Derek W. Morris, Universidad de Cantabria, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Other departments, Adult Psychiatry, Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Anatomy and neurosciences
Subjects: Male, Published Erratum, Image Processing, Brain mapping, Medical and Health Sciences, Functional Laterality, gray-matter, 0302 clinical medicine, Computer-Assisted, Image Processing, Computer-Assisted, 2.1 Biological and endogenous factors, Longitudinal Studies, Prospective Studies, Aetiology, risk, Subcortical, brain volume, schizophrenia, bipolar disorder, Psychiatry, Brain Mapping, Putamen, Brain, Middle Aged, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, 3. Good health, Psychiatry and Mental health, Mental Health, Schizophrenia, Brain size, Biomedical Imaging, antipsychotic treatment, Female, Original Article, Psychology, metaanalysis, Adult, medicine.medical_specialty, Schizophrenia (object-oriented programming), 1st-episode schizophrenia, hippocampal volume, reduction, Neuroimaging, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Rare Diseases, Clinical Research, medicine, Journal Article, voxel-based morphometry, Dementia, Humans, Bipolar disorder, Molecular Biology, Psychology and Cognitive Sciences, Neurosciences, dehydration, Voxel-based morphometry, medicine.disease, 030227 psychiatry, Brain Disorders, Good Health and Well Being, Case-Control Studies, Neuroscience, 030217 neurology & neurosurgery
Abstract: © 2016 Macmillan Publishers Limited. The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.
Published: 2016

46. Identifying Unanticipated Genes and Mechanisms in Serious Mental Illness

Author: Shichun Ling, Theo G.M. van Erp, Steven G. Potkin, Fabio Macciardi, and Xiaohui Xie
Subjects: medicine.medical_specialty, business.industry, medicine, Mental illness, medicine.disease, Psychiatry, business
Published: 2016

47. 628. Polygenic Risk Score for Schizophrenia of CREB1 and BDNF Associated with Structural Brain Dysconnectivity

Author: Vince D. Calhoun, Dara S. Manoach, Jiayu Chen, Juan R. Bustillo, Tonya White, Robert J. Thoma, Nora I. Perrone-Bizzozero, Randy L. Gollub, Scott R. Sponheim, Fabio Macciardi, Stefan Ehrlich, Judith M. Ford, Lei Wu, Steven G. Potkin, Charles S. Schulz, Jessica A. Turner, Jingyu Liu, Cheryl J. Aine, Theo G.M. van Erp, Beng-Choon Ho, Sarah McEwen, and Arvind Caprihan
Subjects: medicine.medical_specialty, biology, business.industry, Schizophrenia (object-oriented programming), 05 social sciences, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, biology.protein, Medicine, 0501 psychology and cognitive sciences, Polygenic risk score, business, Psychiatry, CREB1, 030217 neurology & neurosurgery, Biological Psychiatry
Published: 2017

48. Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort

Author: Douglas C. Wallace, David Keator, Anita Lakatos, Steven G. Potkin, Maria Lvova, Marty C. Brandon, Nicholas J. Schork, Guia Guffanti, Fabio Macciardi, Andrew J. Saykin, Danny Younes, Olga Derbeneva, Dora Reglodi, Michael W. Weiner, and Trygve E. Bakken
Subjects: Male, Senescence, Aging, Mitochondrial DNA, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Haplogroup, Cohort Studies, Random Allocation, Alzheimer Disease, Genetic predisposition, medicine, Humans, Longitudinal Studies, Prospective Studies, Genetic Association Studies, Phylogeny, Aged, Aged, 80 and over, Genetics, General Neuroscience, Genetic Variation, medicine.disease, Genes, Mitochondrial, Case-Control Studies, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Oxidative stress, Follow-Up Studies, Developmental Biology, Human mitochondrial DNA haplogroup
Abstract: Despite the central role of amyloid deposition in the development of Alzheimer's disease (AD), the pathogenesis of AD still remains elusive at the molecular level. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species (ROS) which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. Because the brain relies on aerobic metabolism, it is apparent that mitochondria are critical for the cerebral function. Mitochondrial DNA sequence changes could shift cell dynamics and facilitate neuronal vulnerability. Therefore we postulated that mitochondrial DNA sequence polymorphisms may increase the risk of AD. We evaluated the role of mitochondrial haplogroups derived from 138 mitochondrial polymorphisms in 358 Caucasian Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Our results indicate that the mitochondrial haplogroup UK may confer genetic susceptibility to AD independently of the apolipoprotein E4 (APOE4) allele.
Published: 2010

