{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T23:46:02Z","timestamp":1762299962302,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RC 35\/17 \"Identification of genetic and environmental factors for complex traits in isolated populations\" Burlo Garofolo","RC 01\/21  Burlo Garofolo"],"award-info":[{"award-number":["RC 35\/17 \"Identification of genetic and environmental factors for complex traits in isolated populations\" Burlo Garofolo","RC 01\/21  Burlo Garofolo"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Human personality (i.e., temperament and character) is a complex trait related to mental health, influenced by genetic and environmental factors. Despite the efforts performed during the past decades, its genetic background is only just beginning to be identified. With the aim of dissecting the genetic basis of temperament, we performed a Genome-Wide Association Study (GWAS) on Cloninger\u2019s Temperament and Character Inventory in 587 individuals belonging to different Italian genetic isolates. Data analysis led to the identification of four new genes associated with different temperament scales, such as Novelty Seeking (NS), Harm Avoidance (HA), and Reward Dependence (RD). In detail, we identified suggestive and significant associations between: MAGI2 (highest p-value = 9.14 \u00d7 10\u22128), a gene already associated with schizophrenia and depressive disorder, and the NS\u2013Extravagance scale; CALCB (highest p-value = 4.34 \u00d7 10\u22126), a gene likely involved in the behavioral evolution from wild wolf to domestic dog, and the NS\u2013Disorderliness scale; BTBD3 (highest p-value = 2.152 \u00d7 10\u22128), a gene already linked to obsessive\u2013compulsive disorder, and the HA\u2013Fatigability scale; PRKN (highest p-value = 8.27 \u00d7 10\u22129), a gene described for early onset Parkinson\u2019s disease, and the RD scale. Our work provides new relevant insights into the genetics of temperament, helping to elucidate the molecular basis of psychiatric disorders.<\/jats:p>","DOI":"10.3390\/genes13010004","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T09:50:43Z","timestamp":1640080243000},"page":"4","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genetic Dissection of Temperament Personality Traits in Italian Isolates"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3598-2537","authenticated-orcid":false,"given":"Maria Pina","family":"Concas","sequence":"first","affiliation":[{"name":"Institute for Maternal and Child Health-IRCCS \u201cBurlo Garofolo\u201d, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9463-7808","authenticated-orcid":false,"given":"Alessandra","family":"Minelli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"},{"name":"Genetics Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Aere","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6290-445X","authenticated-orcid":false,"given":"Anna","family":"Morgan","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health-IRCCS \u201cBurlo Garofolo\u201d, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-6422","authenticated-orcid":false,"given":"Paola","family":"Tesolin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health-IRCCS \u201cBurlo Garofolo\u201d, 34127 Trieste, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Gennarelli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"},{"name":"Genetics Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-6589","authenticated-orcid":false,"given":"Giorgia","family":"Girotto","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health-IRCCS \u201cBurlo Garofolo\u201d, 34127 Trieste, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41398-019-0621-4","article-title":"The complex genetics and biology of human temperament: A review of traditional concepts in relation to new molecular findings","volume":"9","author":"Cloninger","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1038\/s41380-018-0264-5","article-title":"Uncovering the complex genetics of human temperament","volume":"25","author":"Zwir","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1038\/s41380-018-0263-6","article-title":"Uncovering the complex genetics of human character","volume":"25","author":"Zwir","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nrg2554","article-title":"Human genetic variation and its contribution to complex traits","volume":"10","author":"Frazer","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1001\/archpsyc.1993.01820240059008","article-title":"A Psychobiological Model of Temperament and Character","volume":"50","author":"Cloninger","year":"1993","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.conctc.2018.09.002","article-title":"Temperament and character in men with autism spectrum disorder: A reanalysis of scores on the Temperament and Character Inventory by individual case matching","volume":"12","author":"Vuijk","year":"2018","journal-title":"Contemp. Clin. Trials Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1080\/08039480801959224","article-title":"Temperament profiles in personality disorders among a young adult population","volume":"62","author":"Miettunen","year":"2008","journal-title":"Nord. J. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.neulet.2018.06.040","article-title":"Temperament traits and executive functions in Parkinson\u2019s disease","volume":"684","author":"Luca","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1176\/ajp.2006.163.5.857","article-title":"A Population-Based Twin Study of the Relationship Between Neuroticism and Internalizing Disorders","volume":"163","author":"Hettema","year":"2006","journal-title":"Am. J. