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1. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author: Jil D. Stegmann, Jeshurun C. Kalanithy, Gabriel C. Dworschak, Nina Ishorst, Enrico Mingardo, Filipa M. Lopes, Yee Mang Ho, Phillip Grote, Tobias T. Lindenberg, Öznur Yilmaz, Khadija Channab, Steve Seltzsam, Shirlee Shril, Friedhelm Hildebrandt, Felix Boschann, André Heinen, Angad Jolly, Katherine Myers, Kim McBride, Mir Reza Bekheirnia, Nasim Bekheirnia, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Annalaura Torella, TUDP consortium, Michele Pinelli, Valeria Capra, Andrea Accogli, Silvia Maitz, Alice Spano, Rory J. Olson, Eric W. Klee, Brendan C. Lanpher, Se Song Jang, Jong-Hee Chae, Philipp Steinbauer, Dietmar Rieder, Andreas R. Janecke, Julia Vodopiutz, Ida Vogel, Jenny Blechingberg, Jennifer L. Cohen, Kacie Riley, Victoria Klee, Laurence E. Walsh, Matthias Begemann, Miriam Elbracht, Thomas Eggermann, Arzu Stoppe, Kyra Stuurman, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Maureen S. Mulhern, Tristan T. Sands, Cheryl Cytrynbaum, Rosanna Weksberg, Federica Isidori, Tommaso Pippucci, Giulia Severi, Francesca Montanari, Michael C. Kruer, Somayeh Bakhtiari, Hossein Darvish, Heiko Reutter, Gregor Hagelueken, Matthias Geyer, Adrian S. Woolf, Jennifer E. Posey, James R. Lupski, Benjamin Odermatt, and Alina C. Hilger
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.
Published: 2024
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2. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author: Trubetskoy, Vassily, Pardiñas, Antonio F, Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B, Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A, Hall, Lynsey S, Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C, Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G, Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z, Alptekin, Köksal, Als, Thomas D, Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A, Bass, Nicholas J, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Benyamin, Beben, Bergen, Sarah E, Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J, Bruggeman, Richard, Buckley, Peter F, Buckner, Randy L, Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J, Calkins, Monica E, Carr, Vaughan J, Castle, David, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, Chaumette, Boris, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L, de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E, Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G, Fañanás, Lourdes, Faraone, Stephen V, Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B, Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, and Gershon, Elliot S
Subjects: Brain Disorders, Human Genome, Mental Health, Schizophrenia, Serious Mental Illness, Biotechnology, Neurosciences, Genetics, Aetiology, 2.1 Biological and endogenous factors, Alleles, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract: Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
Published: 2022

3. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Author: Blokland, Gabriëlla AM, Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Schizophrenia Working Group of the Psychiatric Genomics Consortium, St Clair, David, Lencz, Todd, Mowry, Bryan J, Periyasamy, Sathish, Cairns, Murray J, Tooney, Paul A, Wu, Jing Qin, Kelly, Brian, Kirov, George, Sullivan, Patrick F, Corvin, Aiden, Riley, Brien P, Esko, Tõnu, Milani, Lili, Jönsson, Erik G, Palotie, Aarno, Ehrenreich, Hannelore, Begemann, Martin, Steixner-Kumar, Agnes, Sham, Pak C, Iwata, Nakao, Weinberger, Daniel R, Gejman, Pablo V, Sanders, Alan R, Buxbaum, Joseph D, Rujescu, Dan, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Bramon, Elvira, Murray, Robin M, Pato, Michele T, Lee, Jimmy, Melle, Ingrid, Molden, Espen, Ophoff, Roel A, McQuillin, Andrew, Bass, Nicholas J, Adolfsson, Rolf, Malhotra, Anil K, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Martin, Nicholas G, Fullerton, Janice M, Mitchell, Philip B, Schofield, Peter R, Forstner, Andreas J, Degenhardt, Franziska, Schaupp, Sabrina, Comes, Ashley L, Kogevinas, Manolis, Guzman-Parra, José, Reif, Andreas, Streit, Fabian, Sirignano, Lea, Cichon, Sven, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Lissowska, Jolanta, Mayoral, Fermin, Müller-Myhsok, Bertram, Świątkowska, Beata, Schulze, Thomas G, Nöthen, Markus M, Rietschel, Marcella, Kelsoe, John, Leboyer, Marion, Jamain, Stéphane, Etain, Bruno, Bellivier, Frank, Vincent, John B, Alda, Martin, O'Donovan, Claire, Cervantes, Pablo, Biernacka, Joanna M, Frye, Mark, McElroy, Susan L, Scott, Laura J, Stahl, Eli A, Landén, Mikael, Hamshere, Marian L, Smeland, Olav B, Djurovic, Srdjan, Vaaler, Arne E, Andreassen, Ole A, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Baune, Bernhard T, Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F, Weissman, Myrna M, Potash, James B, and Shi, Jianxin
Subjects: Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Endothelial Cells, Humans, Genetic Predisposition to Disease, Receptors, Vascular Endothelial Growth Factor, Sulfurtransferases, Bipolar Disorder, Depressive Disorder, Major, Psychotic Disorders, Schizophrenia, Sex Characteristics, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Sex differences, Serious Mental Illness, Biotechnology, Mental Health, Genetics, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.ResultsAcross disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022

4. Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Author: Larissa Bilo, Eguzkine Ochoa, Sunwoo Lee, Daniela Dey, Ingo Kurth, Florian Kraft, Fay Rodger, France Docquier, Ana Toribio, Leonardo Bottolo, Gerhard Binder, György Fekete, Miriam Elbracht, Eamonn R. Maher, Matthias Begemann, and Thomas Eggermann
Subjects: Beckwith–Wiedemann syndrome, Silver–Russell syndrome, Multilocus imprinting disturbances, Maternal effect variants, ImprintSeq, MS-MLPA, Medicine, Genetics, QH426-470
Abstract: Abstract Background Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking. Results Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype–phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues. Conclusions Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.
Published: 2023
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5. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author: Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Ripke, Stephan, Neale, Benjamin M, Walters, James TR, Farh, Kai‐How, Holmans, Peter A, Lee, Phil, Bulik‐Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, and Chan, Ronald YL
Subjects: Biological Sciences, Genetics, Clinical Research, Schizophrenia, Brain Disorders, Human Genome, Prevention, Serious Mental Illness, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Chromosome Mapping, DNA Copy Number Variations, Databases, Genetic, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Sequence Analysis, DNA, Exome Sequencing, GWAS, IBD mapping, rare variants, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinical Sciences, Neurosciences, Clinical sciences
Abstract: Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
Published: 2019

