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The Role of Rare Copy Number Variants in the Functional Outcomes of Individuals With Neurodevelopmental Conditions
- Maria Flanagan, Charlotte Dennison, Joanna Martin, Anita Thapar
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- Journal:
- BJPsych Open / Volume 10 / Issue S1 / June 2024
- Published online by Cambridge University Press:
- 01 August 2024, p. S33
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Aims
Copy number variants (CNVs) are large changes in the structure of DNA. Certain rare CNVs are associated with elevated chance of neurodevelopmental conditions and difficulties (NDs), including autism spectrum disorder (ASD) and intellectual disability, alongside various physical health complications. Currently, CNV testing in children with NDs is only recommended under limited circumstances, in part because their impact on outcomes and prognosis remains unknown. We aimed to investigate whether individuals with NDs in childhood, with and without rare pathogenic CNVs, differ in terms of functional outcomes in early adulthood.
MethodsPathogenic CNV carriers were identified in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort of individuals born in 1991–1992. Individuals with the following childhood NDs were identified through parent-reported diagnostic interviews and questionnaires, and assessment with the child: Attention Deficit Hyperactivity-Disorder (ADHD), ASD, reading difficulties, coordination difficulties, language difficulties, and chronic tics. Outcomes were measured at age 25 and included: presence of an emotional disorder, being in receipt of sickness/disability benefit, ability to make and maintain friendships, not being in education, employment, or training (NEET), and self-reported life satisfaction. We will use logistic regression to measure the association between carrying a pathogenic CNV and each functional outcome in ALSPAC. Sensitivity analyses will be conducted on all large (>250kb), rare (<1%) CNVs, as opposed to only pathogenic CNVs.
Results983 individuals with probable NDs (39.4% female, n = 387) were identified in ALSPAC, including 495 people with ASD, 163 with ADHD, 16 with Tourette's syndrome, 210 with reading difficulties, 295 with language difficulties, and 166 with coordination difficulties. Many individuals met criteria for more than one ND.
43 (4.4%) of individuals with an ND carried a pathogenic CNV. CNV carrier status amongst individuals with a ND was not associated with sex (4.4% of females vs 4.4% of males, OR = 1.007 [0.539–1.882] p = 0.981). Analysis of CNV carrier status on outcomes in NDs will be conducted between February and April 2024.
ConclusionEvidence in support of poorer outcomes in CNV carriers could suggest that neurodiverse young people with CNVs may benefit from intervention to improve outcomes, and thus more individuals may benefit from genetic testing. Conversely, evidence indicating that CNVs do not impact outcomes may suggest that current clinical guidelines are appropriate within the current research landscape, and that further research is needed to understand the impact of carrying a pathogenic CNV in young people with NDs.
An Item-Level Systematic Review of the Presentation of Attention Deficit Hyperactivity Disorder (ADHD) in Females
- Annabelle Xiao Hui Lim, Tamara Williams, Louise Horstmann, Anita Thapar, Joanna Martin
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- Journal:
- BJPsych Open / Volume 10 / Issue S1 / June 2024
- Published online by Cambridge University Press:
- 01 August 2024, p. S8
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Sex differences in the prevalence of ADHD are well reported in the literature, with childhood ADHD being diagnosed 7–8 times more frequently in males than females, despite a population sex ratio of 3–4:1. A recent consensus statement argued that ADHD is under-identified and under-diagnosed in the UK, and this is especially concerning with regards to females. This systematic review aims to investigate specific symptoms characterising the manifestation of ADHD in females compared with both males with ADHD and females without ADHD.
MethodsA systematic search of eligible studies was conducted using predefined search criteria across six databases (Ovid MEDLINE, Ovid EMBASE, Ovid APA PsycINFO, ProQuest, EBSCO ERIC and EBSCO British Education Index), in line with a registration protocol on PROSPERO. Eligible studies included those with statistical analysis comparing ADHD, impact or co-occurring mental health difficulties at the item level, which compared ADHD symptoms in both sexes, or contrasted females with and without ADHD. Studies that exclusively reported total scores without item-level statistical results were excluded. A total of 5,378 articles were identified in the search and 13 studies met the criteria for inclusion.
