Genomics of cognitive traits, Brain evolution and paleoneurology, Genetics of language, Computational neurogenomics
2000 NARSAD Independent Investigator Award
1989-1990 Postdoc, Human Molecular Genetics, Yale University, New Haven, CT
My laboratory uses DNA and RNA sequencing methods, ancient DNA sequences, computational neurogenomics and Brain Imaging tools (structural and functional magnetic resonance imaging (MRI/fMRI), diffusion tensor imaging (DTI)) to study the hominin evolution of the human genome and of the normal human cerebral cortex.
I am primarily interested in studying how the non-coding regulatory genome has evolved to regulate networks of co-expressed genes, in characterizing how the neural genome has shaped brain regions of interest (ROIs) for specific human cognitive abilities, with a special focus on language, and how changes in DNA regulatory sequences and in transcriptomes contribute to psychiatric diseases.
In studying the regulatory DNA mechanisms controlling for gene expression, my lab identified and characterized the role that non-reference human specific LINE1s (L1s) - that are part of Transposable Elements (TEs: DNA elements that can move within the genome) - play in re-organizing networks of co-expressed genes. We developed a biologically validated bioinformatics pipeline to study non-reference and de novo L1s and found that the distribution of their retro-transpositions are different in healthy subjects compared to schizophrenic patients, primarily affecting genes involved in neurodevelopment in schizophrenia. In parallel, we are investigating the functional relevance of both L1s and Human Endogenous RetroViruses (HERVs) using RNA-sequencing strategies. Our initial findings strongly suggest that several L1s and HERVs have been exapted as either “promoters” (L1s) or “enhancers” (HERVs) regulating the expression of neural genes in normal subjects and that altered expressions of HERVs and L1s contribute to schizophrenia and autism, by dys-regulating neurodevelopmental gene pathways.
Using a combination of brain imaging genetics techniques in living subjects and post-mortem functional analyses in brain ROIs, we detected and identified genes that are part of the complex etiology of severe psychiatric disorders, specifically schizophrenia and Alzheimer’s Disease. We have identified and functionally characterized the role of genes miR137, TCF4, TNIK and others as etiologic risk factors for these psychiatric disorders. All these genes have been also confirmed as primary risk factors for psychiatric disorders by large Consortia samples like PGC’s (Pstchiatric Genomic Consortium), GPC’s (Genomic Psychiatric Cohort) or ENIGMA’s (Enhancing Neuro Imaging Genetics through Meta Analysis) using many thousands of subjects. We are currently analyzing a defined set of genes that show a fast evolution in the human lineage and that are considered the drivers of our neocortex growth in phylogenesis as well as in embryo neural development.
In our studies of paleoneurology, we have sequenced the whole genomes of two H. sapiens from the Upper Paleolithic (~ 20,000 BCE) and the Mesolithic (~ 7,000 BCE) periods and we rebuilt their virtual “brain cortex” from the images that the original brains left on their skulls. Using evolutionary methods and techniques, we are investigating how our genome and brain cortical structures have co-evolved in the human lineage. These two samples are part of a larger collection that includes more than 70 paleoanthropological samples from the Middle Paleolithic (~ 450,000 BCE) to the Neolithic.
Guffanti G, Bartlett A, Klengel T, Klengel C, Hunter R, Glinsky G, Macciardi F.: Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex. Mol Biol Evol. 2018 35(10):2435-2453
Guffanti G, Bartlett A, DeCrescenzo P, Macciardi F, Hunter R. (2019). Transposable Elements. Curr Top Behav Neurosci. doi: 10.1007/7854_2019_112.
