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Identification of Gene Ontologies Linked to Prefrontal–Hippocampal Retraction and Correction RETRACTION CORRECTION SYSTEMS BIOLOGY CELL BIOLOGY Retraction for “Identification of gene ontologies linked to pre- Correction for “STAT1-induced ASPP2 transcription identifies a frontal–hippocampal functional coupling in the human brain,” by link between neuroinflammation, cell polarity, and tumor sup- Luanna Dixson, Henrik Walter, Michael Schneider, Susanne Erk, pression,” by Casmir Turnquist, Yihua Wang, David T. Severson, Axel Schäfer, Leila Haddad, Oliver Grimm, Manuel Mattheisen, Shan Zhong, Bin Sun, Jingyi Ma, Stefan N. Constaninescu, Olaf Markus M. Nöthen, Sven Cichon, Stephanie H. Witt, Marcella Ansorge, Helen B. Stolp, Zoltán Molnár, Francis G. Szele, and Rietschel, Sebastian Mohnke, Nina Seiferth, Andreas Heinz, Heike Xin Lu, which appeared in issue 27, July 8, 2014, of Proc Natl Tost, and Andreas Meyer-Lindenberg, which appeared in issue 26, Acad Sci USA (111:9834–9839; first published June 23, 2014; July 1, 2014, of Proc Natl Acad Sci USA (111:9657–9662; first 10.1073/pnas.1407898111). published June 16, 2014; 10.1073/pnas.1404082111). The authors note that the author name Constaninescu should The authors wish to note the following: “In this paper we re- instead appear as Constantinescu. The corrected author line ap- port an association of the ‘synapse organization and biogenesis’ pears below. The online version has been corrected. gene set with a neuroimaging phenotype, using gene set en- richment methodology. The methods and results of the paper, as Casmir Turnquist, Yihua Wang, David T. Severson, described, have been conducted after consultation with experts Shan Zhong, Bin Sun, Jingyi Ma, Stefan N. Constantinescu, in the field and support this conclusion. However, a potential Olaf Ansorge, Helen B. Stolp, Zoltán Molnár, confound relating to statistical inference has been brought to our Francis G. Szele, and Xin Lu attention that arises from the fact that several clustered genes, all of which are included in this gene set, have been tagged by the www.pnas.org/cgi/doi/10.1073/pnas.1415682111 same SNP. This problem, which concerns only a small fraction of our tested gene sets (unfortunately including our top finding), belongs to a known category of potential pitfalls in gene set association analyses, and we are sorry that this problem was not detected earlier. Our reanalyses suggest that if adjustments for this confound are applied, the results for our top finding no longer reach experiment-wide significance. Therefore, we feel that the presented findings are not currently sufficiently robust to provide definitive support for the conclusions of our paper, and that an extensive reanalysis of the data is required. The authors have therefore unanimously decided to retract this paper at this time.” Luanna Dixson Henrik Walter Michael Schneider Susanne Erk Axel Schäfer Leila Haddad Oliver Grimm Manuel Mattheisen Markus M. Nöthen Sven Cichon Stephanie H. Witt Marcella Rietschel Sebastian Mohnke Nina Seiferth Andreas Heinz Heike Tost Andreas Meyer-Lindenberg www.pnas.org/cgi/doi/10.1073/pnas.1414905111 13582 | PNAS | September 16, 2014 | vol. 111 | no. 37 www.pnas.org Downloaded by guest on September 30, 2021 Identification of gene ontologies linked to prefrontal– hippocampal functional coupling in the human brain Luanna Dixsona,1, Henrik Walterb,1, Michael Schneidera, Susanne Erkb, Axel Schäfera, Leila Haddada, Oliver Grimma, Manuel Mattheisenc,d,e, Markus M. Nöthenc,d,e, Sven Cichonc,d, Stephanie H. Wittf, Marcella Rietschelf, Sebastian Mohnkeb, Nina Seiferthb, Andreas Heinzb, Heike Tosta,1, and Andreas Meyer-Lindenberga,1,2 Departments of aPsychiatry and Psychotherapy and fGenetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany; bDepartment of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany; cDepartment of Genomics, Life and Brain Center, dInstitute of Human Genetics, and eInstitute for Genomic Mathematics, University of Bonn, 53127 Bonn, Germany Edited by Robert Desimone, Massachusetts Institute of Technology, Cambridge, MA, and approved May 16, 2014 (received for review March 5, 2014) Functional interactions between the dorsolateral prefrontal cor- Previous studies have characterized abnormal prefrontal– tex and hippocampus during working memory have been stud- hippocampal interactions in subjects with genetic risk factors for ied extensively as an intermediate phenotype for schizophrenia. schizophrenia (4, 9, 10, 16). In particular, genome-wide associ- Coupling abnormalities have been found in patients, their un- ation studies (GWAS) have become a standard approach for affected siblings, and carriers of common genetic variants associ- identifying common variants