6. The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies

Author: Anna Grether, Ivan Ivanovski, Martina Russo, Anaïs Begemann, Katharina Steindl, Lucia Abela, Michael Papik, Markus Zweier, Beatrice Oneda, Pascal Joset, and Anita Rauch
Subjects: diagnostic yield, epileptic encephalopathy, whole exome sequencing, whole genome sequencing, Genetics, QH426-470
Abstract: Abstract Background As the technology of next generation sequencing rapidly develops and costs are constantly reduced, the clinical availability of whole genome sequencing (WGS) increases. Thereby, it remains unclear what exact advantage WGS offers in comparison to whole exome sequencing (WES) for the diagnosis of genetic diseases using current technologies. Methods Trio‐WGS was conducted for 20 patients with developmental or epileptic encephalopathies who remained undiagnosed after WES and chromosomal microarray analysis. Results A diagnosis was reached for four patients (20%). However, retrospectively all pathogenic variants could have been detected in a WES analysis conducted with today's methods and knowledge. Conclusion The additional diagnostic yield of WGS versus WES is currently largely explained by new scientific insights and the general technological progress. Nevertheless, it is noteworthy that whole genome sequencing has greater potential for the analysis of small copy number and copy number neutral variants not seen with WES as well as variants in noncoding regions, especially as potentially more knowledge of the function of noncoding regions arises. We, therefore, conclude that even though today the added value of WGS versus WES seems to be limited, it may increase substantially in the future.
Published: 2023
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7. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author: Consortium, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics, Ruderfer, Douglas M, Ripke, Stephan, McQuillin, Andrew, Boocock, James, Stahl, Eli A, Pavlides, Jennifer M Whitehead, Mullins, Niamh, Charney, Alexander W, Ori, Anil PS, Loohuis, Loes M Olde, Domenici, Enrico, Di Florio, Arianna, Papiol, Sergi, Kalman, Janos L, Trubetskoy, Vassily, Adolfsson, Rolf, Agartz, Ingrid, Agerbo, Esben, Akil, Huda, Albani, Diego, Albus, Margot, Alda, Martin, Alexander, Madeline, Alliey-Rodriguez, Ney, Als, Thomas D, Amin, Farooq, Anjorin, Adebayo, Arranz, Maria J, Awasthi, Swapnil, Bacanu, Silviu A, Badner, Judith A, Baekvad-Hansen, Marie, Bakker, Steven, Band, Gavin, Barchas, Jack D, Barroso, Ines, Bass, Nicholas, Bauer, Michael, Baune, Bernhard T, Begemann, Martin, Bellenguez, Celine, Belliveau, Richard A, Bellivier, Frank, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Berrettini, Wade H, Bevilacqua, Elizabeth, Biernacka, Joanna M, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas HR, Pedersen, Carsten Bocker, Boehnke, Michael, Boks, Marco, Borglum, Anders D, Bramon, Elvira, Breen, Gerome, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Budde, Monika, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Bunney, William, Burmeister, Margit, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Casas, Miquel, Catts, Stanley V, Cervantes, Pablo, Chambert, Kimberley D, Chan, Raymond CK, Chen, Eric YH, Chen, Ronald YL, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Clarke, Toni-Kim, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Coleman, Jonathan RI, Collier, David A, Cormican, Paul, Coryell, William, and Craddock, Nicholas
Subjects: Human Genome, Neurosciences, Serious Mental Illness, Bipolar Disorder, Biotechnology, Schizophrenia, Brain Disorders, Genetics, Mental Health, Mental health, Good Health and Well Being, Case-Control Studies, Genetic Loci, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Odds Ratio, Phenotype, Risk, White People, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: douglas.ruderfer@vanderbilt.edu, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, bipolar disorder, polygenic risk, psychosis, schizophrenia, subphenotypes, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.
Published: 2018

8. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author: Vilhjálmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lindström, Sara, Ripke, Stephan, Genovese, Giulio, Loh, Po-Ru, Bhatia, Gaurav, Do, Ron, Hayeck, Tristan, Won, Hong-Hee, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodrguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, and Grove, Jakob
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Schizophrenia, Mental Health, Brain Disorders, Serious Mental Illness, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Models, Theoretical, Multifactorial Inheritance, Multiple Sclerosis, Phenotype, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
Published: 2015

9. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Author: Gusev, Alexander, Lee, S Hong, Trynka, Gosia, Finucane, Hilary, Vilhjálmsson, Bjarni J, Xu, Han, Zang, Chongzhi, Ripke, Stephan, Bulik-Sullivan, Brendan, Stahl, Eli, Kähler, Anna K, Hultman, Christina M, Purcell, Shaun M, McCarroll, Steven A, Daly, Mark J, Pasaniuc, Bogdan, Sullivan, Patrick F, Neale, Benjamin M, Wray, Naomi R, Raychaudhuri, Soumya, Price, Alkes, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Børglum, Anders D, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, and Georgieva, Lyudmila
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Prevention, Computer Simulation, Genetic Diseases, Inborn, Genetic Variation, Genome-Wide Association Study, Humans, Inheritance Patterns, Models, Genetic, Open Reading Frames, Regulatory Elements, Transcriptional, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained
Published: 2014

10. Biological insights from 108 schizophrenia-associated genetic loci

Author: Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A Jr, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, and Joa, Inge
Subjects: Human Genome, Brain Disorders, Serious Mental Illness, Prevention, Schizophrenia, Genetics, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Brain, Enhancer Elements, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Immunity, Multifactorial Inheritance, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Synaptic Transmission, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
Published: 2014

11. SEED EMPOWERS EVERY INPUT DECISION: Balance environment, management practices and genetics to maximize season-long ROI

Author: Begemann, Sonja
Subjects: Genetics, Seed industry, Seeds, Agricultural industry, Business
Abstract: A SYSTEMS APPROACH TO SEED SELECTION Imagine the day you can provide details about each specific field to your seed supplier and they take that information to custom-build the perfect [...]
Published: 2020

12. Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage

Author: Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R. Lupski, and Edoardo Errichiello
Subjects: Genetics, Genetics (clinical)
Abstract: The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as “tightjunctionopathies.”
Published: 2023
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13. Identification of transcription factor binding sites using ATAC-seq

Author: Zhijian Li, Marcel H. Schulz, Thomas Look, Matthias Begemann, Martin Zenke, and Ivan G. Costa
Subjects: Computational footprinting, Open chromatin, ATAC-seq, Cleavage bias, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Transposase-Accessible Chromatin followed by sequencing (ATAC-seq) is a simple protocol for detection of open chromatin. Computational footprinting, the search for regions with depletion of cleavage events due to transcription factor binding, is poorly understood for ATAC-seq. We propose the first footprinting method considering ATAC-seq protocol artifacts. HINT-ATAC uses a position dependency model to learn the cleavage preferences of the transposase. We observe strand-specific cleavage patterns around transcription factor binding sites, which are determined by local nucleosome architecture. By incorporating all these biases, HINT-ATAC is able to significantly outperform competing methods in the prediction of transcription factor binding sites with footprints.
Published: 2019
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14. Novel familial distal imprinting centre 1 (11p15.5) deletion provides further insights in imprinting regulation

Author: Florian Kraft, Katharina Wesseler, Matthias Begemann, Ingo Kurth, Miriam Elbracht, and Thomas Eggermann
Subjects: Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Imprinting centre 1, H19/IGF2:IG-DMR, Deletion, Nanopore sequencing, Medicine, Genetics, QH426-470
Abstract: Abstract Background Deletions of the imprinting centre 1 (IC1) in 11p15.5 are rare and their clinical significance is not only influenced by their parental origin but also by their exact genomic localization. In case the maternal IC1 allele is affected, the deletion is associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and a gain of methylation (GOM) of the IC1. The consequences of deletions of the paternal IC1 allele depend on the localization and probably the binding sites of methylation-specific DNA-binding factors affected by the change. It has been suggested that distal deletions of the paternal allele are associated with a normal IC1 methylation and phenotype, whereas proximal alterations cause a loss of methylation (LOM) and Silver-Russell syndrome (SRS) features. Results In a patient referred for molecular BWS testing and his family, a deletion within the IC1 was identified by MLPA. It was associated with a GOM, corresponding to the transmission of the alteration via the maternal germline. Accordingly, the deletion was also detectable in the maternal grandmother, but here the paternal chromosome 11p15.5 was affected and a IC1 LOM was observed. By nanopore sequencing, the localization of the deletion could be precisely determined. Conclusions We report for the first time both GOM and LOM of the IC1 in the same family, caused by transmission of a 2.2-kb deletion in 11p15.5. Nanopore sequencing allowed the precise characterization of the change by long-read sequencing and thereby provides further insights in the regulation of imprinting in the IC1.
Published: 2019
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15. Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Author: Lischka, Annette, Eggermann, Katja, Record, Christopher J, Dohrn, Maike F, Laššuthová, Petra, Kraft, Florian, Begemann, Matthias, Dey, Daniela, Eggermann, Thomas, Beijer, Danique, Šoukalová, Jana, Laura, Matilde, Rossor, Alexander M, Mazanec, Radim, Lent, Jonas Van, Tomaselli, Pedro J, Ungelenk, Martin, Debus, Karlien Y, Feely, Shawna M E, and Gläser, Dieter
Subjects: DYSAUTONOMIA, SENSORY neurons, CLINICAL trials
Abstract: Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3 -, FLVCR1 - and NGF -associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies. [ABSTRACT FROM AUTHOR]
Published: 2023
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16. Formation of upd(7)mat by trisomic rescue: SNP array typing provides new insights in chromosomal nondisjunction