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/ejhg.2012.229","article-title":"Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversity","volume":"21","author":"Esko","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15927","DOI":"10.1038\/ncomms15927","article-title":"Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations","volume":"8","author":"Xue","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41431-019-0551-x","article-title":"A bird\u2019s-eye view of Italian genomic variation through whole-genome sequencing","volume":"28","author":"Cocca","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Howie, B.N., Donnelly, P., and Marchini, J. (2009). A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000529"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Belonogova, N.M., Svishcheva, G.R., Van Duijn, C.M., Aulchenko, Y.S., and Axenovich, T.I. (2013). Region-Based Association Analysis of Human Quantitative Traits in Related Individuals. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065395"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1093\/bioinformatics\/btm108","article-title":"GenABEL: An R library for genome-wide association analysis","volume":"23","author":"Aulchenko","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.psychres.2007.05.003","article-title":"Inter-correlations between Cloninger\u2019s temperament dimensions\u2014A meta-analysis","volume":"160","author":"Miettunen","year":"2008","journal-title":"Psychiatry Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.neuroimage.2018.08.038","article-title":"Connectome-based individualized prediction of temperament trait scores","volume":"183","author":"Jiang","year":"2018","journal-title":"NeuroImage"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"The GTEx Consortium, Ardlie, K.G., DeLuca, D.S., Segre, A.V., Sullivan, T.J., Young, T.R., Gelfand, E.T., Trowbridge, C.A., Maller, J.B., and Tukiainen, T. (2015). The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science, 348, 648\u2013660.","DOI":"10.1126\/science.1262110"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1093\/bioinformatics\/btv722","article-title":"Fast and efficient QTL mapper for thousands of molecular phenotypes","volume":"32","author":"Ongen","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"Storey","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","first-page":"1","article-title":"Aberrant expression of S-SCAM causes the loss of GABAergic synapses in hippocampal neurons","volume":"10","author":"Shin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s11682-013-9262-z","article-title":"Genetic Analysis of Quantitative Phenotypes in AD and MCI: Imaging, Cognition and Biomarkers","volume":"8","author":"Shen","year":"2014","journal-title":"Brain Imaging Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4941","DOI":"10.1007\/s12035-020-02058-2","article-title":"Identifying Blood Transcriptome Biomarkers of Alzheimer\u2019s Disease Using Transgenic Mice","volume":"57","author":"Ochi","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Koide, T., Banno, M., Aleksic, B., Yamashita, S., Kikuchi, T., Kohmura, K., Adachi, Y., Kawano, N., Kushima, I., and Nakamura, Y. (2012). Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients. PLoS ONE, 7.","DOI":"10.1371\/annotation\/47ca9c23-9fdd-47f6-9d36-db0a31769f22"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1097\/GIM.0b013e3182217a06","article-title":"Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems","volume":"13","author":"Sahoo","year":"2011","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.molbrainres.2004.05.003","article-title":"From wild wolf to domestic dog: Gene expression changes in the brain","volume":"126","author":"Saetre","year":"2004","journal-title":"Mol. Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/0304-3940(94)90782-X","article-title":"Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder","volume":"182","author":"Theodorsson","year":"1994","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1126\/science.1244505","article-title":"BTBD3 Controls Dendrite Orientation Toward Active Axons in Mammalian Neocortex","volume":"342","author":"Matsui","year":"2013","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/mp.2012.85","article-title":"Genome-wide association study of obsessive-compulsive disorder","volume":"18","author":"Stewart","year":"2013","journal-title":"Mol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13041-021-00771-0","article-title":"Establishment of an in vitro model for analyzing mitochondrial ultrastructure in PRKN-mutated patient iPSC-derived dopaminergic neurons","volume":"14","author":"Yokota","year":"2021","journal-title":"Mol. Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.parkreldis.2021.03.026","article-title":"Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe","volume":"86","author":"Milanowski","year":"2021","journal-title":"Park. Relat. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1093\/hmg\/ddaa273","article-title":"Assessing the relationship between monoallelic PRKN mutations and Parkinson\u2019s risk","volume":"30","author":"Lubbe","year":"2021","journal-title":"Hum. Mol. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/4\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:50:33Z","timestamp":1760169033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010004"],"URL":"https:\/\/doi.org\/10.3390\/genes13010004","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,12,21]]}}}