ResultsOutcomes from 13 studies were analysed thematically. 7 studies looked at ADHD at an item level, while 7 studies explored disparities in impairment or other items. Of the eligible studies, 12 compared males and females with ADHD and 4 compared females with and without ADHD. 7 studies focussed on children with ADHD and 6 on adults. Preliminary results from 3 studies of ADHD symptoms in children indicated sex differences in hyperactive and impulsive symptoms: males were more likely to exhibit symptoms such as fidgeting and difficulty remain seated, while females exhibited higher rates of excessive talking and interrupting. Sex differences in impairment showed mixed results. Females with ADHD endorsed self-reported items related to mind-wandering and parent-reported impairment, including friendship difficulties, more than females without ADHD. Overall, the analysis of the results suggested that most studies do show some sex differences in ADHD and impairment items.
ConclusionWhile current studies of individuals diagnosed with ADHD highlight important sex differences, the limited number of direct investigations and predominant focus on total symptoms underscore the need for further research. Item-level analysis of symptoms and their impact is essential in exploring how sex influences the associations between ADHD, risk factors and functional outcomes. Recognising potential sex differences is essential for improving ADHD assessment in females and later life outcomes.
12 - Alexander Hume’s Hymnes, or Sacred Songs
- Edited by Steven J. Reid, University of Glasgow
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- Book:
- Rethinking the Renaissance and Reformation in Scotland
- Published by:
- Boydell & Brewer
- Published online:
- 16 May 2024
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- 05 March 2024, pp 242-260
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Summary
THIS chapter offers the first full critical reading of a much overlooked but significant contribution to Scots Calvinist poetry, Alexander Hume's Hymnes, or Sacred Songs, wherein the right vse of Poesie may be espied, a collection of verse and prose which was printed in Edinburgh in 1599. It demonstrates that the Hymnes is a carefully designed collection of a minister's writings, its sequence of prose and poetry precisely crafted and structured to explore the identities, roles and relationships of the ‘Godly’ poet and his reader, in terms both of delineating a method of private piety and of drawing the reader into a sense of community with other members of the faithful elect. By exploring Hume's collection in depth, the chapter also promotes a more complete understanding of the sophistication and complexity of Scottish devotional poetry at the turn of the seventeenth century, a period on which there is a growing body of scholarship but which remains less well-understood than later seventeenth-century religious writing. Recent work on seminal Reformation writing in Scotland including The Gude and Godlie Ballatis, on poetic and artistic masterpieces by Protestant writers such as Elizabeth Melville and Esther Inglis, on the growth of neo-Latin literature, and on post-Reformation music has done much to expand our knowledge of creative responses to the Reformation in Scotland by the turn of the seventeenth century. Much of this work has been directly facilitated by Professor Roger A. Mason's illumination of Scottish Reformation culture, particularly on the prominent and prolific figures of John Knox, George Buchanan and Andrew Melville. His work on these individuals and the intellectual connections between them, and more generally on Reformation historiography, provides essential context for my re-examination of the Hymnes, or Sacred Songs, its pastoral purpose and literary context. In particular, Mason's work has frequently considered the emergence of the ‘new Protestant self-image’, an important concept for understanding Alexander Hume's exploration of voice, self and identity in the Hymnes, or Sacred Songs. In his essay ‘Usable Pasts’, Mason reminds us of the significance of Arthur Williamson's earlier scholarship on the anxious mental world of early Reformation Scotland and its ‘tortured complexity’, a particularly pertinent piece of advice for any reader of Hume's Hymnes.
Migraine Treatment and Healthcare Resource Utilization in Alberta, Canada
- Erin Graves, Tara Cowling, Suzanne McMullen, Paul Ekwaru, Tram Pham, Michelle Mayer, Marie-Pier Ladouceur, Martine Hubert, Joanna Bougie, Farnaz Amoozegar
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- Journal:
- Canadian Journal of Neurological Sciences , First View
- Published online by Cambridge University Press:
- 16 October 2023, pp. 1-11
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Background:
Migraine poses a significant burden worldwide; however, there is limited evidence as to the burden in Canada. This study examined the treatment patterns, healthcare resource use (HRU), and costs among newly diagnosed or recurrent patients with migraine in Alberta, Canada, from the time of diagnosis or recurrence.
Methods:This retrospective observational study utilized administrative health data from Alberta, Canada. Patients were included in the Total Migraine Cohort if they had: (1) ≥1 International Classification of Diseases diagnostic code for migraine; or (2) ≥1 prescription dispense(s) for triptans from April 1, 2012, to March 31, 2018, with no previous diagnosis or dispensation code from April 1, 2010, to April 1, 2012.