Author: Sandra Chantot-Bastaraud, Svea Stratmann, Frédéric Brioude, Matthias Begemann, Miriam Elbracht, Luitgard Graul-Neumann, Madeleine Harbison, Irène Netchine, and Thomas Eggermann
Subjects: Maternal uniparental Disomy 7, Formation mechanism, Chromosome 7, Trisomic rescue, Genetics, QH426-470
Abstract: Abstract Background Maternal uniparental disomy (UPD) of chromosome 7 (upd(7)mat) accounts for approximately 10% of patients with Silver-Russell syndrome (SRS). For upd(7)mat and trisomy 7, a significant number of mechanisms have been proposed to explain the postzygotic formation of these chromosomal compositions, but all have been based on as small number of cases. To obtain the ratio of isodisomy and heterodisomy in UPDs (hUPD, iUPD) and to determine the underlying formation mechanisms, we analysed a large cohort of upd(7)mat patients (n = 73) by SNP array typing. Based on these data, we discuss the UPDs and their underlying trisomy 7 formation mechanisms. Results A whole chromosome 7 maternal iUPD was confirmed in 28.8%, a mixture or complete maternal hUPD in 71.2% of patients. Conclusions We could demonstrate that nondisjunction mechanism affecting chromosome 7 are similar to that of the chromosomes more frequently involved in trisomy (and/or UPD), and that mechanisms other than trisomic rescue have a lower significance than previously suspected. Furthermore, we suggest SNP array typing for future parent- and cell-stage-of origin studies in human aneuploidies as they allow the definite classification of trisomies and UPDs, and provide information on recombinational events and their suggested association with aneuploidy formation.
Published: 2017
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17. A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms

Author: Katarzyna Lepeta, Katarzyna J Purzycka, Katarzyna Pachulska‐Wieczorek, Marina Mitjans, Martin Begemann, Behnam Vafadari, Krystian Bijata, Ryszard W Adamiak, Hannelore Ehrenreich, Magdalena Dziembowska, and Leszek Kaczmarek
Subjects: dendritic spine morphology, Fragile X mental retardation protein, matrix metalloproteinase 9, phenotype‐based genetic association study, single‐nucleotide polymorphism, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients.
Published: 2017
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18. Cover

Author: Anna Grether, Ivan Ivanovski, Martina Russo, Anaïs Begemann, Katharina Steindl, Lucia Abela, Michael Papik, Markus Zweier, Beatrice Oneda, Pascal Joset, and Anita Rauch
Subjects: Featured Cover, Genetics, Molecular Biology, Genetics (clinical)
Abstract: The cover image is based on the Original Article The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies by Anna Grether et al., https://doi.org/10.1002/mgg3.2148 [Image: see text]
Published: 2023

19. The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies

Author: Grether, Anna, Ivanovski, Ivan, Russo, Martina, Begemann, Anaïs, Steindl, Katharina, Abela, Lucia, Papik, Michael, Zweier, Markus, Oneda, Beatrice, Joset, Pascal, Rauch, Anita, and University of Zurich
Subjects: whole genome sequencing, epileptic encephalopathy, 10036 Medical Clinic, 10039 Institute of Medical Genetics, diagnostic yield, Genetics, 570 Life sciences, biology, 610 Medicine & health, Molecular Biology, Genetics (clinical), whole exome sequencing
Published: 2023
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20. Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Author: R Asadollahi, I Delvendahl, R Muff, G Tan, D G Rodríguez, S Turan, M Russo, B Oneda, P Joset, P Boonsawat, R Masood, M Mocera, I Ivanovski, A Baumer, R Bachmann-Gagescu, R Schlapbach, H Rehrauer, K Steindl, A Begemann, A Reis, J Winkler, B Winner, M Müller, and A Rauch
Subjects: Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract: Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel Na(V)1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that Na(V)1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower Na(V)1.2 protein levels. In neurons with the frameshift variant, Na(V)1.2 mRNA and protein levels were reduced by similar to 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying Na(V)1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced Na(V)1.2 levels. In contrast, epilepsy neurons displayed no change in Na(V)1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced Na(V)1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to Na(V)1.2 dysfunction and can guide further investigations., Human Molecular Genetics, 32 (13), ISSN:0964-6906, ISSN:1460-2083
Published: 2023
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21. Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage

Author: Lecca, Mauro, Pehlivan, Davut, Suñer, Damià Heine, Weiss, Karin, Coste, Thibault, Zweier, Markus, Oktay, Yavuz, Danial-Farran, Nada, Rosti, Vittorio, Bonasoni, Maria Paola, Malara, Alessandro, Contrò, Gianluca, Zuntini, Roberta, Pollazzon, Marzia, Pascarella, Rosario, Neri, Alberto, Fusco, Carlo, Marafi, Dana, Mitani, Tadahiro, Posey, Jennifer Ellen, Bayramoglu, Sadik Etka, Gezdirici, Alper, Hernandez-Rodriguez, Jessica, Cladera, Emilia Amengual, Miravet, Elena, Roldan-Busto, Jorge, Ruiz, María Angeles, Bauzá, Cristofol Vives, Ben-Sira, Liat, Sigaudy, Sabine, Begemann, Anaïs, Rauch, Anita, et al, and University of Zurich
Subjects: tight junctions, 10039 Institute of Medical Genetics, neurodevelopmental disorders, 610 Medicine & health, global developmental delay, ESAM, blood, intellectual disability, retinopathy, Genetics, 570 Life sciences, biology, epilepsy, pregnancy loss, exome sequencing, Genetics (clinical), brain barrier, intracranial haemorrhage
Published: 2023
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22. Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

Author: Thomas Eggermann, Elzem Yapici, Jet Bliek, Arrate Pereda, Matthias Begemann, Silvia Russo, Pierpaola Tannorella, Luciano Calzari, Guiomar Perez de Nanclares, Paola Lombardi, I. Karen Temple, Deborah Mackay, Andrea Riccio, Masayo Kagami, Tsutomu Ogata, Pablo Lapunzina, David Monk, Eamonn R. Maher, Zeynep Tümer, Eggermann, Thomas [0000-0002-8419-0264], Apollo - University of Cambridge Repository, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Eggermann, Thoma, Yapici, Elzem, Bliek, Jet, Pereda, Arrate, Begemann, Matthia, Russo, Silvia, Tannorella, Pierpaola, Calzari, Luciano, de Nanclares, Guiomar Perez, Lombardi, Paola, Temple, I Karen, Mackay, Deborah, Riccio, Andrea, Kagami, Masayo, Ogata, Tsutomu, Lapunzina, Pablo, Monk, David, Maher, Eamonn R, and Tümer, Zeynep
Subjects: Beckwith-Wiedemann Syndrome, Ubiquitin-Protein Ligases, Endocrinology and Metabolic Epigenetics, Differentially methylated regions, Loss of methylation, Multi locus imprinting disturbance, Growth disturbances, Growth disturbance, Imprinting disorder, Genomic Imprinting, Transient neonatal diabetes mellitu, Beckwith–Wiedemann syndrome spectrum, Pregnancy, Genetics, Epimutation, Humans, Transient neonatal diabetes mellitus, Molecular Biology, Genetics (clinical), Adaptor Proteins, Signal Transducing, Research, Uniparental disomy, Gain of methylation, Differentially methylated region, DNA Methylation, Epimutations, Silver-Russell Syndrome, CCAAT-Enhancer-Binding Proteins, Female, Maternal Inheritance, Imprinting disorders, Silver–Russell syndrome spectrum, Developmental Biology
Abstract: Clin Epigenetics 14, 41 (2022). doi:10.1186/s13148-022-01259-x, Published by BioMed Central, [S.l.]
Published: 2022
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23. Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Author: Asadollahi, Reza, Delvendahl, Igor, Muff, Rebecca, Tan, Ge, Rodríguez, Daymé González, Turan, Soeren, Russo, Martina, Oneda, Beatrice, Joset, Pascal, Boonsawat, Paranchai, Masood, Rahim, Mocera, Martina, Ivanovski, Ivan, Baumer Wolz, Alessandra, Bachmann-Gagescu, Ruxandra, Schlapbach, Ralph, Rehrauer, Hubert, Steindl, Katharina, Begemann, Anaïs, Reis, André, Winkler, Jürgen, Winner, Beate, Müller, Martin, Rauch, Anita, and University of Zurich
Subjects: 10036 Medical Clinic, 10039 Institute of Medical Genetics, 10076 Center for Integrative Human Physiology, Genetics, 570 Life sciences, biology, 610 Medicine & health, 10071 Functional Genomics Center Zurich, General Medicine, 10064 Neuroscience Center Zurich, Molecular Biology, 10124 Institute of Molecular Life Sciences, Genetics (clinical)
Published: 2023
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24. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

