With few exceptions, the marked advances in knowledge about the genetic basis for psychiatric disorders have not converged on findings that can be confidently used for systematically interrogating underlying mechanisms for disease onset and progression. Functional genomics aims to provide mechanistic insights from genetic association studies and has the potential to facilitate biological insight. This series of presentations is from members of the newly started PGC working group for Functional Genomics and showcases how the use of data and methodology with single-cell resolution can further our understanding of the etiology of psychiatric disorders and the mechanism of drug action. The first talk describes an approach that allows the identification and characterization of cell type-specific and/or dynamic regulatory elements. The second talk leverages a new method to analyze cellular states and how these states relate to heritability enrichment for major depression disorder. The third talk describes a meta-analysis for optimizing sampling parameters for single-cell case/control studies which will provide much-needed rigor to an emerging field of study. The fourth talk is on the analysis of peripheral blood samples in the search for an immunological component to psychiatric disorders. Our four speakers all have expertise in single-cell methods and genetic association analysis. Each speaker has a complimentary background and methodological approach and will present the latest findings alongside the strengths and limitations of each approach and the datasets on which these analyses are based.
{"title":"FUNCTIONAL GENOMIC APPROACHES WITH SINGLE-CELL RESOLUTION PROVIDE MECHANISTIC AND BIOLOGICAL INSIGHTS BASED ON GENETIC ASSOCIATION STUDIES","authors":"Jens Hjerling-Leffler (Chair) , Mary-Ellen Lynall (Co-chair) , Shuyang Yao Ph.D. (Discussant)","doi":"10.1016/j.euroneuro.2024.08.023","DOIUrl":"10.1016/j.euroneuro.2024.08.023","url":null,"abstract":"<div><div>With few exceptions, the marked advances in knowledge about the genetic basis for psychiatric disorders have not converged on findings that can be confidently used for systematically interrogating underlying mechanisms for disease onset and progression. Functional genomics aims to provide mechanistic insights from genetic association studies and has the potential to facilitate biological insight. This series of presentations is from members of the newly started PGC working group for Functional Genomics and showcases how the use of data and methodology with single-cell resolution can further our understanding of the etiology of psychiatric disorders and the mechanism of drug action. The first talk describes an approach that allows the identification and characterization of cell type-specific and/or dynamic regulatory elements. The second talk leverages a new method to analyze cellular states and how these states relate to heritability enrichment for major depression disorder. The third talk describes a meta-analysis for optimizing sampling parameters for single-cell case/control studies which will provide much-needed rigor to an emerging field of study. The fourth talk is on the analysis of peripheral blood samples in the search for an immunological component to psychiatric disorders. Our four speakers all have expertise in single-cell methods and genetic association analysis. Each speaker has a complimentary background and methodological approach and will present the latest findings alongside the strengths and limitations of each approach and the datasets on which these analyses are based.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 8"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.062
Helena Davies , Yasmin Ahmadzadeh , Joanna K. Bright , Anti-Racism Working Group
The Anti-Racism Working Group (ARWG) of the Social, Genetic, Developmental Psychiatry (SGDP) Centre aims to help identify, propose, instigate, and support change consistent with an anti-racist agenda within the department. This talk will showcase the work done by the ARWG, the challenges we faced along the way, and where the team plans to go next. The ARWG was established in 2020 consists of three subgroups: (1) SGDP Centre Protocol, which aims to help develop and embed anti-racist procedures and practices within the department, (2) SGDP Centre Internal Events and Communication, which organises events on anti-racism for members of the department and the wider King's College London community, and (3) SGDP Centre External Events and Wider Opportunities, which aims to provide mentoring, allyship, training, and communication for people and organisations outside of King's College London. Since our inception, we have organised multiple events, including a talk from Dr Jedidiah Carlson titled ‘Disrupting the Weaponisation of Genetics Research by Extremists’, and have supervised multiple undergraduate projects with an anti-racism focus, for example, ‘Exploring anti-racist terminology and research practices for mental health researchers’. We also coordinate the annual faculty-wide outreach programme for London-based teenagers that aims to encourage continuation of science education to university level. To track and communicate perceptions and opinions about racism within the SGDP Centre, we distribute surveys and present the findings to the department, as well as deliver regular reports on our progress. A key challenge we encountered was fostering support and engagement from a wider audience. Building capacity across the university has been improved through collaboration with other departments and Culture, Equity, Diversity and Inclusion groups. Currently, the team is developing an anti-racist toolkit for use as an individual or within a team, guidelines on how to increase inclusivity of teaching, and a terminology guide for researchers measuring and reporting diversity. Moving forward, we hope to develop sustainable tools and initiatives that are embedded within departmental practice that promote diversity and equality of opportunity among students and staff across all levels of seniority.