Results:The mean age of the cohort (n = 199,931) was 40.0 years and 72.3% were women. The most common comorbidity was depression (19.7%). In each medication class examined, less than one-third of the cohort was prescribed triptans and fewer than one-fifth was prescribed a preventive. Among patients with ≥1 dispense, the mean rate of opioid prescriptions was 4.61 per patient-year, compared to 2.28 triptan prescriptions per patient-year. Migraine-related HRU accounted for 3%–10% of all use.
Conclusion:Comorbidities and high all-cause HRU were observed among newly diagnosed or recurrent patients with migraine. There is an underutilization of acute and preventive medications in the management of migraine. The high rate of opioid use reinforces the suboptimal management of migraine in Alberta. Migraine management may improve by educating healthcare professionals to optimize treatment strategies.
Burden of Episodic Migraine, Chronic Migraine, and Medication Overuse Headache in Alberta
- Suzanne McMullen, Erin Graves, Paul Ekwaru, Tram Pham, Michelle Mayer, Marie-Pier Ladouceur, Martine Hubert, Joanna Bougie, Farnaz Amoozegar
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- Journal:
- Canadian Journal of Neurological Sciences , First View
- Published online by Cambridge University Press:
- 05 October 2023, pp. 1-11
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Objective:
To describe demographic and clinical characteristics, healthcare resource use, costs, and treatment patterns in three migraine cohorts.
Methods:This retrospective observational study using administrative data examined patients with episodic migraine (EM), chronic migraine (CM) (without medication overuse headache [MOH]), and medication overuse headache in Alberta, Canada. Migraine patients were identified between 2012 and 2018 based on ≥ 1 diagnostic codes or triptan prescription. Patients with CM were defined using parameter estimates of a logistic regression model, and MOH was defined as patients with an average of ≥ 15 supply days covered of acute medications. EM was defined as patients without CM or MOH. Study outcomes were summarized using descriptive statistics.
Results:Patients with EM (n = 144,574), CM (n = 27,283), and MOH (n = 11,485) were included. Higher rates of healthcare use and costs were observed for CM (mean [SD] all-cause cost: ($12,693 [40,664]) and MOH ($16,611.5 [$38,748]) versus episodic migraine ($4,251 [$40,637]). Across all cohorts, opioids were the most dispensed acute medication (range across cohorts: 31.7%–89.8%), while antidepressants and anticonvulsants were the most dispensed preventive medication. Preventative medication classes were used by a minority of patients in each cohort, except anticonvulsants, where 50% of medication overuse patients had a dispensation.
Conclusions:Patients with CM and MOH have a greater burden of illness compared to patients with EM. The overutilization of acute medication, particularly opioids, and the underutilization of preventive medications highlight an unmet need to more effectively manage migraine.
Agricultural Research Service Weed Science Research: Past, Present, and Future
- Stephen L. Young, James V. Anderson, Scott R. Baerson, Joanna Bajsa-Hirschel, Dana M. Blumenthal, Chad S. Boyd, Clyde D. Boyette, Eric B. Brennan, Charles L. Cantrell, Wun S. Chao, Joanne C. Chee-Sanford, Charlie D. Clements, F. Allen Dray, Stephen O. Duke, Kayla M. Eason, Reginald S. Fletcher, Michael R. Fulcher, John F. Gaskin, Brenda J. Grewell, Erik P. Hamerlynck, Robert E. Hoagland, David P. Horvath, Eugene P. Law, John D. Madsen, Daniel E. Martin, Clint Mattox, Steven B. Mirsky, William T. Molin, Patrick J. Moran, Rebecca C. Mueller, Vijay K. Nandula, Beth A. Newingham, Zhiqiang Pan, Lauren M. Porensky, Paul D. Pratt, Andrew J. Price, Brian G. Rector, Krishna N. Reddy, Roger L. Sheley, Lincoln Smith, Melissa C. Smith, Keirith A. Snyder, Matthew A. Tancos, Natalie M. West, Gregory S. Wheeler, Martin M. Williams, Julie Wolf, Carissa L. Wonkka, Alice A. Wright, Jing Xi, Lew H. Ziska
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- Journal:
- Weed Science / Volume 71 / Issue 4 / July 2023
- Published online by Cambridge University Press:
- 16 August 2023, pp. 312-327
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The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.
DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts
- Amy J. Lynham, Sarah Knott, Jack F. G. Underwood, Leon Hubbard, Sharifah S. Agha, Jonathan I. Bisson, Marianne B. M. van den Bree, Samuel J. R. A. Chawner, Nicholas Craddock, Michael O'Donovan, Ian R. Jones, George Kirov, Kate Langley, Joanna Martin, Frances Rice, Neil P. Roberts, Anita Thapar, Richard Anney, Michael J. Owen, Jeremy Hall, Antonio F. Pardiñas, James T. R. Walters
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- Journal:
- BJPsych Open / Volume 9 / Issue 2 / March 2023
- Published online by Cambridge University Press:
- 08 February 2023, e32
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Background
Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood.
AimsWell-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research.
MethodAs part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant.
ResultsWe have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation.
ConclusionsDRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.
Evidence does not confirm that lithium prevents suicide: a reply to Bschor et al.
- Joanna Moncrieff, Martin Plöderl, Zainab Nabi, Jacki Stansfeld, Lisa Wood
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- Journal:
- Epidemiology and Psychiatric Sciences / Volume 31 / 2022
- Published online by Cambridge University Press:
- 13 December 2022, e88
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Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials
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- Zainab Nabi, Jacki Stansfeld, Martin Plöderl, Lisa Wood, Joanna Moncrieff
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- Epidemiology and Psychiatric Sciences / Volume 31 / 2022
- Published online by Cambridge University Press:
- 16 September 2022, e65
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Aims
Lithium has long been believed to reduce the risk of suicide and suicidal behaviour in people with mood disorders. Previous meta-analyses appeared to support this belief, but excluded relevant data due to the difficulty of conducting meta-analysis of rare events. The current study is an updated systematic review and meta-analysis that includes all eligible data, and evaluates suicide, non-fatal suicidal behaviour (including suicidal ideation) and suicide attempts.
MethodsWe searched PubMed, PsycINFO and Embase and some trial registers. We included all randomised trials comparing lithium and placebo or treatment as usual in mood disorders published after 2000, to ensure suicide was reliably reported. Trial quality was assessed using the Cochrane Risk of Bias tool. Pooled data were analysed using Fisher's Exact test. In addition, meta-analysis was conducted using various methods, prioritizing the Exact method. All trials were included in the analysis of suicide initially, regardless of whether they reported on suicide or not. We conducted a sensitivity analysis with trials that specifically reported on suicides and one that included trials published before 2000. Pre-specified subgroup analyses were performed involving suicide prevention trials, trials excluding people already taking lithium, trials involving people with bipolar disorder exclusively and those involving people with mixed affective diagnoses. Non-fatal suicidal behaviour and suicide attempts were analysed using the same methods, but only trials that reported these outcomes were included. PROSPERO registration: CRD42021265809.
ResultsTwelve eligible studies involving 2578 participants were included. The pooled suicide rate was 0.2% for people randomised to lithium and 0.4% with placebo or treatment as usual, which was not a statistically significant difference; odds ratio (OR) = 0.41 (95% confidence interval 0.03–2.49), p = 0.45. Meta-analysis using the Exact method produced an OR of 0.42 (95% confidence interval 0.01–4.5). The result was not substantially different when restricted to 11 trials that explicitly reported suicides and remained statistically non-significant when including 15 trials published before 2000 (mostly in the 1970s). There were no significant differences in any subgroup analysis. There was no difference in rates of all non-fatal suicidal behaviour in seven trials that reported this outcome, or in five trials that reported suicide attempts specifically. Meta-analyses using other methods also revealed no statistically significant differences.
ConclusionsEvidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.
20 - Undergraduate Research in Biology
- from Part III.1 - STEM
- Edited by Harald A. Mieg, Humboldt-Universität zu Berlin, Elizabeth Ambos, Angela Brew, Macquarie University, Sydney, Dominique Galli, Indiana University–Purdue University, Indianapolis, Judith Lehmann, Universidad de Buenos Aires, Argentina
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- The Cambridge Handbook of Undergraduate Research
- Published online:
- 11 August 2022
- Print publication:
- 07 July 2022, pp 207-214
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Summary
Future biologists require a profound understanding of leading biological concepts, mechanisms, methods, experimental design and data analysis on top of subject-specific expertise. Early and continued exposure to undergraduate research (UR) formats offers a central key to train the next generation of biologists, to drive student motivation and to facilitate early career decisions. UR formats can be classified at different pedagogical levels. At the highest level, students conduct their own independent research and create new knowledge. Course-based research experiences (CUREs) are suitable for larger groups and produce outcomes similar to research internships but require increased creativity on the side of faculty, depending on the respective framework and group size. To implement UR represents a challenge for faculty, as roles change from teaching toward mentoring, increasing the workload. Nevertheless, biology offers a wide variety of anchors for UR formats that are most suitable as an active learning element in biology education to balances pedagogical and research goals and increase student motivation.
Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach – CORRIGENDUM
- Micah Cearns, Azmeraw T. Amare, Klaus Oliver Schubert, Anbupalam Thalamuthu, Joseph Frank, Fabian Streit, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, JeanMichel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Pablo Cervantes, HsiChung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Andrea Hofmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O'Donovan, Norio Ozaki, Vincent Millischer, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fasil TekolaAyele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Stephanie H. Witt, Gloria Roberts, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Thomas G. Schulze, Marcella Rietschel, Scott R. Clark, Bernhard T. Baune
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- Journal:
- The British Journal of Psychiatry / Volume 221 / Issue 2 / August 2022
- Published online by Cambridge University Press:
- 04 May 2022, p. 494
- Print publication:
- August 2022
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Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach
- Micah Cearns, Azmeraw T. Amare, Klaus Oliver Schubert, Anbupalam Thalamuthu, Joseph Frank, Fabian Streit, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Andrea Hofmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O'Donovan, Norio Ozaki, Vincent Millischer, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fasil Tekola-Ayele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Stephanie H. Witt, Gloria Roberts, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Thomas G. Schulze, Marcella Rietschel, Scott R. Clark, Bernhard T. Baune
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- Journal:
- The British Journal of Psychiatry / Volume 220 / Issue 4 / April 2022
- Published online by Cambridge University Press:
- 28 February 2022, pp. 219-228
- Print publication:
- April 2022
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Background
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
AimsTo use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
MethodThis study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
ResultsThe best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
ConclusionsUsing PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Characterisation of age and polarity at onset in bipolar disorder
- Janos L. Kalman, Loes M. Olde Loohuis, Annabel Vreeker, Andrew McQuillin, Eli A. Stahl, Douglas Ruderfer, Maria Grigoroiu-Serbanescu, Georgia Panagiotaropoulou, Stephan Ripke, Tim B. Bigdeli, Frederike Stein, Tina Meller, Susanne Meinert, Helena Pelin, Fabian Streit, Sergi Papiol, Mark J. Adams, Rolf Adolfsson, Kristina Adorjan, Ingrid Agartz, Sofie R. Aminoff, Heike Anderson-Schmidt, Ole A. Andreassen, Raffaella Ardau, Jean-Michel Aubry, Ceylan Balaban, Nicholas Bass, Bernhard T. Baune, Frank Bellivier, Antoni Benabarre, Susanne Bengesser, Wade H Berrettini, Marco P. Boks, Evelyn J. Bromet, Katharina Brosch, Monika Budde, William Byerley, Pablo Cervantes, Catina Chillotti, Sven Cichon, Scott R. Clark, Ashley L. Comes, Aiden Corvin, William Coryell, Nick Craddock, David W. Craig, Paul E. Croarkin, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Srdjan Djurovic, Howard J. Edenberg, Mariam Al Eissa, Torbjørn Elvsåshagen, Bruno Etain, Ayman H. Fanous, Frederike Fellendorf, Alessia Fiorentino, Andreas J. Forstner, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Julie Garnham, Elliot Gershon, Michael Gill, Fernando S. Goes, Katherine Gordon-Smith, Paul Grof, Jose Guzman-Parra, Tim Hahn, Roland Hasler, Maria Heilbronner, Urs Heilbronner, Stephane Jamain, Esther Jimenez, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, John R. Kelsoe, James L. Kennedy, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Farah Klöhn-Saghatolislam, James A. Knowles, Thorsten M. Kranz, Trine Vik Lagerberg, Mikael Landen, William B. Lawson, Marion Leboyer, Qingqin S. Li, Mario Maj, Dolores Malaspina, Mirko Manchia, Fermin Mayoral, Susan L. McElroy, Melvin G. McInnis, Andrew M. McIntosh, Helena Medeiros, Ingrid Melle, Vihra Milanova, Philip B. Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Markus M. Nöthen, Tomas Novak, John I. Nurnberger, Niamh O'Brien, Kevin S. O'Connell, Claire O'Donovan, Michael C. O'Donovan, Nils Opel, Abigail Ortiz, Michael J. Owen, Erik Pålsson, Carlos Pato, Michele T. Pato, Joanna Pawlak, Julia-Katharina Pfarr, Claudia Pisanu, James B. Potash, Mark H Rapaport, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Jonathan Repple, Hélène Richard-Lepouriel, Marcella Rietschel, Kai Ringwald, Gloria Roberts, Guy Rouleau, Sabrina Schaupp, William A Scheftner, Simon Schmitt, Peter R. Schofield, K. Oliver Schubert, Eva C. Schulte, Barbara Schweizer, Fanny Senner, Giovanni Severino, Sally Sharp, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Alessio Squassina, Pavla Stopkova, John Strauss, Alfonso Tortorella, Gustavo Turecki, Joanna Twarowska-Hauser, Marin Veldic, Eduard Vieta, John B. Vincent, Wei Xu, Clement C. Zai, Peter P. Zandi, Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group, International Consortium on Lithium Genetics (ConLiGen), Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Arianna Di Florio, Jordan W. Smoller, Joanna M. Biernacka, Francis J. McMahon, Martin Alda, Bertram Müller-Myhsok, Nikolaos Koutsouleris, Peter Falkai, Nelson B. Freimer, Till F.M. Andlauer, Thomas G. Schulze, Roel A. Ophoff
