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1. Integrating structural variant calling, annotation and prioritization into whole genome analysis workflows: a practical application in the molecular diagnosis of neurodevelopmental disorders

Author

Seri, Marco, Iovino, Emanuela <1987>, Seri, Marco, and Iovino, Emanuela <1987>

Abstract

Background: WGS is increasingly used as a first-line diagnostic test for patients with rare genetic diseases such as neurodevelopmental disorders (NDD). Clinical applications require a robust infrastructure to support processing, storage and analysis of WGS data. The identification and interpretation of SVs from WGS data also needs to be improved. Finally, there is a need for a prioritization system that enables downstream clinical analysis and facilitates data interpretation. Here, we present the results of a clinical application of WGS in a cohort of patients with NDD. Methods: We developed highly portable workflows for processing WGS data, including alignment, quality control, and variant calling of SNVs and SVs. A benchmark analysis of state-of-the-art SV detection tools was performed to select the most accurate combination for SV calling. A gene-based prioritization system was also implemented to support variant interpretation. Results: Using a benchmark analysis, we selected the most accurate combination of tools to improve SV detection from WGS data and build a dedicated pipeline. Our workflows were used to process WGS data from 77 NDD patient-parent families. The prioritization system supported downstream analysis and enabled molecular diagnosis in 32% of patients, 25% of which were SVs and suggested a potential diagnosis in 20% of patients, requiring further investigation to achieve diagnostic certainty. Conclusion: Our data suggest that the integration of SNVs and SVs is a main factor that increases diagnostic yield by WGS and show that the adoption of a dedicated pipeline improves the process of variant detection and interpretation.

Published
2023

2. A machine learning based method to detect genomic imbalances exploiting X chromosome exome reads

Author

Seri, Marco, Dimartino, Paola <1992>, Seri, Marco, and Dimartino, Paola <1992>

Abstract

Whole Exome Sequencing (WES) is rapidly becoming the first-tier test in clinics, both thanks to its declining costs and the development of new platforms that help clinicians in the analysis and interpretation of SNV and InDels. However, we still know very little on how CNV detection could increase WES diagnostic yield. A plethora of exome CNV callers have been published over the years, all showing good performances towards specific CNV classes and sizes, suggesting that the combination of multiple tools is needed to obtain an overall good detection performance. Here we present TrainX, a ML-based method for calling heterozygous CNVs in WES data using EXCAVATOR2 Normalized Read Counts. We select males and females’ non pseudo-autosomal chromosome X alignments to construct our dataset and train our model, make predictions on autosomes target regions and use HMM to call CNVs. We compared TrainX against a set of CNV tools differing for the detection method (GATK4 gCNV, ExomeDepth, DECoN, CNVkit and EXCAVATOR2) and found that our algorithm outperformed them in terms of stability, as we identified both deletions and duplications with good scores (0.87 and 0.82 F1-scores respectively) and for sizes reaching the minimum resolution of 2 target regions. We also evaluated the method robustness using a set of WES and SNP array data (n=251), part of the Italian cohort of Epi25 collaborative, and were able to retrieve all clinical CNVs previously identified by the SNP array. TrainX showed good accuracy in detecting heterozygous CNVs of different sizes, making it a promising tool to use in a diagnostic setting.