{"title":"PROGRESS OF AND CHALLENGES FACED BY THE ANTI-RACISM WORKING GROUP AT KING'S COLLEGE LONDON","authors":"Helena Davies , Yasmin Ahmadzadeh , Joanna K. Bright , Anti-Racism Working Group","doi":"10.1016/j.euroneuro.2024.08.062","DOIUrl":"10.1016/j.euroneuro.2024.08.062","url":null,"abstract":"<div><div>The Anti-Racism Working Group (ARWG) of the Social, Genetic, Developmental Psychiatry (SGDP) Centre aims to help identify, propose, instigate, and support change consistent with an anti-racist agenda within the department. This talk will showcase the work done by the ARWG, the challenges we faced along the way, and where the team plans to go next. The ARWG was established in 2020 consists of three subgroups: (1) SGDP Centre Protocol, which aims to help develop and embed anti-racist procedures and practices within the department, (2) SGDP Centre Internal Events and Communication, which organises events on anti-racism for members of the department and the wider King's College London community, and (3) SGDP Centre External Events and Wider Opportunities, which aims to provide mentoring, allyship, training, and communication for people and organisations outside of King's College London. Since our inception, we have organised multiple events, including a talk from Dr Jedidiah Carlson titled ‘Disrupting the Weaponisation of Genetics Research by Extremists’, and have supervised multiple undergraduate projects with an anti-racism focus, for example, ‘Exploring anti-racist terminology and research practices for mental health researchers’. We also coordinate the annual faculty-wide outreach programme for London-based teenagers that aims to encourage continuation of science education to university level. To track and communicate perceptions and opinions about racism within the SGDP Centre, we distribute surveys and present the findings to the department, as well as deliver regular reports on our progress. A key challenge we encountered was fostering support and engagement from a wider audience. Building capacity across the university has been improved through collaboration with other departments and Culture, Equity, Diversity and Inclusion groups. Currently, the team is developing an anti-racist toolkit for use as an individual or within a team, guidelines on how to increase inclusivity of teaching, and a terminology guide for researchers measuring and reporting diversity. Moving forward, we hope to develop sustainable tools and initiatives that are embedded within departmental practice that promote diversity and equality of opportunity among students and staff across all levels of seniority.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 23-24"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.093
Ruby Tsang, Nicholas Timpson
Depression is a complex and multifactorial disorder that has genetic and environmental influences. Genome-wide association studies have shown that common genetic variants are implicated in depression. These common variants, when combined into polygenic risk scores, are associated with depression case status, severity and age of onset. However, less is known about how genetic risk affects change in depression symptoms longitudinally. Furthermore, psychiatric disorders are comorbid and recent studies have shown genetic risk is shared between them, but the association between this shared polygenic risk and how depression manifests and changes over time is not yet understood.
We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Self-reported depressive symptoms were assessed on 10 occasions between the ages of 10 and 25 using the 13-item Short Mood and Feelings Questionnaire. Polygenic risk scores (PRS) for major depressive disorder (MDD), anxiety (ANX), neuroticism (NEU), and schizophrenia (SCZ) were computed with PRSice-2 using summary statistics from recent genome-wide associations studies, in which ALSPAC was not included. Additionally, we used genomic structural equation modelling (GSEM) to create a multi-trait PRS of MDD, ANX, NEU, SCZ, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder, to capture the spectrum of psychopathology and explored how this genetic risk score was associated with depression trajectories.