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- Journal:
- The British Journal of Psychiatry / Volume 219 / Issue 6 / December 2021
- Published online by Cambridge University Press:
- 25 August 2021, pp. 659-669
- Print publication:
- December 2021
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Background
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
7 - Gwen
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 83-93
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Summary
Harry agreed, albeit reluctantly, to try living in London for a year. In May 1869 he and Georgina, accompanied by a servant maid and three pugs, left Beaumaris and took the train to the capital. Georgina was to stay with her mother in Stratford Place, and Harry with Freddy Warre, whilst they looked for lodgings.
By this time a great plan was beginning to evolve in Georgina's mind. Since her theatrical ambitions had been thwarted, she would become a music teacher instead. She had already achieved some success with her first pupil, a sickly, nervous girl called Gwendoline Jones, the daughter of a clergyman and goddaughter to Georgina's friend Catherine Wynne Jones. In 1866 Catherine had brought Gwen to see Georgina. The girl, who was said to have ‘a great taste for music’, had already had some lessons with Manuel García at the Royal Academy of Music in London and wished to become a professional singer. Her neighbours all thought that she had ‘such a sweet voice’ and sang ‘so charmingly’. Georgina, as ‘the great musical oracle of the county’ was asked to hear her sing. She agreed to do so, and gave her opinion that Gwen's talent was ‘very mediocre’ and ‘needed cultivation’. The girl was, moreover, ‘very unattractive in appearance’ and had ‘no more manner than might be expected of a Welsh goat’. Nevertheless, Catherine begged her friend to take the girl under her wing, to help her with her singing and to sing with her. Flattered by this request, and wishing to please the older woman who had been kind to her, Georgina agreed.
During the first few months of 1867 Gwen came for a lesson every few days – rather more often than she was really wanted. But she soon fell ill and returned to her parents, suffering (it was said) from ‘hysteria’. Two years later, just before the Weldons left Beaumaris, Gwen turned up again, apparently recovered, and told Georgina that she wished to settle in London, to study singing seriously, and to become a professional singer. She begged Georgina to recommend a suitable master. Georgina suggested that they should try Alberto Randegger, a well-known music teacher and composer, who had recently been appointed professor of singing at the Royal Academy.
15 - Mad-Doctors
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 196-212
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After resting for a day, Georgina returned to Tavistock House on the afternoon of 4 April, accompanied by Villiers and a friend, ‘dear old’ Professor Lloyd Birkbeck. The door was opened by James Bell, the broker's man and caretaker put into the house on Harry's behalf, and they pushed their way in. All around them were boxes full of Georgina's belongings which Ménier was about to carry off with the help of André Sauvadet, who was waiting outside in a hansom cab. Suddenly, Ménier himself emerged from the basement, where he and his Hungarian ‘secretary’ Alexander de Barathy were busy packing up more of Georgina's possessions. On seeing Georgina, Ménier ‘turned as pale as a ghost’ and rushed out of the house without a word, leaving his mistress, Olive Nicholls, behind. ‘Cheer up Madam’, Bell told Georgina, ‘I never saw a party run away from his debtor before.’ Georgina felt some sympathy for the girl, ‘the erring and deluded victim of this old scamp, this old and dirty Don Juan’, but she ordered her to leave the house. The girl went, threatening ‘You will not be here long’. But Bell (‘a pleasant old man’) was prepared to let Georgina stay and she remained in Tavistock House, receiving visits from Harry's London lawyer, James Neal, ‘a fool’, and the broker, Washington Hirschfield, ‘a fanfaron [braggart]’, both of whom were anxious to find out what was going on.