Published
2022

3. Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

Author

Rossi, Salvatore, Rubegni, Anna, Riso, Vittorio, Barghigiani, Melissa, Bassi, Maria Teresa, Battini, Roberta, Bertini, Enrico, Cereda, Cristina, Cioffi, Ettore, Criscuolo, Chiara, Dal Fabbro, Beatrice, Dato, Clemente, D'Angelo, Maria Grazia, Di Muzio, Antonio, Diamanti, Luca, Dotti, Maria Teresa, Filla, Alessandro, Gioiosa, Valeria, Liguori, Rocco, Martinuzzi, Andrea, Massa, Roberto, Mignarri, Andrea, Moroni, Rossana, Musumeci, Olimpia, Nicita, Francesco, Orologio, Ilaria, Orsi, Laura, Pegoraro, Elena, Petrucci, Antonio, Plumari, Massimo, Ricca, Ivana, Rizzo, Giovanni, Romano, Silvia, Rumore, Roberto, Sampaolo, Simone, Scarlato, Marina, Seri, Marco, Stefan, Cristina, Straccia, Giulia, Tessa, Alessandra, Travaglini, Lorena, Trovato, Rosanna, Ulgheri, Lucia, Vazza, Giovanni, Orlacchio, Antonio, Silvestri, Gabriella, Santorelli, Filippo Maria, Melone, Mariarosa Anna Beatrice, Casali, Carlo, Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Rossi, Salvatore, Rubegni, Anna, Riso, Vittorio, Barghigiani, Melissa, Bassi, Maria Teresa, Battini, Roberta, Bertini, Enrico, Cereda, Cristina, Cioffi, Ettore, Criscuolo, Chiara, Dal Fabbro, Beatrice, Dato, Clemente, D'Angelo, Maria Grazia, Di Muzio, Antonio, Diamanti, Luca, Dotti, Maria Teresa, Filla, Alessandro, Gioiosa, Valeria, Liguori, Rocco, Martinuzzi, Andrea, Massa, Roberto, Mignarri, Andrea, Moroni, Rossana, Musumeci, Olimpia, Nicita, Francesco, Orologio, Ilaria, Orsi, Laura, Pegoraro, Elena, Petrucci, Antonio, Plumari, Massimo, Ricca, Ivana, Rizzo, Giovanni, Romano, Silvia, Rumore, Roberto, Sampaolo, Simone, Scarlato, Marina, Seri, Marco, Stefan, Cristina, Straccia, Giulia, Tessa, Alessandra, Travaglini, Lorena, Trovato, Rosanna, Ulgheri, Lucia, Vazza, Giovanni, Orlacchio, Antonio, Silvestri, Gabriella, Santorelli, Filippo Maria, Melone, Mariarosa Anna Beatrice, Casali, Carlo, and Silvestri, Gabriella (ORCID:0000-0002-1950-1468)

Abstract

Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1

Published
2022

4. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

Author

Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, De Giorgio, Roberto, Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, and De Giorgio, Roberto

Abstract

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized

Published
2021

5. Partial trisomy 21 map:Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21

Author

Pelleri, Maria Chiara, Cicchini, Elena, Petersen, Michael B., Tranebjærg, Lisbeth, Mattina, Teresa, Magini, Pamela, Antonaros, Francesca, Caracausi, Maria, Vitale, Lorenza, Locatelli, Chiara, Seri, Marco, Strippoli, Pierluigi, Piovesan, Allison, Cocchi, Guido, Pelleri, Maria Chiara, Cicchini, Elena, Petersen, Michael B., Tranebjærg, Lisbeth, Mattina, Teresa, Magini, Pamela, Antonaros, Francesca, Caracausi, Maria, Vitale, Lorenza, Locatelli, Chiara, Seri, Marco, Strippoli, Pierluigi, Piovesan, Allison, and Cocchi, Guido

Abstract

BACKGROUND: Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined.METHODS: Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map.RESULTS: The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found.CONCLUSIONS: The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS.

Published
2019

6. Partial trisomy 21 map:Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21

Author

Pelleri, Maria Chiara, Cicchini, Elena, Petersen, Michael B., Tranebjærg, Lisbeth, Mattina, Teresa, Magini, Pamela, Antonaros, Francesca, Caracausi, Maria, Vitale, Lorenza, Locatelli, Chiara, Seri, Marco, Strippoli, Pierluigi, Piovesan, Allison, Cocchi, Guido, Pelleri, Maria Chiara, Cicchini, Elena, Petersen, Michael B., Tranebjærg, Lisbeth, Mattina, Teresa, Magini, Pamela, Antonaros, Francesca, Caracausi, Maria, Vitale, Lorenza, Locatelli, Chiara, Seri, Marco, Strippoli, Pierluigi, Piovesan, Allison, and Cocchi, Guido

Abstract

BACKGROUND: Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined.METHODS: Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map.RESULTS: The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found.CONCLUSIONS: The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS.