Author: Beata Stepniak, Anne Kästner, Giulia Poggi, Marina Mitjans, Martin Begemann, Annette Hartmann, Sandra Van der Auwera, Farahnaz Sananbenesi, Dilja Krueger‐Burg, Gabriela Matuszko, Cornelia Brosi, Georg Homuth, Henry Völzke, Fritz Benseler, Claudia Bagni, Utz Fischer, Alexander Dityatev, Hans‐Jörgen Grabe, Dan Rujescu, Andre Fischer, and Hannelore Ehrenreich
Subjects: FMR1, FMR2, FXR1, FXR2, miR‐181, PGAS, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high‐ versus low‐risk constellation regarding the accumulation model. Thereby, the brain‐expressed miR‐181 species emerged as potential “umbrella regulator”, with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
Published: 2015
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25. Preadult polytoxicomania—strong environmental underpinnings and first genetic hints

Author: Martin Begemann, Agnes A. Steixner-Kumar, Vinicius Daguano Gastaldi, Jan Seidel, Hannelore Ehrenreich, and Albert Rosenberger
Subjects: Adult, Addiction, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, Environmental risk, medicine, Genetic predisposition, Genetics, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetic Association Studies, Genetic association, medicine.disease, biology.organism_classification, Psychiatry and Mental health, Sexual abuse, Schizophrenia, Cannabis, Demography, Genome-Wide Association Study
Abstract: Considering the immense societal and personal costs and suffering associated with multiple drug use or “polytoxicomania”, better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p = 1.5 × 10−45; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10−33) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10−24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS–PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.
Published: 2021

26. Mild expression differences of MECP2 influencing aggressive social behavior

Author: Martesa Tantra, Christian Hammer, Anne Kästner, Liane Dahm, Martin Begemann, Chiranjeevi Bodda, Kurt Hammerschmidt, Ina Giegling, Beata Stepniak, Aracely Castillo Venzor, Bettina Konte, Begun Erbaba, Annette Hartmann, Asieh Tarami, Walter Schulz‐Schaeffer, Dan Rujescu, Ashraf U Mannan, and Hannelore Ehrenreich
Subjects: genetic background, human, microRNA, mouse, phenotype‐based genetic association study, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract The X‐chromosomal MECP2/Mecp2 gene encodes methyl‐CpG‐binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype‐based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele‐specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain‐expressed, species‐conserved miR‐511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.
Published: 2014
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27. A polygenic resilience score moderates the genetic risk for schizophrenia

Author: Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez
Subjects: Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).
Published: 2021
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28. Molecular testing for imprinting disorders

Author: Matthias Begemann, Jasmin Beygo, Deniz Kanber, and Thomas Eggermann
Subjects: Genetics, Molecular genetic testing, Medizin, medicine, Copy-number variation, Biology, medicine.disease, Imprinting (organizational theory), Genetics (clinical), Uniparental disomy
Abstract: Imprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances. The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements. Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.
Published: 2020
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29. Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy

Author: K. Eggermann, R. Meyer, M. Begemann, D. Dey, E. Bültmann, I. Kurth, G. C. Korenke, and C. Knopp
Subjects: Genetics, Genetics (clinical)
Abstract: Genes 13(12), 2356 (2022). doi:10.3390/genes13122356 special issue: "Special Issue "Identification of Genes in Rare Syndromes" / Special Issue Editor Dr. Dagmar Wieczorek, Guest Editor", Published by MDPI, Basel
Published: 2022
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30. A Xp22.11-p21.3 microdeletion in a three-generation family supports male lethality of POLA1 nullisomy resulting in reduced fertility of female carriers

Author: Begemann, Anaïs, Oneda, Beatrice, Baumer Wolz, Alessandra, Guldimann, Marina, Tutschek, Boris, Rauch, Anita, and University of Zurich
Subjects: Male, Heterozygote, 10039 Institute of Medical Genetics, DNA polymerase alpha, 610 Medicine & health, Genetic Diseases, X-Linked, General Medicine, DNA Polymerase I, POLA1, Van Esch, Fertility, 10036 Medical Clinic, early pregnacy loss, Genes, X-Linked, Intellectual Disability, Genetics, 570 Life sciences, biology, Humans, Female, O’Driscoll syndrome, Genetics (clinical)
Abstract: POLA1 encodes a subunit of the DNA polymerase alpha, a key enzyme for the initiation of DNA synthesis. In males, hemizygous hypomorphic variants in POLA1 have been identified as the cause of X-linked pigmentary reticulate disorder (XLPDR) and a novel X-linked neurodevelopmental disorder termed Van Esch-O'Driscoll syndrome (VEODS), while female carriers have been reported to be healthy. Nullisomy for POLA1 was speculated to be lethal due to its crucial function, while the effect of loss of one allele in females remained unknown. Here, we report on a three-generation family harboring a deletion of POLA1 in females showing subfertility as the only phenotype. Our findings show that heterozygous deletions or truncating variants in females with skewed X inactivation do not cause VEODS and support the hypothesis of very early embryonic lethality in males with POLA1 nullisomy.
Published: 2022
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31. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
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32. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS interaction (rs7302529,p=1.6×10−7; rs73033497,p=8.8×10−7; rs7914279,p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

33. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Author: Katharina Steindl, Alain Verloes, Cornelia Kraus, Rachel Fisher, Katrin Õunap, Amber Begtrup, Steffen Syrbe, Theresa Brunet, Antonio Vitobello, Laurence Faivre, Reza Asadollahi, Jessica Becker, Maja Hempel, Dave A Dyment, Christiane Zweier, John H McDermott, Bernt Popp, Elaine Suk-Ying Goh, Lynette G. Sadleir, Anaïs Begemann, Siddharth Banka, Gwenaël Le Guyader, Elisabeth Schuler, Anne-Sophie Denommé-Pichon, Kathleen Brown, Gaetan Lesca, Frédéric Tran Mau-Them, Lucia Ribeiro Machado Haertel, Maryline Carneiro, Amelie Theresa Van der Ven, Markus Zweier, Hartmut Engels, Heinrich Sticht, Theresia Herget, Jessika Johannsen, Bader Alhaddad, Nadine N. Hauer, Robert C. Day, Tiia Reimand, M. J. Hajianpour, Manuel Schiff, Kirsty McWalter, Margarita Saenz, Tatjana Bierhals, Pierre Meyer, Ange-Line Bruel, Martina Russo, Korbinian M. Riedhammer, Kirsten Cremer, Anita Rauch, Marjolaine Willems, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Robert Debré
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, WAVEregulatory complex (WRC), 030105 genetics & heredity, Biology, Article, Intellectual disability, Epilepsy, CYFIP2, WAVE-regulatory complex (WRC), WASF, 03 medical and health sciences, Neurodevelopmental disorder, Seizures, medicine, Missense mutation, Humans, Genetics(clinical), Gene, Genetics (clinical), Actin, Adaptor Proteins, Signal Transducing, Genetics, medicine.disease, Actin cytoskeleton, Phenotype, Hypotonia, Actins, 3. Good health, ddc, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neurodevelopmental Disorders, intellectual disability, epilepsy, medicine.symptom
Abstract: International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Published: 2020
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34. Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion

Author: Imam Hassouna, Felicia J. van der Flier, Martin S. Weber, Nadine Schopf, Sahab Arinrad, Laura Fernandez Garcia-Agudo, Hana Janova, Hannelore Ehrenreich, Anja Ronnenberg, Susann Boretius, Henrik Martens, Klaus-Armin Nave, Evan Balmuth, Lea E. Sendler, Martin Begemann, and Agnes Steixner
Subjects: 0301 basic medicine, chemistry.chemical_classification, Microglia, Phagocytosis, Inflammation, Biology, Biochemistry, Cell biology, White matter, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Genetics, medicine, Nucleotide, medicine.symptom, Molecular Biology, 030217 neurology & neurosurgery, Biotechnology
Abstract: Reduced expression of 2'-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by...
Published: 2019
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35. C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Author: Claudia Stollbrink-Peschgens, Patricia Klemm, Lambert P. van den Heuvel, Ingo Kurth, Clara D.M. van Karnebeek, Michael Mull, Eva Lausberg, C. Libioulle, Robert Meyer, Thomas Eggermann, Emile Van Schaftingen, Klaus Tenbrock, Daniela Choukair, Joseph P. Dewulf, François-Guillaume Debray, Joachim Weis, Kim Ohl, Norbert Wagner, Prasad T Oommen, Claudia Haase, Elsa Wiame, Dagmar Wieczorek, Arndt Borkhardt, Matthias Begemann, Sebastian Gießelmann, Anja Holz, Florian Kraft, Harald Surowy, Miriam Elbracht, Clemens Sommer, Ramona Salvarinova, Stephanie Demuth, Till Braunschweig, Martin Häusler, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, and UCL - (SLuc) Service de biochimie médicale
Subjects: 0301 basic medicine, Microcephaly, Respiratory chain, Biology, Mitochondrion, Cell Line, Mitochondrial Proteins, Transcriptome, Mice, Open Reading Frames, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Loss of Function Mutation, Glycogen branching enzyme, medicine, Animals, Humans, Gene, Mice, Knockout, Genetics, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Glycogen Debranching Enzyme System, General Medicine, medicine.disease, Mitochondria, Open reading frame, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Clinical Medicine, Signal transduction, Glycogen
Abstract: BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell’s function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid–Schiff–positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism. CONCLUSIONS. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.
Published: 2021
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36. Atlas of clinical hematology, 3rd revised edition Herbert Begemann and Johann Rastetter Springer-Verlag, New York, 1979 275 pages, $164.90 (Hardbound)

Author: Avery A. Sandberg
Subjects: Cancer Research, medicine.anatomical_structure, Atlas (anatomy), Genetics, medicine, Art history, Biology, Molecular Biology
Published: 1981
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37. Erythropoietin as candidate for supportive treatment of severe COVID-19

Author: Hannelore Ehrenreich, Eduard Vieta, Martin Begemann, Karin Weissenborn, Kamilla W. Miskowiak, and Markus Busch
Subjects: 0301 basic medicine, PATHOGENESIS, Respiratory System Agents, Review, Severity of Illness Index, law.invention, DOUBLE-BLIND, 0302 clinical medicine, Randomized controlled trial, respiratory function, law, INFECTION, lcsh:QD415-436, Respiratory function, Lung, Genetics (clinical), Randomized Controlled Trials as Topic, Recombinant Proteins, Respiratory Muscles, Phrenic Nerve, Neuroprotective Agents, Spinal Cord, Eritropoetina, cytokine storm, Molecular Medicine, neuroprotection, Coronavirus Infections, Cytokine Release Syndrome, medicine.drug, medicine.medical_specialty, Pneumonia, Viral, MEDLINE, Proof of Concept Study, Neuroprotection, ACUTE LUNG INJURY, lcsh:Biochemistry, Betacoronavirus, 03 medical and health sciences, Double-Blind Method, Severity of illness, Genetics, medicine, Humans, recombinant human erythropoietin, Intensive care medicine, Pandemics, SARS-CoV-2, Molecular Biology, Erythropoietin, business.industry, Clinical study design, lcsh:RM1-950, COVID-19, RECOMBINANT-HUMAN-ERYTHROPOIETIN, medicine.disease, clinical trial design, MODEL, EPO, inflammation, MICE, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, business, Cytokine storm, 030217 neurology & neurosurgery, Brain Stem
Abstract: In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.
Published: 2020
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38. A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69

Author: J. P. Dewulf, Matthias Begemann, E. Van Schaftingen, L. van den Heuvel, C. Van Karnebeek, Thomas Eggermann, Joachim Weis, Prasad T Oommen, Claudia Haase, Daniela Choukair, François-Guillaume Debray, Anja Holz, M. Haeusler, Robert Meyer, S. Giesselmann, Eva Lausberg, Kim Ohl, Harald Surowy, Dagmar Wieczorek, C. Libioulle, Ramona Salvarinova, Stephanie Demuth, Elsa Wiame, Klaus Tenbrock, Florian Kraft, Miriam Elbracht, Till Braunschweig, Clemens Sommer, Michael Mull, Patricia Klemm, Ingo Kurth, and Arndt Borkhardt
Subjects: Signal peptide, Genetics, Transcriptome, Microcephaly, Open reading frame, biology, medicine, Respiratory chain, Glycogen branching enzyme, biology.protein, Signal transduction, medicine.disease, Gene
Abstract: BackgroundDeciphering the function of the many genes previously classified as uncharacterized “open reading frame” (orf) completes our understanding of cell function and its pathophysiology.MethodsWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.ResultsWe identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients show signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 shows comparable respiratory chain defects. Patient-derived cells reveal alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicate an additional impact of C2orf69 on glycogen metabolism.ConclusionOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.Graphical Abstract
Published: 2021
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39. Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

Author: Cordula Knopp, Petra Holschbach, Stephanie DiTroia, Maggie Brett, Ingo Kurth, Muna Al-Saffar, Ganeshwaran H. Mochida, Lynn Pais, Matthias Begemann, Jennifer E. Neil, Ene-Choo Tan, Angeline H. M. Lai, Lars Buschmann, Natja Haag, Christopher A. Walsh, Laila Bastaki, and Florian Kraft
Subjects: Adult, Male, Microcephaly, Developmental Disabilities, Mutation, Missense, Diseases, Biology, Short stature, Article, Holoprosencephaly, Hypogonadotropic hypogonadism, Loss of Function Mutation, Intellectual Disability, Proto-Oncogene Proteins, Intellectual disability, Genetics, medicine, Missense mutation, Humans, Allele, Child, Genetics (clinical), Disease genetics, Membrane Proteins, medicine.disease, Phenotype, Pedigree, Female, medicine.symptom
Abstract: Heterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.
Published: 2021

40. Unusual deletion of the maternal 11p15 allele in Beckwith–Wiedemann syndrome with an impact on both imprinting domains

Author: Thomas Eggermann, Matthias Begemann, and Lutz Pfeiffer
Subjects: 0301 basic medicine, Adult, Male, Heterozygote, Beckwith-Wiedemann Syndrome, Matricaria, 11p15.5 deletion, Beckwith–Wiedemann syndrome, 030105 genetics & heredity, Biology, 03 medical and health sciences, Genomic Imprinting, Insulin-Like Growth Factor II, Genetics, medicine, Humans, Imprinting (psychology), Allele, Paternal Inheritance, Molecular Biology, Gene, Genetics (clinical), Alleles, KCNQ1, Research, IGF2, IC2 hypomethylation, DNA Methylation, medicine.disease, Phenotype, Human genetics, Pedigree, Silver-Russell Syndrome, 030104 developmental biology, KCNQ1 Potassium Channel, Female, Developmental Biology
Abstract: Clinical epigenetics 13, 30 (2021). doi:10.1186/s13148-021-01020-w, Published by BioMed Central, [S.l.]
Published: 2021
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41. Addressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