49. Fine mapping ofAHI1as a schizophrenia susceptibility gene: from association to evolutionary evidence

Author: Chiara Dal Fiume, Paolo Cozzi, Jacques S. Beckmann, Manuela Sironi, Daniela Amann-Zalcenstein, Richard B. Ebstein, Rachele Cagliani, Yoav Kohn, Luciano Milanesi, Bernard Lerer, Doron Lancet, Erika Salvi, Federica Torri, Luisa Strik Lievers, Edna Ben-Asher, Sara Lupoli, Anna Akelai, Gabriele Trombetti, Matteo Fumagalli, Alessandro Orro, Kyra Kanyas, and Fabio Macciardi
Subjects: Candidate gene, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Biochemistry, Joubert syndrome, 03 medical and health sciences, 0302 clinical medicine, Intergenic region, Genetics, medicine, Humans, Genetic Predisposition to Disease, Selection, Genetic, Molecular Biology, Genetic Association Studies, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Cyclic Nucleotide Phosphodiesterases, Type 7, Haplotype, medicine.disease, Biological Evolution, Hardy–Weinberg principle, Adaptor Proteins, Vesicular Transport, Haplotypes, Schizophrenia, Autism, Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Biotechnology
Abstract: In previous studies, we identified a locus for schizophrenia on 6q23.3 and proposed the Abelson helper integration site 1 (AHI1) as the candidate gene. AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism. The neurodevelopmental role of AHI1 fits with etiological hypotheses of schizophrenia. To definitively confirm our hypothesis, we searched for associations using a dense map of the region. Our strongest findings lay within the AHI1 gene: single-nucleotide polymorphisms rs11154801 and rs7759971 showed significant associations (P=6.23E-06; P=0.84E-06) and haplotypes gave P values in the 10E-8 to 10E-10 range. The second highest significant region maps close to AHI1 and includes the intergenic region between BC040979 and PDE7B (rs2038549 at P=9.70E-06 and rs1475069 at P=6.97E-06), and PDE7B and MAP7. Using a sample of Palestinian Arab families to confirm these findings, we found isolated signals. While these results did not retain their significance after correction for multiple testing, the joint analysis across the 2 samples supports the role of AHI1, despite the presence of heterogeneity. Given the hypothesis of positive selection of schizophrenia genes, we resequenced a 11 kb region within AHI1 in ethnically defined populations and found evidence for a selective sweep. Network analysis indicates 2 haplotype clades, with schizophrenia-susceptibility haplotypes clustering within the major clade. In conclusion, our data support the role of AHI1 as a susceptibility gene for schizophrenia and confirm it has been subjected to positive selection, also shedding light on new possible candidate genes, MAP7 and PDE7B.-Torri, F., Akelai, A., Lupoli, S., Sironi, M., Amann-Zalcenstein, D., Fumagalli, M., Dal Fiume, C., BenAsher, E., Kanyas, K., Cagliani, R., Cozzi, P., Trombetti, G., Lievers, L. S., Salvi, E., Orro, A., Beckmann, J. S., Lancet, D., Kohn, Y., Milanesi, L., Ebstein, R. B., Lerer, B., Macciardi, F. Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.
Published: 2010

50. Pilot Study on Schizophrenia in Sardinia

Author: Antoniettina Rinaldi, Mauro Giovanni Carta, Renato Robledo, Fabio Macciardi, Marcello Siniscalco, Licinio Contu, Riccardo Triunfo, Yuanyuan Shen, Jurg Ott, and Andrea Murru
Subjects: Adult, Male, Pilot Projects, Genome-wide association study, Chromosome 9, Disease, Biology, Polymorphism, Single Nucleotide, Gene Frequency, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetics (clinical), Genetic association, Original Paper, Chromosome, Small sample, Middle Aged, medicine.disease, Italy, Schizophrenia, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: Objective: Based on a small sample of cases with schizophrenia and control individuals from an isolated population, a genome-wide association study was undertaken to find variants conferring susceptibility to this disease. Methods: Standard association tests were employed, followed by newer multilocus association methods (genotype patterns). Results: Individually, no variant produced a significant result. However, the best two variants (rs1360382 on chromosome 9 and rs1303 on chromosome 14) showed significantly different genotype pattern distributions between patients and control individuals. The risk genotype pattern AA-TT is highly predictive of schizophrenia, with estimated sensitivity and specificity of 1 and 0.96, respectively. Conclusions: These findings support the hypothesis that schizophrenia is partly due to multiple genetic variants, each with a relatively small effect.
Published: 2010

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