Published
2019

7. Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Author

Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, Van Hasselt, Peter M., Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, and Van Hasselt, Peter M.

Published
2018

8. Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Author

Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, Van Hasselt, Peter M., Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, and Van Hasselt, Peter M.

Published
2018

9. Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Author

Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, Van Hasselt, Peter M., Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, and Van Hasselt, Peter M.

Published
2018

10. Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Author

Metabole ziekten onderzoek 1, Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cluster C, Metabole ziekten patientenzorg, Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, Van Hasselt, Peter M., Metabole ziekten onderzoek 1, Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cluster C, Metabole ziekten patientenzorg, Milev, Miroslav P., Graziano, Claudio, Karall, Daniela, Kuper, Willemijn F.E., Al-Deri, Noraldin, Cordelli, Duccio Maria, Haack, Tobias B., Danhauser, Katharina, Iuso, Arcangela, Palombo, Flavia, Pippucci, Tommaso, Prokisch, Holger, Saint-Dic, Djenann, Seri, Marco, Stanga, Daniela, Cenacchi, Giovanna, Van Gassen, Koen L.I., Zschocke, Johannes, Fauth, Christine, Mayr, Johannes A., Sacher, Michael, and Van Hasselt, Peter M.

Published
2018

11. Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Author

D'Amore, Angelica, Tessa, Alessandra, Casali, Carlo, Dotti, Maria Teresa, Filla, Alessandro, Silvestri, Gabriella, Antenora, Antonella, Astrea, Guja, Barghigiani, Melissa, Battini, Roberta, Battisti, Carla, Bruno, Irene, Cereda, Cristina, Dato, Clemente, Di Iorio, Giuseppe, Donadio, Vincenzo, Felicori, Monica, Fini, Nicola, Fiorillo, Chiara, Gallone, Salvatore, Gemignani, Federica, Gigli, Gian Luigi, Graziano, Claudio, Guerrini, Renzo, Gurrieri, Fiorella, Kariminejad, Ariana, Lieto, Maria, Marques LourenḈo, Charle, Malandrini, Alessandro, Mandich, Paola, Marcotulli, Christian, Mari, Francesco, Massacesi, Luca, Melone, Maria A B, Mignarri, Andrea, Milone, Roberta, Musumeci, Olimpia, Pegoraro, Elena, Perna, Alessia, Petrucci, Antonio, Pini, Antonella, Pochiero, Francesca, Pons, Maria Roser, Ricca, Ivana, Rossi, Salvatore, Seri, Marco, Stanzial, Franco, Tinelli, Francesca, Toscano, Antonio, Valente, Mariarosaria, Federico, Antonio, Rubegni, Anna, Santorelli, Filippo Maria, Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Gurrieri, Fiorella (ORCID:0000-0002-6775-5972), D'Amore, Angelica, Tessa, Alessandra, Casali, Carlo, Dotti, Maria Teresa, Filla, Alessandro, Silvestri, Gabriella, Antenora, Antonella, Astrea, Guja, Barghigiani, Melissa, Battini, Roberta, Battisti, Carla, Bruno, Irene, Cereda, Cristina, Dato, Clemente, Di Iorio, Giuseppe, Donadio, Vincenzo, Felicori, Monica, Fini, Nicola, Fiorillo, Chiara, Gallone, Salvatore, Gemignani, Federica, Gigli, Gian Luigi, Graziano, Claudio, Guerrini, Renzo, Gurrieri, Fiorella, Kariminejad, Ariana, Lieto, Maria, Marques LourenḈo, Charle, Malandrini, Alessandro, Mandich, Paola, Marcotulli, Christian, Mari, Francesco, Massacesi, Luca, Melone, Maria A B, Mignarri, Andrea, Milone, Roberta, Musumeci, Olimpia, Pegoraro, Elena, Perna, Alessia, Petrucci, Antonio, Pini, Antonella, Pochiero, Francesca, Pons, Maria Roser, Ricca, Ivana, Rossi, Salvatore, Seri, Marco, Stanzial, Franco, Tinelli, Francesca, Toscano, Antonio, Valente, Mariarosaria, Federico, Antonio, Rubegni, Anna, Santorelli, Filippo Maria, Silvestri, Gabriella (ORCID:0000-0002-1950-1468), and Gurrieri, Fiorella (ORCID:0000-0002-6775-5972)