that may contribute to risk pheno- ated with schizophrenia, but the global genetic architecture of this types in structural and functional neuroimaging data (10, 16, 17). imaging phenotype is unclear. To achieve genome-wide hypothesis- However, although this approach has been effective in identify- free identification of genes and pathways associated with pre- ing genetic risk variants for imaging phenotypes, post hoc in- frontal–hippocampal interactions, we combined gene set enrich- terpretation of results is challenging. Detected risk variants often ment analysis with whole-genome genotyping and functional fall within intronic sequences, where a lack of prior knowledge magnetic resonance imaging data from 269 healthy German volun- on functionality hinders a mechanistic explanation of how they teers. We found significant enrichment of the synapse organization impact brain function (18). and biogenesis gene set. This gene set included known schizophre- Increasing evidence suggests that common genetic risk variants NRCAM for psychiatric disorders are not distributed randomly but rather SYSTEMS BIOLOGY nia risk genes, such as neural cell adhesion molecule ( )and – calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as lie among sets of genes with overlapping functions (19 22). Gene well as genes with well-defined roles in neurodevelopmental and set enrichment analysis (GSEA) is a data analytical approach that plasticity processes that are dysfunctional in schizophrenia and have leverages a priori knowledge to gain insight into the biological functions of genes and pathways in the analysis of genetic data (23, mechanistic links to prefrontal–hippocampal functional interactions. 24). This approach relies on analysis of sets of genes grouped by Our results demonstrate a readily generalizable approach that can common biological characteristics, such as a shared role in par- be used to identify the neurogenetic basis of systems-level pheno- ticular molecular functions or metabolic pathways. GSEA can then types. Moreover, our findings identify gene sets in which genetic be used to test whether genes that are more strongly associated with variation may contribute to disease risk through altered prefrontal– hippocampal functional interactions and suggest a link to both on- going and developmental synaptic plasticity. Significance functional connectivity | GSEA | endophenotype | genetic risk variants This study combines neuroimaging and whole-genome geno- typing techniques with a gene set enrichment analysis to unravel the genetic basis of a well-validated intermediate maging genetics is widely used to identify neural circuits linked phenotype for schizophrenia, dorsolateral prefrontal cortex– to genetic risk for heritable neuropsychiatric disorders, such as I hippocampal connectivity. We found significant enrichment of schizophrenia, autism, or bipolar disorder (1). A well-established genes with roles in synaptic plasticity and neurodevelopment imaging genetics phenotype is functional connectivity between the that are consistent with the neurobiological basis of pre- right dorsolateral prefrontal cortex (DLPFC) and the left hippo- – – frontal hippocampal interactions in schizophrenia. We further campus (HC) during working memory (WM) performance (2 4). provide additional independent evidence for the intermediate Specifically, impaired interaction of the HC and prefrontal cortex phenotype concept and present a readily generalizable ap- (PFC) has been proposed as a core abnormality during neuro- proach for a biologically driven analysis of imaging and development in schizophrenia. The hippocampus provides input to genetic data. the DLPFC through long-range glutamatergic connections, which have been linked to the glutamate hypothesis of the illness. Author contributions: L.D., H.W., M.S., M.M.N., M.R., A.H., H.T., and A.M.-L. designed Moreover, selective lesions of the hippocampus in primates and research; L.D., H.W., M.S., S.E., A.S., L.H., O.G., M.M., M.M.N., S.C., S.H.W., M.R., S.M., rodents have been shown to result in postpubescent changes in N.S., A.H., H.T., and A.M.-L. performed research; L.D., H.W., M.S., M.M., S.C., S.H.W., H.T., and A.M.-L. analyzed data; and L.D., M.S., H.T., and A.M.-L. wrote the paper. prefrontal regions that are consistent with neuropathological find- Conflict of interest statement: A.M.-L. has received consultant fees and travel expenses ings in schizophrenic patients (5, 6). Brain physiology during WM from Alexza Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Defined Health, Deci- performance is highly heritable (7), and anomalies of prefrontal– sion Resources, Desitin Arzneimittel, Elsevier, F. Hoffmann–La Roche, Gerson Lehrman hippocampal functional
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