We modelled depression trajectories using generalised additive models, with age as the time metric, and included sex, age-sex interaction, PRS, age-PRS interaction, and the first 10 principal components as predictors. We ran separate models for each PRS.
Depression trajectories for those in the top and bottom deciles of MDD and NEU PRS start to show divergence around mid- to late-adolescence with higher genetic risk associated with worse trajectories. With the multi-trait PRS, differences emerge as early as childhood, again with higher genetic risk indicative of worse trajectories. In these three models, the separation between the trajectories then continues to increase into adulthood. No clear pattern of separation was observed with the ANX or SCZ PRS.
These findings suggest that psychiatric PRS are associate with (and may influence) the longitudinal course of depressive symptoms from childhood into early adulthood. The multi-trait PRS was superior to PRS of individual psychiatricdisorders in delineating depression trajectories in association with genetic risk. One interpretation is that a spectrum of psychiatric genetic risk could underpin developmental differences in depression trajectories.
{"title":"POLYGENIC RISK SCORES FOR A SPECTRUM OF PSYCHIATRIC OUTCOMES ARE ALSO ASSOCIATED WITH DEPRESSION TRAJECTORIES FROM CHILDHOOD TO EARLY ADULTHOOD: FINDINGS FROM THE AVON LONGITUDINAL STUDY OF PARENTS AND CHILDREN","authors":"Ruby Tsang, Nicholas Timpson","doi":"10.1016/j.euroneuro.2024.08.093","DOIUrl":"10.1016/j.euroneuro.2024.08.093","url":null,"abstract":"<div><div>Depression is a complex and multifactorial disorder that has genetic and environmental influences. Genome-wide association studies have shown that common genetic variants are implicated in depression. These common variants, when combined into polygenic risk scores, are associated with depression case status, severity and age of onset. However, less is known about how genetic risk affects change in depression symptoms longitudinally. Furthermore, psychiatric disorders are comorbid and recent studies have shown genetic risk is shared between them, but the association between this shared polygenic risk and how depression manifests and changes over time is not yet understood.</div><div>We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Self-reported depressive symptoms were assessed on 10 occasions between the ages of 10 and 25 using the 13-item Short Mood and Feelings Questionnaire. Polygenic risk scores (PRS) for major depressive disorder (MDD), anxiety (ANX), neuroticism (NEU), and schizophrenia (SCZ) were computed with PRSice-2 using summary statistics from recent genome-wide associations studies, in which ALSPAC was not included. Additionally, we used genomic structural equation modelling (GSEM) to create a multi-trait PRS of MDD, ANX, NEU, SCZ, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder, to capture the spectrum of psychopathology and explored how this genetic risk score was associated with depression trajectories.</div><div>We modelled depression trajectories using generalised additive models, with age as the time metric, and included sex, age-sex interaction, PRS, age-PRS interaction, and the first 10 principal components as predictors. We ran separate models for each PRS.</div><div>Depression trajectories for those in the top and bottom deciles of MDD and NEU PRS start to show divergence around mid- to late-adolescence with higher genetic risk associated with worse trajectories. With the multi-trait PRS, differences emerge as early as childhood, again with higher genetic risk indicative of worse trajectories. In these three models, the separation between the trajectories then continues to increase into adulthood. No clear pattern of separation was observed with the ANX or SCZ PRS.</div><div>These findings suggest that psychiatric PRS are associate with (and may influence) the longitudinal course of depressive symptoms from childhood into early adulthood. The multi-trait PRS was superior to PRS of individual psychiatricdisorders in delineating depression trajectories in association with genetic risk. One interpretation is that a spectrum of psychiatric genetic risk could underpin developmental differences in depression trajectories.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 38-39"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.103
David Crepaz-Keay
As someone who grew up living with a diagnosis of schizophrenia - among others - at a time when our view of genetics was much simpler and deterministic, the work of “communicating about psychiatric genetics in a diverse world" is a priority for me. Like many living with a diagnosis, my search of answers actually uncovered more questions. My conversations with skilled professionals in the world of psychiatric genetics have been productive and informative for both me and them. Such an experience encouraged me to try and engage more people who share my diagnoses to participate in these discussions.