Abstract

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy

Published
2018

12. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

Author

Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Rubio, Vicente [0000-0001-8124-1196], Escamilla-Honrubia, Juan Manuel [0000-0003-0154-6569], Panza, Emanuele, Escamilla-Honrubia, Juan Manuel, Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Brescia Morra, Vincenzo, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Nemeth, Andrea H, Smithson, Sarah, Davies, Sally, Hurst, Jane A, Bordo, Domenico, Rubio, Vicente, Seri, Marco, Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Rubio, Vicente [0000-0001-8124-1196], Escamilla-Honrubia, Juan Manuel [0000-0003-0154-6569], Panza, Emanuele, Escamilla-Honrubia, Juan Manuel, Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Brescia Morra, Vincenzo, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Nemeth, Andrea H, Smithson, Sarah, Davies, Sally, Hurst, Jane A, Bordo, Domenico, Rubio, Vicente, and Seri, Marco

Published
2016

13. MYH9-related disease: A novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations

Author

UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de malformations vasculaires congénitales, Pecci, Alessandro, Klersy, Catherine, Gresele, Paolo, Lee, Kieran J.D., De Rocco, Daniela, Bozzi, Valeria, Russo, Giovanna, Heller, Paula G., Loffredo, Giuseppe, Ballmaier, Matthias, Fabris, Fabrizio, Beggiato, Eloise, Kahr, Walter H.A., Pujol-Moix, Nuria, Platokouki, Helen, Van Geet, Christel, Noris, Patrizia, Yerram, Preethi, Hermans, Cédric, Gerber, Bernhard, Economou, Marina, De Groot, Marco, Zieger, Barbara, De Candia, Erica, Fraticelli, Vincenzo, Kersseboom, Rogier, Piccoli, Giorgina B., Zimmermann, Stefanie, Fierro, Tiziana, Glembotsky, Ana C., Vianello, Fabrizio, Zaninetti, Carlo, Nicchia, Elena, Güthner, Christiane, Baronci, Carlo, Seri, Marco, Knight, Peter J., Balduini, Carlo L., Savoia, Anna, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de malformations vasculaires congénitales, Pecci, Alessandro, Klersy, Catherine, Gresele, Paolo, Lee, Kieran J.D., De Rocco, Daniela, Bozzi, Valeria, Russo, Giovanna, Heller, Paula G., Loffredo, Giuseppe, Ballmaier, Matthias, Fabris, Fabrizio, Beggiato, Eloise, Kahr, Walter H.A., Pujol-Moix, Nuria, Platokouki, Helen, Van Geet, Christel, Noris, Patrizia, Yerram, Preethi, Hermans, Cédric, Gerber, Bernhard, Economou, Marina, De Groot, Marco, Zieger, Barbara, De Candia, Erica, Fraticelli, Vincenzo, Kersseboom, Rogier, Piccoli, Giorgina B., Zimmermann, Stefanie, Fierro, Tiziana, Glembotsky, Ana C., Vianello, Fabrizio, Zaninetti, Carlo, Nicchia, Elena, Güthner, Christiane, Baronci, Carlo, Seri, Marco, Knight, Peter J., Balduini, Carlo L., and Savoia, Anna

Abstract

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD. © 2013 WILEY PERIODICALS, INC.

