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4. In vivo hippocampal subfield volumes in bipolar disorder—A mega‐analysis from The Enhancing Neuro Imaging Genetics through Meta‐Analysis Bipolar Disorder Working Group

Author

Haukvik, Unn K, Gurholt, Tiril P, Nerland, Stener, Elvsåshagen, Torbjørn, Akudjedu, Theophilus N, Alda, Martin, Alnæs, Dag, Alonso‐Lana, Silvia, Bauer, Jochen, Baune, Bernhard T, Benedetti, Francesco, Berk, Michael, Bettella, Francesco, Bøen, Erlend, Bonnín, Caterina M, Brambilla, Paolo, Canales‐Rodríguez, Erick J, Cannon, Dara M, Caseras, Xavier, Dandash, Orwa, Dannlowski, Udo, Delvecchio, Giuseppe, Díaz‐Zuluaga, Ana M, Erp, Theo GM, Fatjó‐Vilas, Mar, Foley, Sonya F, Förster, Katharina, Fullerton, Janice M, Goikolea, José M, Grotegerd, Dominik, Gruber, Oliver, Haarman, Bartholomeus CM, Haatveit, Beathe, Hajek, Tomas, Hallahan, Brian, Harris, Mathew, Hawkins, Emma L, Howells, Fleur M, Hülsmann, Carina, Jahanshad, Neda, Jørgensen, Kjetil N, Kircher, Tilo, Krämer, Bernd, Krug, Axel, Kuplicki, Rayus, Lagerberg, Trine V, Lancaster, Thomas M, Lenroot, Rhoshel K, Lonning, Vera, López‐Jaramillo, Carlos, Malt, Ulrik F, McDonald, Colm, McIntosh, Andrew M, McPhilemy, Genevieve, Meer, Dennis, Melle, Ingrid, Melloni, Elisa MT, Mitchell, Philip B, Nabulsi, Leila, Nenadić, Igor, Oertel, Viola, Oldani, Lucio, Opel, Nils, Otaduy, Maria CG, Overs, Bronwyn J, Pineda‐Zapata, Julian A, Pomarol‐Clotet, Edith, Radua, Joaquim, Rauer, Lisa, Redlich, Ronny, Repple, Jonathan, Rive, Maria M, Roberts, Gloria, Ruhe, Henricus G, Salminen, Lauren E, Salvador, Raymond, Sarró, Salvador, Savitz, Jonathan, Schene, Aart H, Sim, Kang, Soeiro‐de‐Souza, Marcio G, Stäblein, Michael, Stein, Dan J, Stein, Frederike, Tamnes, Christian K, Temmingh, Henk S, Thomopoulos, Sophia I, Veltman, Dick J, Vieta, Eduard, Waltemate, Lena, Westlye, Lars T, Whalley, Heather C, Sämann, Philipp G, Thompson, Paul M, Ching, Christopher RK, Andreassen, Ole A, Agartz, Ingrid, and Group, ENIGMA Bipolar Disorder Working

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Brain Disorders, Mental Health, Serious Mental Illness, Neurosciences, Biomedical Imaging, Bipolar Disorder, Mental health, Genetics, Hippocampus, Humans, Magnetic Resonance Imaging, Neuroimaging, ENIGMA Bipolar Disorder Working Group, bipolar disorder subtype, hippocampus, large-scale, lithium, psychosis, structural brain MRI, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Published
2022

10. Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function.

Author

Ali, Deema, Laighneach, Aodán, Corley, Emma, Patlola, Saahithh Redddi, Mahoney, Rebecca, Holleran, Laurena, McKernan, Declan P., Kelly, John P., Corvin, Aiden P., Hallahan, Brian, McDonald, Colm, Donohoe, Gary, and Morris, Derek W.