This presentation will draw on my work with people with psychiatric diagnoses and their families, exploring the journey from initial hesitation to meaningful engagement in psychiatric genetics. I will discuss how we can bridge clinical knowledge with real-world dialogues, revealing the transformative power of informed discussions.
Drawing on ten years of experience, I will begin with the common initial reactions—either a belief that psychiatric genetics was too complex or a question of its relevance. I will share how we navigated these perceptions to foster a genuine interest and understanding. In addition, I will share the strategies that helped demystify complex genetic concepts and the explanations that resonated, as well as how simplifying our approach made genetic science accessible and relevant. I will highlight the most effective questions and topics that emerged during our discussions, such as genetic risk factors and their implications for treatment choices and lifestyle decisions. The presentation will emphasise the mutual benefits gained from these interactions, underscoring a shared journey of discovery that enriched both the participants' and the professionals' understanding.
We started from a place where many felt that psychiatric genetics was either too complex to grasp or simply irrelevant. Overall, this presentation will demonstrate how we moved from those initial doubts to a deeper, more informed understanding that empowers - rather than confounds - people with psychiatric diagnoses. I hope this presentation will encourage and give confidence to enable skilled professionals to navigate complex issues and share their knowledge with those who stand to benefit most.
{"title":"ENGAGING INSIGHTS: CONNECTING WITH PEOPLE WITH PSYCHIATRIC DIAGNOSES AND THEIR FAMILIES AROUND PSYCHIATRIC GENETICS","authors":"David Crepaz-Keay","doi":"10.1016/j.euroneuro.2024.08.103","DOIUrl":"10.1016/j.euroneuro.2024.08.103","url":null,"abstract":"<div><div>As someone who grew up living with a diagnosis of schizophrenia - among others - at a time when our view of genetics was much simpler and deterministic, the work of “communicating about psychiatric genetics in a diverse world\" is a priority for me. Like many living with a diagnosis, my search of answers actually uncovered more questions. My conversations with skilled professionals in the world of psychiatric genetics have been productive and informative for both me and them. Such an experience encouraged me to try and engage more people who share my diagnoses to participate in these discussions.</div><div>This presentation will draw on my work with people with psychiatric diagnoses and their families, exploring the journey from initial hesitation to meaningful engagement in psychiatric genetics. I will discuss how we can bridge clinical knowledge with real-world dialogues, revealing the transformative power of informed discussions.</div><div>Drawing on ten years of experience, I will begin with the common initial reactions—either a belief that psychiatric genetics was too complex or a question of its relevance. I will share how we navigated these perceptions to foster a genuine interest and understanding. In addition, I will share the strategies that helped demystify complex genetic concepts and the explanations that resonated, as well as how simplifying our approach made genetic science accessible and relevant. I will highlight the most effective questions and topics that emerged during our discussions, such as genetic risk factors and their implications for treatment choices and lifestyle decisions. The presentation will emphasise the mutual benefits gained from these interactions, underscoring a shared journey of discovery that enriched both the participants' and the professionals' understanding.</div><div>We started from a place where many felt that psychiatric genetics was either too complex to grasp or simply irrelevant. Overall, this presentation will demonstrate how we moved from those initial doubts to a deeper, more informed understanding that empowers - rather than confounds - people with psychiatric diagnoses. I hope this presentation will encourage and give confidence to enable skilled professionals to navigate complex issues and share their knowledge with those who stand to benefit most.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 42"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.047