Gunz P, Tilot AK, Wittfeld K, Teumer A, Shapland CY, van Erp TGM, Dannemann M, Vernot B, Neubauer S, Guadalupe T, Fernández G, Brunner HG, Enard W, Fallon J, Hosten N, Völker U, Profico A, Di Vincenzo F, Manzi G, Kelso J, St Pourcain B, Hublin JJ, Franke B, Pääbo S, Macciardi F, Grabe HJ, Fisher SE. (2019). Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity. Curr Biol. 29(1):120-127.e5. doi: 10.1016/j.cub.2018.10.065
Gross T, Mapstone M, Miramontes R, Padilla R, Cheema AK, Macciardi F, Federoff HJ, Fiandaca MS (2018). Toward Reproducible Results from Targeted Metabolomic Studies: Perspectives for Data Pre-processing and a Basis for Analytic Pipeline Development. Curr Top Med Chem. 18(11):883-895. doi: 10.2174/1568026618666180711144323
van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, Agartz I, Westlye LT, Haukvik UK, Dale AM, Melle I, Hartberg CB, Gruber O, Kraemer B, Zilles D, Donohoe G, Kelly S, McDonald C, Morris DW, Cannon DM, Corvin A, Machielsen MW, Koenders L, de Haan L, Veltman DJ, Satterthwaite TD, Wolf DH, Gur RC, Gur RE, Potkin SG, Mathalon DH, Mueller BA, Preda A,Macciardi F, Ehrlich S, Walton E, Hass J, Calhoun VD, Bockholt HJ, Sponheim SR, Shoemaker JM, van Haren NE, Pol HE, Ophoff RA, Kahn RS, Roiz-Santiañez R, Crespo-Facorro B, Wang L, Alpert KI, Jönsson EG, Dimitrova R, Bois C, Whalley HC, McIntosh AM, Lawrie SM, Hashimoto R, Thompson PM, Turner JA.: Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry. 2015 doi: 10.1038/mp.2015.63
Brami-Cherrier K, Anzalone A, Ramos M, Forne I, Macciardi F, Imhof A, Borrelli E.: Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits. Mol Psychiatry. 2014 doi: 10.1038/mp.2014.67
Guffanti G, Gaudi S, Fallon JH, Sobell J, Potkin SG, Pato C, Macciardi F: Transposable elements and psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet. 2014 165B(3):201-16. doi: 10.1002/ajmg.b.32225
Guella I, Sequeira A, Rollins B, Morgan L, Torri F, van Erp TG, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Bunney WE, Potkin SG, Macciardi F, Vawter MP: Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. Psychiatr Res. 2013. doi:10.1016/j.jpsychires.2013.05.021
van Erp TG, Guella I, Vawter MP, Turner J, Brown GG, McCarthy G, Greve DN, Glover GH, Calhoun VD, Lim KO, Bustillo JR, Belger A, Ford JM, Mathalon DH, Diaz M, Preda A, Nguyen D, Macciardi F, Potkin SG.: Schizophrenia miR-137 Locus Risk Genotype is Associated with Dorsolateral Prefrontal Cortex Hyperactivation. Biol Psychiatry. 2013 Aug doi: 10.1016/j.biopsych.2013.06.016
Balestrieri E, Arpino C, Matteucci C, Sorrentino R, Pica F, Alessandrelli R, Coniglio A, Curatolo P, Rezza G, Macciardi F, Garaci E, Gaudi S, Sinibaldi-Vallebona P: HERVs Expression in Autism Spectrum Disorders. PLoS One 2012;7(11):e48831. doi: 10.1371/journal.pone.0048831
Torri F., Dinov I.D., Zamanyan A., Hobel S., Genco A., Petrosyan P., Clark A.P., Liu Z., Eggert P., Pierce J., Knowles J.A., Ames J., Kesselman C., Toga A.W., Potkin S.G., Vawter M.P., Macciardi F. Next Generation Sequence Analysis and Computational Genomics Using Graphical Pipeline Workflows. Genes. 2012; 3(3):545-575
Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, Lakatos A, Miles MF, Lander A, Vawter MP, Xie XH. 2010. Identifying gene regulatory networks in schizophrenia. Neuroimage. 53:839-847. DOI: 10.1016/j.neuroimage.2010.06.036
Torri F, Akelai A, Lupoli S, Sironi M, Amann-Zalcenstein D, Fumagalli M, Ben-Asher E, Kanyas K, Cagliani R, Cozzi P, Trombetti G, Strik Lievers L, Salvi E, Orro A, Beckmann JS, Lancet D, Kohn Y, Milanesi L, Ebstein RB, Lerer B, Macciardi F. 2010. Fine Mapping of AHI1 as a Schizophrenia Susceptibility Gene: from Association to Evolutionary Evidence. FASEB Journal. 24:3066-82. DOI: 10.1096/fj.09-152611
Potkin SG, Turner JA, Guffanti G, Lakatos A, Fallon JH, Nguyen DD, Mathalon D, Ford J, Lauriello J, Macciardi F. 2009. FBIRN: A genome-wide association study of schizophrenia using brain activation as a quantitative phenotype. Schizophrenia Bulletin. 35:96-108. DOI: 10.1093/schbul/sbn155
American Society of Human Genetics (ASHG)
American Association of Physical Anthropologists (AAPA)
Director of the Department of Genetic Epidemiology and Biostatistics
Genset SA, Paris, France 2002—2005
Joanne Murphy Endowed Chair in Behavioral Neuroscience
University of Toronto, Canada 2001—2005
Associate Professor, Medical Genetics
University of Milano (Italy) 2001—2010
Center for Epigenetics and Metabolism - School of Medicine (joint with BioSci)
Center for Autism Research and Treatment (CART)