Subjects
LOCUS (Genetics), NEURAL stem cells, GENE expression, NEURON development, GENOME-wide association studies
Abstract

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes. Author summary: Schizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability, leading to unemployment, homelessness and social isolation. Large-scale genetic studies of schizophrenia and cognitive function have been effective at identifying individual SNPs and genes that contribute to these phenotypes but have struggled to immediately uncover the bigger picture of the underlying biology of the disorder. Here we take an individual gene associated with schizophrenia and cognitive function called MEF2C, which on its own is a very important regulator of brain development. We use functional genomics data from studies where MEF2C has been mutated to identify sets of other genes that are influenced by MEF2C in developing and mature neurons. We show that several of these gene-sets are enriched for common variants associated with schizophrenia and cognitive function, and for rare variants that increase risk of various neurodevelopmental disorders. These gene-sets are involved in neuron development and mitochondrial function, providing evidence that these biological processes may be important in the context of the molecular mechanisms that underpin schizophrenia and cognitive function. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neurogenesis and mitochondrial function

Author

Ali, Deema, primary, Laighneach, Aodán, additional, Corley, Emma, additional, Patlola, Saahithh Redddi, additional, Holleran, Laurena, additional, McKernan, Declan P., additional, Kelly, John P., additional, Corvin, Aiden P., additional, Hallahan, Brian, additional, McDonald, Colm, additional, Donohoe, Gary, additional, and Morris, Derek W, additional

Published
2023
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22. Complete genome of an inhibitor-resistant blaTEM-30 encoding Escherichia coli sequence type 127 isolate identified in human saliva with a high genotypic virulence load

Author

McEvoy, Niamh, primary, O'Connor, Andy, additional, McDonagh, Francesca, additional, Lonappan, Aneesa Mangalam, additional, Farrell, Maeve Louise, additional, Kovarova, Aneta, additional, Burke, Liam, additional, Ryan, Kate, additional, Hallahan, Brian, additional, and Miliotis, Georgios, additional

Published
2023
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23. Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry

Author

Nabulsi, Leila, primary, Chandio, Bramsh Q., additional, McPhilemy, Genevieve, additional, Martyn, Fiona M., additional, Roberts, Gloria, additional, Hallahan, Brian, additional, Dannlowski, Udo, additional, Kircher, Tilo, additional, Haarman, Benno, additional, Mitchell, Philip, additional, McDonald, Colm, additional, Cannon, Dara M., additional, Andreassen, Ole A., additional, Ching, Christopher R. K., additional, and Thompson, Paul M., additional

Published
2023
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25. Uncinate fasciculus microstructural organisation and emotion recognition in schizophrenia: controlling for hit rate bias.

Author

Stevens, Matthew, Mhurchú, Síle Ní, Corley, Emma, Egan, Ciara, Hallahan, Brian, McDonald, Colm, Donohoe, Gary, and Burke, Tom

Subjects
EMOTION recognition, STIMULUS & response (Psychology), COGNITIVE ability, ADVERSE childhood experiences, SOCIAL perception
Abstract

Introduction: Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterised by functional and structural brain dysconnectivity and disturbances in perception, cognition, emotion, and social functioning. In the present study, we investigated whether the microstructural organisation of the uncinate fasciculus (UF) was associated with emotion recognition (ER) performance. Additionally, we investigated the usefulness of an unbiased hit rate (UHR) score to control for response biases (i.e., participant guessing) during an emotion recognition task (ERT). Methods: Fifty-eight individuals diagnosed with SCZ were included. The CANTAB ERT was used to measure social cognition. Specific ROI manual tract segmentation was completed using ExploreDTI and followed the protocol previously outlined by Coad et al. (2020). Results: We found that the microstructural organisation of the UF was significantly correlated with physical neglect and ER outcomes. Furthermore, we found that the UHR score was more sensitive to ERT subscale emotion items than the standard HR score. Finally, given the association between childhood trauma (in particular childhood neglect) and social cognition in SCZ, a mediation analysis found evidence that microstructural alterations of the UF mediated an association between childhood trauma and social cognitive performance. Discussion: The mediating role of microstructural alterations in the UF on the association between childhood trauma and social cognitive performance suggests that early life adversity impacts both brain development and social cognitive outcomes for people with SCZ. Limitations of the present study include the restricted ability of the tensor model to correctly assess multi-directionality at regions where fibre populations intersect. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Corpus callosum microstructural organization mediates the effects of physical neglect on social cognition in schizophrenia

Author

Corley, Emma, primary, Gleeson, Christina, additional, Godfrey, Emmet, additional, Cowman, Megan, additional, Patlola, Saahithh Redddi, additional, Cannon, Dara M., additional, McKernan, Declan P., additional, Kelly, John P., additional, Hallahan, Brian, additional, McDonald, Colm, additional, Morris, Derek W., additional, Burke, Tom, additional, and Donohoe, Gary, additional

Published
2023
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32. The arcuate fasciculus network and verbal deficits in psychosis

Author

Kenney Joanne P.M., McPhilemy Genevieve, Scanlon Cathy, Najt Pablo, McInerney Shane, Arndt Sophia, Scherz Elisabeth, Byrne Fintan, Leemans Alexander, Jeurissen Ben, Hallahan Brian, McDonald Colm, and Cannon Dara M.