Published
2014

14. Identifying Gene-Environment Interactions in Schizophrenia: Contemporary Challenges for Integrated, Large-scale Investigations

Author

van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, Mirjanic, Tijana, van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, and Mirjanic, Tijana

Abstract

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

Published
2014

15. Identifying Gene-Environment Interactions in Schizophrenia: Contemporary Challenges for Integrated, Large-scale Investigations

Author

van Os, Jim, van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, Mirjanic, Tijana, van Os, Jim, van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, and Mirjanic, Tijana

Abstract

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

Published
2014

16. Identifying Gene-Environment Interactions in Schizophrenia: Contemporary Challenges for Integrated, Large-scale Investigations

Author

van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, Mirjanic, Tijana, van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, and Mirjanic, Tijana

Abstract

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

Published
2014

17. Identifying Gene-Environment Interactions in Schizophrenia: Contemporary Challenges for Integrated, Large-scale Investigations

Author

van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, Mirjanic, Tijana, van Os, Jim, Rutten, Bart P., Myin-Germeys, Inez, Delespaul, Philippe, Viechtbauer, Wolfgang, van Zelst, Catherine, Bruggeman, Richard, Reininghaus, Ulrich, Morgan, Craig, Murray, Robin M., Di Forti, Marta, McGuire, Philip, Valmaggia, Lucia R., Kempton, Matthew J., Gayer-Anderson, Charlotte, Hubbard, Kathryn, Beards, Stephanie, Stilo, Simona A., Onyejiaka, Adanna, Bourque, Francois, Modinos, Gemma, Tognin, Stefania, Calem, Maria, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Williams, Nigel, Craddock, Nicholas, Richards, Alexander, Humphreys, Isla, Meyer-Lindenberg, Andreas, Leweke, F. Markus, Tost, Heike, Akdeniz, Ceren, Rohleder, Cathrin, Bumb, J. Malte, Schwarz, Emanuel, Alptekin, Koksal, Ucok, Alp, Saka, Meram Can, Atbasoglu, E. Cem, Guloksuz, Sinan, Gumus-Akay, Guvem, Cihan, Burin, Karadag, Hasan, Soygur, Haldan, Cankurtaran, Eylem Sahin, Ulusoy, Semra, Akdede, Berna, Binbay, Tolga, Ayer, Ahmet, Noyan, Handan, Karadayi, Gulsah, Akturan, Elin, Ulas, Halis, Arango, Celso, Parellada, Mara, Bernardo, Miguel, Sanjuan, Julio, Bobes, Julio, Arrojo, Manuel, Luis Santos, Jose, Cuadrado, Pedro, Rodriguez Solano, Jose Juan, Carracedo, Angel, Garcia Bernardo, Enrique, Roldan, Laura, Lopez, Gonzalo, Cabrera, Bibiana, Cruz, Sabrina, Diaz Mesa, Eva Ma, Pouso, Maria, Jimenez, Estela, Sanchez, Teresa, Rapado, Marta, Gonzalez, Emiliano, Martinez, Covadonga, Sanchez, Emilio, Soledad Olmeda, Ma, de Haan, Lieuwe, Velthorst, Eva, van der Gaag, Mark, Selten, Jean-Paul, van Dam, Daniella, van der Ven, Elsje, van der Meer, Floor, Messchaert, Elles, Kraan, Tamar, Burger, Nadine, Leboyer, Marion, Szoke, Andrei, Schurhoff, Franck, Llorca, Pierre-Michel, Jamain, Stephane, Tortelli, Andrea, Frijda, Flora, Vilain, Jeanne, Galliot, Anne-Marie, Baudin, Gregoire, Ferchiou, Aziz, Richard, Jean-Romain, Bulzacka, Ewa, Charpeaud, Thomas, Tronche, Anne-Marie, De Hert, Marc, van Winkel, Ruud, Decoster, Jeroen, Derom, Catherine, Thiery, Evert, Stefanis, Nikos C., Sachs, Gabriele, Aschauer, Harald, Lasser, Iris, Winklbaur, Bernadette, Schlogelhofer, Monika, Riecher-Rossler, Anita, Borgwardt, Stefan, Walter, Anna, Harrisberger, Fabienne, Smieskova, Renata, Rapp, Charlotte, Ittig, Sarah, Soguel-Dit-Piquard, Fabienne, Studerus, Erich, Klosterkotter, Joachim, Ruhrmann, Stephan, Paruch, Julia, Julkowski, Dominika, Hilboll, Desiree, Sham, Pak C., Cherny, Stacey S., Chen, Eric Y. H., Campbell, Desmond D., Li, Miaoxin, Maria Romeo-Casabona, Carlos, Emaldi Cirion, Aitziber, Urruela Mora, Asier, Jones, Peter, Kirkbride, James, Cannon, Mary, Rujescu, Dan, Tarricone, Ilaria, Berardi, Domenico, Bonora, Elena, Seri, Marco, Marcacci, Thomas, Chiri, Luigi, Chierzi, Federico, Storbini, Viviana, Braca, Mauro, Minenna, Maria Gabriella, Donegani, Ivonne, Fioritti, Angelo, La Barbera, Daniele, La Cascia, Caterina Erika, Mule, Alice, Sideli, Lucia, Sartorio, Rachele, Ferraro, Laura, Tripoli, Giada, Seminerio, Fabio, Marinaro, Anna Maria, McGorry, Patrick, Nelson, Barnaby, Amminger, G. Paul, Pantelis, Christos, Menezes, Paulo R., Del-Ben, Cristina M., Tenan, Silvia H. Gallo, Shuhama, Rosana, Ruggeri, Mirella, Tosato, Sarah, Lasalvia, Antonio, Bonetto, Chiara, Ira, Elisa, Nordentoft, Merete, Krebs, Marie-Odile, Barrantes-Vidal, Neus, Cristobal, Paula, Kwapil, Thomas R., Brietzke, Elisa, Bressan, Rodrigo A., Gadelha, Ary, Maric, Nadja P., Andric, Sanja, Mihaljevic, Marina, and Mirjanic, Tijana