Author: Onnen Moerer, Martin Begemann, Oliver Gross, Hannelore Ehrenreich, Kamilla W. Miskowiak, Dominik Wincewicz, Karin Weissenborn, Rüdiger Hardeland, Vinicius Daguano Gastaldi, and Eduard Vieta
Subjects: Dysfunctional family, Inflammation, Review, RM1-950, QD415-436, Bioinformatics, Neuroprotection, Biochemistry, law.invention, Post-Acute COVID-19 Syndrome, Randomized controlled trial, law, Darbepoetin, Recombinant human EPO, Genetics, medicine, Humans, Hypoxia, Molecular Biology, Lung, Pandemics, Erythropoietin, Genetics (clinical), Outcome, Kidney, business.industry, SARS-CoV-2, COVID-19, Hypoxia (medical), Recombinant Proteins, Signaling, COVID-19 Drug Treatment, Clinical trial, Treatment, Critical care, medicine.anatomical_structure, Eritropoetina, Molecular Medicine, Therapeutics. Pharmacology, medicine.symptom, business, medicine.drug
Abstract: Background Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called ‘long COVID’ and ‘neuroCOVID’, becomes increasingly evident. Main body of the abstract Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term ‘hypoxia paradox’. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this ‘hypoxia paradox’ caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. Short conclusion Substitution of EPO may—among other beneficial EPO effects in severe COVID-19—circumvent downstream consequences of the ‘hypoxia paradox’. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.
Published: 2021

42. One test for all : Whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

Author: Ulrike Schara, Stephanie Demuth, Matthias Begemann, György Fekete, Laima Ambrozaityte, Magdeldin Elgizouli, Alma Kuechler, Daniela Dey, Asmaa Kenawy, Robert Meyer, Christian Thomas Hübner, Thomas Eggermann, Birute Burnyte, Miriam Elbracht, Thomas Opladen, Carmen Schröder, Peter M. Kroisel, University of Zurich, and Eggermann, Thomas
Subjects: 0301 basic medicine, 2716 Genetics (clinical), 10039 Institute of Medical Genetics, Genetic counseling, Medizin, lcsh:Medicine, 610 Medicine & health, 030105 genetics & heredity, DNA sequencing, Silver–Russell syndrome, 03 medical and health sciences, Next generation sequencing, Exome Sequencing, Clinical heterogeneity, parasitic diseases, 2736 Pharmacology (medical), Humans, Medicine, Diagnostic detection rate, Pharmacology (medical), Genetics (clinical), Exome sequencing, Chromosome 7 (human), Genetics, business.industry, Research, lcsh:R, Whole exome sequencing, next generation sequencing, diagnostic detection rate, whole exome sequencing, targeted multigene panel NGS, General Medicine, DNA Methylation, Uniparental Disomy, medicine.disease, Phenotype, Human genetics, Targeted multigene panel NGS, Silver-Russell Syndrome, 030104 developmental biology, Molecular Diagnostic Techniques, 570 Life sciences, biology, business
Abstract: Orphanet journal of rare diseases 16(1), 42 (2021). doi:10.1186/s13023-021-01683-x, Published by BioMed Central, London
Published: 2021
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43. Molecular characterization of temple syndrome families with 14q32 epimutations

Author: Matthias Begemann, Miriam Elbracht, Daniela Dey, Thomas Eggermann, and Johanna Brück
Subjects: 0301 basic medicine, Candidate gene, Chromosome Disorders, 030105 genetics & heredity, Biology, 03 medical and health sciences, Maternal uniparental disomy, Genomic Imprinting, Genetics, Humans, Imprinting (psychology), Genetics (clinical), Exome sequencing, MEG3, Chromosomes, Human, Pair 14, Maternal effect, General Medicine, Methylation, Temple Syndrome, DNA Methylation, Pedigree, 030104 developmental biology, Phenotype, Mutation, Paternal Inheritance
Abstract: Temple Syndrome (TS14) is an imprinting disorder caused by molecular disruptions of the imprinted region in 14q32 (MEG3:TSS-DMR). The frequency of the three known TS14 subtypes (deletions, maternal uniparental disomy (upd(14)mat), loss of methylation (LOM)) is currently in discussion, and within the LOM group, the occurrence of Multilocus Imprinting Disturbances (MLID) has been identified. We present 16 TS14 patients with molecular alterations affecting the MEG3:TSS-DMR, comprising seven patients (43.8%) with LOM, six carriers with upd(14)mat (37.5%), and three cases (18.8%) with a deletion affecting the paternal MEG3:TSS-DMR. We did not find any evidence for MLID in the LOM group, including two cases in which different tissues were available. Whole exome sequencing (WES) in the MEG3:TSS-DMR LOM patients and their parents (Trio WES) did not reveal an obvious pathogenic variant which might cause aberrant methylation at imprinted loci. By summarizing our data with those from the literature, we could show that MLID affecting clinically relevant imprinted loci is rare in TS14 and therefore differs markedly from other imprinting disorders associated with MLID, e.g. Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). However, consistent with the clinical overlap with TS14, in SRS patients carrying MLID the MEG3:TSS-DMR is frequently affected. Variants in the known candidate genes for maternal effect variants causing MLID and fetal MLID determinants could not be identified in TS14 patients. Thus, 14q32 epimutations probably have other molecular causes than epimutations in BWS or SRS patients.
Published: 2020

44. Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family

Author: Thomas Eggermann, Miriam Elbracht, Gundula Kadgien, and Matthias Begemann
Subjects: Infertility, Adult, Abortion, Habitual, Biology, Genome, Article, 03 medical and health sciences, Genomic Imprinting, Protein-Arginine Deiminase Type 6, Genetics, medicine, Humans, Imprinting (psychology), Gene, Genetics (clinical), Cells, Cultured, 0303 health sciences, Pregnancy, 030305 genetics & heredity, Maternal effect, Methylation, DNA Methylation, medicine.disease, NLRP7, Mutation, Female
Abstract: The term multilocus imprinting disturbance (MLID) describes the aberrant methylation of multiple imprinted loci in the genome, and MLID occurs in patients suffering from imprinting disorder carrying methylation defects. First data indicate that functional variants in factors expressed from both the fetal as well as the maternal genome cause MLID. Molecular changes in such genes of the maternal genome are called maternal effect variants, they affect members of the subcortical maternal complex (SCMC) in the oocyte which plays an important role during early embryonic development. Whereas the contribution of variants in the SCMC genes NLRP2, NLRP5, NLRP7, and KHDC3L to the etiology of reproductive failure and aberrant imprinting is widely accepted, the involvement of PADI6 variants in the formation of MLID is in discussion. We now report on the identification of biallelic variants in a woman suffering from different miscarriages and giving birth to two children with MLID. Thereby the role of PADI6 in maintaining the proper imprinting status during early development is confirmed. Thus, PADI6 variants do not only cause (early) pregnancy losses, but maternal effect variants in this gene cause the same spectrum of pregnancy outcomes as variants in other SCMC encoding genes, including chromosomal aberrations and disturbed imprinting. The identification of maternal effect variants requires genetic and reproductive counseling as carriers of these variants are at high risks for reproductive failure.
Published: 2020

45. Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies

Author: Florian Kraft, Matthias Begemann, Thomas Eggermann, Stephanie Demuth, Klaus Zerres, Martin Häusler, Sabine Busse, Robert Meyer, Herdit M. Schüler, Miriam Elbracht, Ingo Kurth, and Daniela Dey
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Familial transmission, 030105 genetics & heredity, Audiology, 03 medical and health sciences, Young Adult, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Language Development Disorders, Autistic Disorder, Child, Genetics (clinical), Exome sequencing, Dysmorphic facies, business.industry, Facies, Middle Aged, medicine.disease, Developmental disorder, 030104 developmental biology, Phenotype, Child, Preschool, Speech delay, Autism, Female, medicine.symptom, business, Transcription Factors
Abstract: De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.
Published: 2020

46. Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures

Author: Britta Müller, Miriam Elbracht, Ute Hehr, Matthias Begemann, Martin Häusler, Petra Holschbach, Ildiko M. Kabat, Ingo Kurth, Michael Mull, and Florian Kraft
Subjects: 0301 basic medicine, Heterozygote, Pathology, medicine.medical_specialty, Contracture, Nedd4 Ubiquitin Protein Ligases, NEDD4L, Mutation, Missense, Hypokinesia, Toe syndactyly, Clinical Reports, arthrogryposis, fetal hypokinesia, 03 medical and health sciences, 0302 clinical medicine, Periventricular Nodular Heterotopia, Genetics, medicine, Humans, Missense mutation, Child, Molecular Biology, Genetics (clinical), Arthrogryposis, Fetus, Clinical Report, business.industry, Syndrome, medicine.disease, Developmental disorder, Phenotype, 030104 developmental biology, periventricular nodular heterotopias, nanopore sequencing, Flexion contractures, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Mutations in the HECT domain of NEDD4L have recently been identified in a cohort of eight patients with a syndromic form of bilateral periventricular nodular heterotopia (PVNH) in association with neurodevelopmental delay, cleft palate, and toe syndactyly (PVNH7). Methods Case report based on NGS sequencing. Results Here, we describe a girl with a novel heterozygous NEDD4L missense variant, p.Tyr679His, and characteristic clinical findings, including bilateral periventricular nodular heterotopia, cleft palate and mild toe syndactyly. Molecular testing from peripheral blood identified the healthy father to carry the NEDD4L variant in mosaic state. Notably, a previous pregnancy of the couple had been terminated due to a complex fetal developmental disorder, including hypokinesia and flexion contractures. Upon review, this affected fetus was also shown to carry the familial NEDD4L variant. Conclusion Our findings may suggest a broader spectrum of NEDD4L‐associated phenotypes, including severe prenatal neurodevelopmental manifestations, which might represent yet another genetic form of fetal hypokinesia with flexion contractures.
Published: 2018
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47. Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers

Author: Florian Kraft, Thomas Eggermann, Ingo Kurth, Matthias Begemann, Miriam Elbracht, Lukas Soellner, and Sabrina Sauer
Subjects: Genetics, 0303 health sciences, Non-Mendelian inheritance, Polymorphism, Genetic, Chromosomes, Human, Pair 11, 030305 genetics & heredity, Copy number analysis, Maternal effect, Nuclear Proteins, Methylation, DNA Methylation, Biology, Autoantigens, Article, DNA sequencing, Mitochondrial Proteins, Silver-Russell Syndrome, 03 medical and health sciences, DNA methylation, Humans, Maternal Inheritance, Imprinting (psychology), Gene, Genetics (clinical)
Abstract: Silver-Russell syndrome is an imprinting disorder characterized by severe intrauterine and postnatal growth retardation. The majority of patients show loss of methylation (LOM) of the H19/IGF2 IG-DMR (ICR1) in 11p15.5. In ~10% of these patients aberrant methylation of additional imprinted loci on other chromosomes than 11 can be observed (multilocus imprinting defect – MLID). Recently, genomic variations in the ICR1 have been associated with disturbed methylation of the ICR1. In addition, variants in factors contributing to the life cycle of imprinting are discussed to cause aberrant imprinting, including MLID. These variants can either be identified in the patients with imprinting disorders themselves or in their mothers. We performed comprehensive studies to elucidate the role of both cis-acting variants in 11p15.5 as well as of maternal effect variants in the etiology of ICR1 LOM. Whereas copy number analysis and next generation sequencing in the ICR1 did not provide any evidence for a variant, search for maternal effect variants in 21 mothers of patients with ICR1 LOM identified two carriers of NLRP5 variants. By considering our results as well as those from the literature, we conclude that the causes for epimutations are heterogeneous. MLID might be regarded as an own etiological subgroup, associated with maternal effect variants in NLRP and functionally related genes. In addition, these variants might also contribute to LOM of single imprinted loci. Furthermore, genomic variants in the patients themselves might result in aberrant methylation patterns and need further investigation.
Published: 2018
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48. Search for altered imprinting marks in Mayer-Rokitansky-Küster-Hauser patients