That evening Georgina wrote to Angèle to tell her what had happened:
I have thrown Ménier out. I stopped everything. They were carrying everything away – bed linen, beds, coverlets, your velvet dress! Don't worry. I will have my revenge. I will avenge you! The house is full of putains [whores]. I am exhausted – dead – but too happy to have saved something. Everything is ruined: the magnificent ceiling in the music room has a hole big enough for three men to get through. It's dreadful. They have stolen everything. God knows how much has gone. The gas has been cut off. I’ll have to pay 300 francs [£12]. They wanted to take my piano to pay the taxes.
1 - Georgina
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 1-19
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Georgina Thomas was born on 24 May 1837, a day of general rejoicing throughout Great Britain. Church bells rang; schools and shops were closed; and there were firework displays, tea parties and public dinners with speeches and toasts. It was ‘a day that the old would talk about for a long time, and the young would never forget’. This had, however, nothing whatsoever to do with Georgina, who happened to share her birthday with the young heir to the throne, Princess Victoria. In May 1837 Victoria turned eighteen and, under the provisions of the Regency Bill of 1831, attained her ‘royal majority’. This meant that she was able to rule alone, in her own right, when her uncle William IV died, less than a month after her birthday. The knowledge that she had been born on such an important day gave Georgina a ‘vague idea of superiority and of relationship to the Royal Family’ from an early age. This feeling was reinforced by the erroneous belief that the Thomases were descended from Edward III and would be entitled to claim the throne of England ‘if anything should happen to the reigning family’.
Georgina was the second daughter of Morgan Thomas of Gate House in the parish of Mayfield in Sussex and his wife, Louisa Frances Dalrymple. An elder sister, Cordelia, died of whooping cough when she was just seventeen months old, a few weeks after Georgina's birth. Morgan and Louisa had convinced themselves that their second child would be the longed-for son who was to continue the family line, and they made no attempt to hide their disappointment when the new baby turned out to be a girl. Georgina always felt that her parents had been dissatisfied with her since the day of her birth, somehow blaming her for her sister's early death. As Louisa wept beside Cordelia's empty cot, Georgina (with, as she later wrote, her habitual lack of tact) ‘kicked and screamed with life and joy’.
The Thomas family was of Welsh origin. There is no evidence for their supposed royal descent, but they could trace their ancestry back in the male line to one Traherne ap Thomas, who was living at Lletty Mawr in Llannon, Carmarthenshire, in 1597.
29 - Sillwood House
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 414-430
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Georgina arrived at Sillwood House late in the evening on 16 November 1904. This was to be her base for the remaining years of her life, though she spent most of her time in London until 1912 when illness finally prevented her from travelling. The original intention seems to have been for her to rent a flat, but it was not long before she took over the whole house. Whilst she was away, Grace Ashford and her younger sister Annie acted as caretakers and housekeepers. Occasional lodgers helped to subsidise the household expenses.
Georgina travelled to Paris for the last time in mid May 1905, returning to Brighton two months later to prepare for a new round of legal actions. One evening she and Annie Ashford went to the theatre to see Ellen Terry in Alice-Sit-by-the-Fire, a comedy written especially for the actress by J.M. Barrie. Georgina was critical of her old friend, whom she had not seen for nearly twenty years: ‘Ellen charming, fascinating, but as she [has] grown so stout, and being so tall, she is ponderous, and the way her figure is strapped up is a marvel. It does not look natural. I would not do it. She blacks up her eyes too much.’ On the following day the two women spent two hours together and ‘jabbered our heads off’.