Abstract

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

Published
2014

18. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.

Author

Pecci, Alessandro, Panza, Emanuele, Pujol-Moix, Núria, Klersy, Catherine, Di Bari, Filomena, Bozzi, Valeria, Gresele, Paolo, Lethagen, Stefan, Fabris, Fabrizio, Dufour, Carlo, Granata, Antonio, Doubek, Michael, Pecoraro, Carmine, Koivisto, Pasi A, Heller, Paula G, Iolascon, Achille, Alvisi, Patrizia, Schwabe, Dirk, De Candia, Erica, Rocca, Bianca, Russo, Umberto, Ramenghi, Ugo, Noris, Patrizia, Seri, Marco, Balduini, Carlo L, Savoia, Anna, Pecci, Alessandro, Panza, Emanuele, Pujol-Moix, Núria, Klersy, Catherine, Di Bari, Filomena, Bozzi, Valeria, Gresele, Paolo, Lethagen, Stefan, Fabris, Fabrizio, Dufour, Carlo, Granata, Antonio, Doubek, Michael, Pecoraro, Carmine, Koivisto, Pasi A, Heller, Paula G, Iolascon, Achille, Alvisi, Patrizia, Schwabe, Dirk, De Candia, Erica, Rocca, Bianca, Russo, Umberto, Ramenghi, Ugo, Noris, Patrizia, Seri, Marco, Balduini, Carlo L, and Savoia, Anna

Published
2008

19. Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

Author

Savoia, Anna, Dufour, Carlo, Locatelli, Franco, Noris, Patrizia, Ambaglio, Chiara, Rosti, Vittorio, Zecca, Marco, Ferrari, Simona, di Bari, Filomena, Corcione, Anna, Di Stazio, Mariateresa, Seri, Marco, Balduini, Carlo L, Locatelli, Franco (ORCID:0000-0002-7976-3654), Ferrari, Simona (ORCID:0000-0003-3736-1320), Savoia, Anna, Dufour, Carlo, Locatelli, Franco, Noris, Patrizia, Ambaglio, Chiara, Rosti, Vittorio, Zecca, Marco, Ferrari, Simona, di Bari, Filomena, Corcione, Anna, Di Stazio, Mariateresa, Seri, Marco, Balduini, Carlo L, Locatelli, Franco (ORCID:0000-0002-7976-3654), and Ferrari, Simona (ORCID:0000-0003-3736-1320)

Abstract

Background and ObjectivesCongenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients.Design and MethodsWe diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences.ResultsIn all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-alpha and interferon-gamma was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course.Interpretation and ConclusionsThese results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.

Published
2007

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