Author: Matthias Begemann, Thomas Eggermann, Susanne Ledig, Peter Wieacker, Miriam Elbracht, and Ingo Kurth
Subjects: Adult, 0301 basic medicine, Mayer rokitansky kuster hauser, 46, XX Disorders of Sex Development, 030209 endocrinology & metabolism, Bioinformatics, Clinical Reports, Congenital Abnormalities, Genomic Imprinting, Silver–Russell syndrome, 03 medical and health sciences, 0302 clinical medicine, Mayer–Rokitansky–Küster–Hauser syndrome, Genetics, Humans, Medicine, Mayer-Rokitansky-Kuster-Hauser Syndrome, Epigenetics, Imprinting (psychology), Primary amenorrhea, Mullerian Ducts, Molecular Biology, Genetics (clinical), Clinical Report, business.industry, Aberrant methylation, Chromosomes, Human, Pair 11, DNA Methylation, medicine.disease, ICR1 hypomethylation, Silver-Russell Syndrome, 030104 developmental biology, Etiology, Female, imprinting, business
Abstract: Background Mayer–Rokitansky–Küster–Hauser syndrome (MRKH) is the second most common cause of primary amenorrhea and characterized by absence of the uterus and the upper part of the vagina. The etiology of MRKH is mainly unknown but a contribution of genomic alterations is probable. A molecular disturbance so far neglected in MRKH research is aberrant methylation at imprinted loci. In fact, MRKH has been reported in patients with the imprinting disorder Silver–Russell syndrome. Methods We report on a rare patient with MRKH and SRS due to an ICR1 hypomethylation in 11p15.5. On the basis of this observation we screened a large cohort of MRKH patients (n > 100) for aberrant methylation at nine imprinted loci. Results We failed to detect any epimutation, thus we conclude that imprinting defects at least at the currently known disease‐relevant imprinted loci do not contribute to the isolated MRKH phenotype. However, it cannot be excluded that altered methylation marks at other loci are involved in the etiology of MRKH. Conclusion The molecular basis for MRKH remains unclear in the majority of patients, but future studies on the association between MRKH and ICR1 hypomethylation/SRS will to enlighten the role of epigenetics in the etiology of MRKH.
Published: 2018
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49. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author: Fritz Zimprich, Manuel Mattheisen, Edward M. Scolnick, Ayman H. Fanous, Henrik B. Rasmussen, Steven A. McCarroll, Ingrid Agartz, Carmel M. Loughland, Aiden Corvin, Ann Olincy, Anders D. Børglum, F. Anthony O'Neill, T. Scott Stroup, Elizabeth Bevilacqua, Sandra Meier, Ulrich Schall, Jouko Lönnqvist, Jianxin Shi, C. Robert Cloninger, Judit Bene, Veikko Salomaa, George N. Papadimitriou, Milica Pejovic-Milovancevic, Béla Melegh, Kari Stefansson, Brendan Bulik-Sullivan, Janis Klovins, Enrico Domenici, Sibylle G. Schwab, Dai Wang, Assen Jablensky, Mari Nelis, Sang Yun Oh, Peter Holmans, Aaron R. Wolen, Hualin Simon Xi, Eric Strengman, Bryan J. Mowry, Michael Gill, Kung Yee Liang, William Byerley, Rolf Adolfsson, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Brien P. Riley, Engilbert Sigurdsson, Benjamin M. Neale, Miaoxin Li, Michael Davidson, Bernard Lerer, Michele T. Pato, Xuebin Zheng, Patrick F. Sullivan, Frans Henskens, Madeline Alexander, Andrew M. McIntosh, Inez Myin-Germeys, Draga Toncheva, Liene Nikitina-Zake, Kenneth S. Kendler, Carin J. Meijer, Robin M. Murray, Richard E. Straub, Ann E. Pulver, Menachem Fromer, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, Giulio Genovese, Brion S. Maher, Stanley V. Catts, David St Clair, Robert W. McCarley, David Cohen, Nancy G. Buccola, Dan Rujescu, Carlos N. Pato, Kristin K. Nicodemus, Josef Frank, Claudine Laurent, Dominique Campion, Guiyan Ni, James L. Kennedy, Sena Karachanak-Yankova, Nicholas John Craddock, Peter M. Visscher, Valentina Escott-Price, Jeffrey A. Lieberman, Deborah A. Nertney, Bertram Müller-Myhsok, Marcella Rietschel, Dimitris Dikeos, Stephanie Godard, Stephanie Williams, Andres Metspalu, John L. Waddington, Sophie E. Legge, Roel A. Ophoff, Jonathan Pimm, Richard Bruggeman, Tim B. Bigdeli, Gerald Nestadt, Mark Weiser, Kieran C. Murphy, Eric F.C. Cheung, Kang Sim, Jordan W. Smoller, David J. Kavanagh, Inge Joa, Jens R. Wendland, Thomas G. Schulze, Richard A. Belliveau, Sarah E. Bergen, Ditte Demontis, David Curtis, Todd Lencz, Danielle Posthuma, René S. Kahn, Lili Milani, Randy L. Buckner, Jianjun Liu, Petr Slominsky, Wiepke Cahn, Hana Kuzelova-Ptackova, Sergi Papiol, Tune H. Pers, Stephan Ripke, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Larry J. Seidman, Eli A. Stahl, David A. Collier, Michael Conlon O'Donovan, Svetlana A. Limborska, James T.R. Walters, Farooq Amin, Noa Carrera, Ronald Y.L. Chen, Pablo V. Gejman, Joel N. Hirschhorn, Zita Ausrele Kucinskiene, Michael John Owen, Ina Giegling, Stephanie H. Witt, Timothy G. Dinan, Margot Albus, Wei Cheng, Marian L. Hamshere, Markus M. Nöthen, Thomas Werge, Guiqing Cai, Raquelle I. Mesholam-Gately, Annette M. Hartmann, Ingrid Melle, Ole A. Andreassen, Preben Bo Mortensen, Hannelore Ehrenreich, Tiina Paunio, James A. Knowles, Pak C. Sham, Marion Friedl, Teimuraz Silagadze, Dermot Walsh, Emily H. M. Wong, Igor Nenadic, Matthew C. Keller, John Powell, Naomi R. Wray, Patricia T. Michie, Bradley T. Webb, Lude Franke, Mark Hansen, Masashi Ikeda, Sven Cichon, Elvira Bramon, Frank Dudbridge, Erik G. Jönsson, Annelie Nordin, Wolfgang Maier, Peter Eichhammer, Christian R. Schubert, J. Mallet, Jacob Gratten, Andrey Khrunin, Jacqueline I. Goldstein, Panos Roussos, Pamela Sklar, Diana O. Perkins, Srdjan Djurovic, Phil Lee, Elodie Drapeau, Douglas F. Levinson, Nadine Cohen, Luba Kalaydjieva, Brandon Wormley, Tao Li, Tõnu Esko, Alexander Richards, Srihari Gopal, Jubao Duan, Anil K. Malhotra, Elisabeth Stögmann, Gary Donohoe, Kimberly Chambert, Sara Marsal, Hreinn Stefansson, Jo Knight, Ole Mors, Per Hoffmann, Dieter B. Wildenauer, James J. Crowley, Srinivas Thirumalai, Vahram Haroutunian, A. Hofman, Hailiang Huang, Thomas Hansen, Daniel R. Weinberger, Andrew McQuillin, Vaughan J. Carr, Vaidutis Kučinskas, Jimmy Lee Chee Keong, Digby Quested, Aarno Palotie, Robert Freedman, Hon-Cheong So, Jennifer L. Moran, Donald W. Black, Mark Reimers, Abraham Reichenberg, Jurgen Del Favero, Paola Giusti-Rodríguez, Tracey L. Petryshen, Olli Pietiläinen, Franziska Degenhardt, Laurent Essioux, Esben Agerbo, Qiang Wang, Jana Strohmaier, Siow Ann Chong, Johan G. Eriksson, Martin Begemann, Younes Mokrab, Colm McDonald, Silviu Alin Bacanu, Martilias S. Farrell, Christos Pantelis, Kai How Farh, Line Olsen, Naser Durmishi, Antonio Julià, Stefan Herms, Qingqin S. Li, Bettina Konte, George Kirov, Rodney J. Scott, Nelson B. Freimer, Mads V. Hollegaard, Shaun Purcell, Erik Söderman, Dragan M. Svrakic, Patrik K. E. Magnusson, Douglas Blackwood, Jin P. Szatkiewicz, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, Morten Mattingsdal, Jim van Os, Sarah Tosato, Milan Macek, Joshua L. Roffman, Jan Lubinski, Eadbhard O'Callaghan, Juha Karjalainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Laura Nisenbaum, Eric Y.H. Chen, David M. Hougaard, Jaana Suvisaari, Chris C. A. Spencer, Alan R. Sanders, Alkes L. Price, Vihra Milanova, Juha Veijola, Christian Hammer, Raymond C.K. Chan, Stacy Steinberg, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Lieuwe de Haan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Ni, Guiyan, Gratten, Jacob, Wray, Naomi R, Lee, Sang Hong, Germeys, Inez, Complex Trait Genetics, Háskóli Íslands, University of Iceland, Child and Adolescent Psychiatry / Psychology, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, University Management, Department of Psychiatry, Center for Population, Health and Society, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, Multifactorial Inheritance, PATERNAL-AGE, 3124 Neurology and psychiatry, COMMON SNPS, fluids and secretions, 0302 clinical medicine, CHILD, Risk Factors, Pregnancy, 2.1 Biological and endogenous factors, Medicine, Aetiology, Pediatric, PROPORTION, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Multidisciplinary, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, Biobank, 3. Good health, AFB, Mental Health, Schizophrenia, Female, Erfðarannsóknir, Psychosocial, TRAITS, schizophrenia, age at birth, AFB, Maternal Age, Adult, age at first birth in women, genetic association, Offspring, Science, Genetic correlation, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Geðklofi, Genetics, age at birth, Humans, Genetic Predisposition to Disease, Bipolar disorder, General, Biology, Genetic association study, 030304 developmental biology, Genetic association, business.industry, Genetic heterogeneity, Prevention, average aged parents, Parturition, SCORE REGRESSION, bacterial infections and mycoses, medicine.disease, Mental health, Brain Disorders, respiratory tract diseases, schizophrenia, Good Health and Well Being, 030104 developmental biology, younger and older parents, DE-NOVO MUTATIONS, ddc:000, Human medicine, business, 030217 neurology & neurosurgery, Demography
Abstract: Publisher's version (útgefin grein), Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health., This research is supported by the Australian National Health and Medical Research Council (1080157, 1087889, 1103418, 1127440), and the Australian Research Council (DP160102126, FT160100229). This research has been conducted using the UK Biobank Resource. UK Biobank (http://www.ukbiobank.ac.uk) Research Ethics Committee (REC) approval number is 11/NW/0382. Our reference number approved by UK Biobank is 14575.
Published: 2017
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50. Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring

Author: Annegret Geipel, Lukas Soellner, Franziska Degenhardt, Matthias Begemann, Thomas Eggermann, and Elisabeth Mangold
Subjects: Adult, 0301 basic medicine, Heterozygote, Offspring, Perinatal Death, 030105 genetics & heredity, Biology, Article, Genomic Imprinting, 03 medical and health sciences, Pregnancy, Genetics, medicine, Humans, Imprinting (psychology), Allele, Fetal Viability, Fetal Death, Alleles, Genetics (clinical), Adaptor Proteins, Signal Transducing, Infant, Newborn, Maternal effect, DNA Methylation, medicine.disease, NLRP7, 030104 developmental biology, Codon, Nonsense, DNA methylation, Female, Genomic imprinting, Infant, Premature
Abstract: It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternal heterozygous NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-year-old woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Next-generation sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p.(Phe671Glnfs*18)). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers.
Published: 2017
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