In the second week of October, Georgina sent nine cases and baskets and an armchair to the Salisbury Hotel, just off Fleet Street, where she had rented a room. It was only ten minutes’ walk from the Royal Courts of Justice, and very convenient. When the Courts reopened, she vowed that she would not go near ‘the beastly place’ – but she was there almost every day. She was soon involved in a convoluted series of claims against everyone who had had anything to do with the biography of Gounod published in the previous year. She also renewed her attacks on the booksellers and librarians, W.H. Smith. They had all, she claimed, contributed to holding her up to ‘hatred, ridicule and contempt’, and had forced her once again ‘into that litigation which has occasioned her to be contemptuously treated in Courts of Justice and elsewhere, and unjustly twitted and bantered and spoken of and “at” as though she were a low designing courtezan, a common scold, without either talent, birth, education or reputation’.
19 - Disaster
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 260-277
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Georgina's ‘At Homes’ at Tavistock House had continued throughout September 1879. The room was almost always full, due to the publicity generated by her appearances at the Aquarium and in the police courts. The programmes were the usual mixture of readings and lectures (mainly by the hostess) and musical items. The takings, however, remained low. Georgina claimed that she was raising money to support her orphanage, but members of the audience may well have wondered what had happened to the orphans themselves. Most of them were still in France and Georgina quickly disposed of the only one left in London, ‘that little wretch’ Tommy, who was ‘planted’ at a place where he would be ‘trained on board ship’. Georgina was only too pleased to see him go.
As Rivière had deprived her of her Benefit Concert, Georgina decided to hold one of her own. On 5 November, the day of the cancelled concert at Covent Garden, she booked St James's Hall for St Cecilia's Day, 22 November. She sent a circular to the members of the choir, informing them
As you all know, I work for my orphanage and the reform of an iniquitous system which has broken my life and, well-nigh, my heart. I have no desire and no pleasure in public singing myself, and I have the sense to know that I am too old to dream of making a career. The choir is a great pleasure to me, and I entertain a sincere feeling of affectionate regard towards many of its members. I am, however, advised there are several backbiting, slanderous tongues among them. I am in a most extraordinarily difficult position, the target for lies, and, till now, the victim of injustice in its most cruel and cowardly form. I have to contend against public and private pique; against hundreds of thousand pounds sterling a year, which are able to buy up the very courts where justice is supposed to be meted out to the subjects of this realm, and the newspapers which are supposed to give fair play.
Apart from one or two ‘turncoats’, the choir remained loyal. Georgina received numerous letters of support and most of the singers still came to rehearsals.
30 - Angel or Devil?
- Joanna Martin
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- Book:
- Georgina Weldon
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- Boydell & Brewer
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- 09 April 2021
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- 21 May 2021, pp 431-436
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Georgina would no doubt have been pleased by the number of publications that took notice of her death, though she would not have been happy with everything that was written. Back in 1902 she had complained about the fact that her name did not appear in Who's Who, either in her own right or under her husband's name. She had even written her own entry:
Weldon, Georgina. Vocalist, composer, musical conductor, educationalist; trained Gounod's Choir, Mrs Weldon's Choir; founded Mrs Weldon's Orphanage. Celebrated through her successful agitation of Copyright Laws, Married Women's Property, Lunacy Laws and Litigation in person; also for Criminal Court of Appeal. Gained her suit for RCR (1882), against Forbes Winslow, MD, Sir Henry de Bathe, Gounod, Rivière and many others, being awarded heavy damages during 1884–86. Contributed many letters and articles on Spiritualism, Musical Reform, Education etc. Recreation: Requires none.
To which she added:
I have no hesitation in saying that my work has been more useful, more brave, more loyal, more arduous, more painful and more ungrateful than any woman's work recorded in Who's Who. Why, therefore, honor me by singling me out for boycottage? I bravely, laboriously, successfully – as a torpedo among men of war – steered my way alone and blew all calumnies and insinuations to blazes. I believe myself to be the bravest woman in the world.
The obituary in the Daily Telegraph paid more attention to Georgina's friendship with Gounod, which ‘has been described as romantic’ but ‘turned to woeful discord’, and to her fame as a litigant: ‘A handsome woman, proud of her abilities and strong of will, she rather courted than avoided law suits’. The notice in the Daily Mirror was headed ‘A Famous Woman Litigant who Liked the Way Fish was Cooked’, and told how the ‘aged litigant’ had described her time in Holloway Gaol as the happiest days of her life because ‘the way they cooked fish there was a dream’. She was, the journalist added, ‘the most celebrated woman litigant in the history of the British Law Courts’.
Contents
- Joanna Martin
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- Book:
- Georgina Weldon
- Published by:
- Boydell & Brewer
- Published online:
- 09 April 2021
- Print publication:
- 21 May 2021, pp vii-viii
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