Subjects
arcuate fasciculus, cortical language regions, verbal learning, verbal fluency, psychosis, structural mri, diffusion mri, lateralization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Verbal learning (VL) and fluency (VF) are prominent cognitive deficits in psychosis, of which the precise neuroanatomical contributions are not fully understood. We investigated the arcuate fasciculus (AF) and its associated cortical regions to identify structural abnormalities contributing to these verbal impairments in early stages of psychotic illness.

Published
2017
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34. Corrigendum to ’Childhood trauma is associated with altered white matter microstructural organization in schizophrenia’ Psychiatry Research: Neuroimaging, 330 (2023) 111616

Author

Costello, Laura, primary, Dauvermann, Maria R., additional, Tronchin, Giulia, additional, Holleran, Laurena, additional, Mothersill, David, additional, Rokita, Karolina I., additional, Kane, Ruán, additional, Hallahan, Brian, additional, Corvin, Aiden, additional, Morris, Derek, additional, McKernan, Declan P., additional, Kelly, John, additional, McDonald, Colm, additional, Donohoe, Gary, additional, and Cannon, Dara M., additional

Published
2023
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39. Complete genome of an inhibitor-resistant blaTEM-30encoding Escherichia colisequence type 127 isolate identified in human saliva with a high genotypic virulence load

Author

McEvoy, Niamh, O'Connor, Andy, McDonagh, Francesca, Lonappan, Aneesa Mangalam, Farrell, Maeve Louise, Kovarova, Aneta, Burke, Liam, Ryan, Kate, Hallahan, Brian, and Miliotis, Georgios

Abstract

Escherichia colisequence type (ST) 127 is a pandemic lineage that belongs to the extraintestial pathogenic (ExPEC) family, mainly associated with urinary tract infections and bloodstream infections. Here, we report the complete genome of an E. coliST 127 isolate which was identified in the saliva of a patient with treatment-resistant schizophrenia (TRS) exhibiting no signs of infection. The objective of this work is to determine the mobile genetic elements (MGEs), antibiotic resistance genes (ARGs), and virulence factors (VFs) that contribute to the pathogenicity of such ST127 isolates.

Published
2023
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41. Volume and shape analysis of subcortical brain structures and ventricles in euthymic bipolar I disorder

Author

Quigley, Stephen J., Scanlon, Cathy, Kilmartin, Liam, Emsell, Louise, Langan, Camilla, Hallahan, Brian, Murray, Michael, Waters, Conor, Waldron, Mairead, Hehir, Sarah, Casey, Helen, McDermott, Emma, Ridge, Jason, Kenney, Joanne, O’Donoghue, Stefani, Nannery, Rory, Ambati, Srinath, McCarthy, Peter, Barker, Gareth J., Cannon, Dara M., and McDonald, Colm

Published
2015
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45. Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia

Author

King, Sinead, primary, Mothersill, David, additional, Holleran, Laurena, additional, Patlola, Saahithh, additional, McManus, Ross, additional, Kenyon, Marcus, additional, McDonald, Colm, additional, Hallahan, Brian, additional, Corvin, Aiden, additional, Morris, Derek W., additional, Kelly, John P., additional, McKernan, Declan, additional, and Donohoe, Gary, additional

Published
2022
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48. Corpus Callosum Microstructural Tract Integrity Relates to Longer Emotion Recognition Reaction Time in People with Schizophrenia

Author

Burke, Tom, primary, Gleeson, Christina, additional, Holleran, Laurena, additional, Mothersill, David, additional, Holland, Jessica, additional, Costello, Laura, additional, Kane, Ruán, additional, McKernan, Declan P., additional, Morris, Derek W., additional, Kelly, John P., additional, Corvin, Aiden P., additional, Hallahan, Brian P., additional, McDonald, Colm, additional, and Donohoe, Gary, additional

Published
2022
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