Jinjie Duan , Jakob Grove , Ditte Demontis , F. Kyle Satterstrom , Jack Fu , Caitlin Carey , Stephan Sanders , Bernie Devlin , Kathryn Roeder , Joseph Buxbaum , Elise Robinson , Michael Talkowski , Benjamin Neale , Mark Daly , Anders Børglum
<div><div>Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental disorders with high heritability and frequent co-occurrence. Our previous work on the first phase of iPSYCH exomes (Satterstrom et al., 2019) suggested a similar burden of rare protein-truncating variants (PTVs) across ASD and ADHD and identified MAP1A as a shared risk gene implicated by rare PTVs in both disorders. This study aims to 1) extend these findings, employing a significantly larger iPSYCH exome dataset for gene discovery, 2) estimate the burden heritability explained by rare coding variants in ASD and ADHD, and 3) assess the burden genetic correlation between the two disorders.</div><div>We analyzed exomes of 25,208 individuals from iPSYCH, encompassing 7,119 individuals diagnosed with ASD alone (ASD-only), 5,598 with ADHD alone (ADHD-only), 3,794 with both ASD and ADHD (ASD+ADHD), and 8,697 controls. We used multivariate Poisson regression models to systematically evaluate rare variant burdens in different gene sets across the three case groups and controls, stratified further by the presence or absence of intellectual disability (ID). The gene sets included all genes, genes intolerant to loss-of-function variants (pLI > 0.9), and gene sets associated with different disorders including ID, ASD, ADHD, schizophrenia, and a broader group of neurodevelopmental disorders. We applied c-alpha tests to assess whether the distribution of rare deleterious variants differs between ASD and ADHD. We employed burden heritability regression to estimate the burden heritability of ASD and ADHD, respectively, and the burden genetic correlation between the two disorders. For gene discovery, we combined individuals diagnosed with ASD and/or ADHD into a single case group and applied TADA+ to integrate with family data and Swedish PAGES case-control data from a recent large-scale ASD rare variant study (Fu et al., 2022).</div><div>We observed similar burdens of class I variants including rare PTVs and rare deleterious missense variants (MPC > 3) in constrained genes across the three case groups, while they all showed a significant excess compared to controls: OR = 1.35, 95% CI = [1.26, 1.45] for ASD-only; OR = 1.35, CI = [1.25, 1.45] for ADHD-only; and OR = 1.39, CI = [1.28, 1.52] for ASD+ADHD. The c-alpha tests indicated no significant differences in the distribution of class I variants in constrained genes between ASD-only and ADHD-only groups (P= 0.39) while, when comparing the case groups to controls, significant differences were observed. The burden heritability of class I variants on the liability scale was estimated to 1.87% (SE = 0.51%) for ASD and 2.42% (s.e. = 0.72%) for ADHD. The class I variant burden genetic correlation between ASD and ADHD was 0.31 (s.e. = 0.26), which approximates the point estimate of their common-variant genetic correlation of 0.42 (s.e. = 0.05) (Demontis et al., 2023).</div><div>Our findi
{"title":"CROSS-DISORDER RARE VARIANT ANALYSIS OF AUTISM AND ADHD","authors":"Jinjie Duan , Jakob Grove , Ditte Demontis , F. Kyle Satterstrom , Jack Fu , Caitlin Carey , Stephan Sanders , Bernie Devlin , Kathryn Roeder , Joseph Buxbaum , Elise Robinson , Michael Talkowski , Benjamin Neale , Mark Daly , Anders Børglum","doi":"10.1016/j.euroneuro.2024.08.047","DOIUrl":"10.1016/j.euroneuro.2024.08.047","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental disorders with high heritability and frequent co-occurrence. Our previous work on the first phase of iPSYCH exomes (Satterstrom et al., 2019) suggested a similar burden of rare protein-truncating variants (PTVs) across ASD and ADHD and identified MAP1A as a shared risk gene implicated by rare PTVs in both disorders. This study aims to 1) extend these findings, employing a significantly larger iPSYCH exome dataset for gene discovery, 2) estimate the burden heritability explained by rare coding variants in ASD and ADHD, and 3) assess the burden genetic correlation between the two disorders.</div><div>We analyzed exomes of 25,208 individuals from iPSYCH, encompassing 7,119 individuals diagnosed with ASD alone (ASD-only), 5,598 with ADHD alone (ADHD-only), 3,794 with both ASD and ADHD (ASD+ADHD), and 8,697 controls. We used multivariate Poisson regression models to systematically evaluate rare variant burdens in different gene sets across the three case groups and controls, stratified further by the presence or absence of intellectual disability (ID). The gene sets included all genes, genes intolerant to loss-of-function variants (pLI > 0.9), and gene sets associated with different disorders including ID, ASD, ADHD, schizophrenia, and a broader group of neurodevelopmental disorders. We applied c-alpha tests to assess whether the distribution of rare deleterious variants differs between ASD and ADHD. We employed burden heritability regression to estimate the burden heritability of ASD and ADHD, respectively, and the burden genetic correlation between the two disorders. For gene discovery, we combined individuals diagnosed with ASD and/or ADHD into a single case group and applied TADA+ to integrate with family data and Swedish PAGES case-control data from a recent large-scale ASD rare variant study (Fu et al., 2022).</div><div>We observed similar burdens of class I variants including rare PTVs and rare deleterious missense variants (MPC > 3) in constrained genes across the three case groups, while they all showed a significant excess compared to controls: OR = 1.35, 95% CI = [1.26, 1.45] for ASD-only; OR = 1.35, CI = [1.25, 1.45] for ADHD-only; and OR = 1.39, CI = [1.28, 1.52] for ASD+ADHD. The c-alpha tests indicated no significant differences in the distribution of class I variants in constrained genes between ASD-only and ADHD-only groups (P= 0.39) while, when comparing the case groups to controls, significant differences were observed. The burden heritability of class I variants on the liability scale was estimated to 1.87% (SE = 0.51%) for ASD and 2.42% (s.e. = 0.72%) for ADHD. The class I variant burden genetic correlation between ASD and ADHD was 0.31 (s.e. = 0.26), which approximates the point estimate of their common-variant genetic correlation of 0.42 (s.e. = 0.05) (Demontis et al., 2023).</div><div>Our findi","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 17"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.079
Aiden Corvin (Chair) , Andrew McIntosh (Co-chair) , Niamh Ryan (Discussant)
To our knowledge it is ten years since the last symposium on pedigree-based analyses at the WCPG. In the era of whole genome sequencing a review is timely. As costs fall, the field of psychiatric genomics is transitioning from GWAS to next generation sequencing, with power to expand our understanding of the contribution of rare mutations to genetic burden across disorders. Identified rare pathogenic variants may be more informative in understanding disease biology than the common variants of small effect that represent the majority of discovery to date.
Rare variant association studies require sample sizes an order of magnitude larger than GWAS studies. This is because rare mutations tend to be selected against in populations over a few generations. However, such mutations may be identifiable where multiple generations of the same family are available. Moreover, families do not suffer the same population stratification or other confounds that are present at a population level. This approach, with small sample numbers in a family, allows for detailed phenotypic assessment and is accessible to clinicians and researchers with limited resources who want to contribute to the field.
This symposium will provide an update on progress made in ASD, where significant understanding of the genetic architecture and disease biology is emerging, in part due to trio- and quad-based approaches. We review progress from the PGC Pedigree Sequencing Group with an example of how sequencing individual families, with small numbers of individuals can identify relevant risk mutations only identifiable with thousands of samples using case-control approaches. We describe progress in other adult disorders from the international "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. Finally, we review the findings from colleagues working in India who are applying pedigree-based sequencing study approaches across disorders. Across presentations we consider recruitment, and how emerging findings indicate a need for broader inclusion criteria within families than might traditionally have been considered. This session will also present new methods for investigating pedigrees in the era of whole genome sequencing.
据我们所知，距离上一次在世界基因组大会上举办基于谱系分析的研讨会已经过去了十年。在全基因组测序时代，进行一次回顾是非常及时的。随着成本的下降，精神疾病基因组学领域正在从全球基因组分析系统（GWAS）向新一代测序系统过渡，这将有助于我们进一步了解罕见变异对各种疾病遗传负担的影响。在了解疾病生物学方面，发现的罕见致病变异可能比迄今为止发现的大多数影响较小的常见变异更有参考价值。罕见变异关联研究需要的样本量要比 GWAS 研究大一个数量级。这是因为罕见变异在人群中往往会经过几代人的选择而被淘汰。然而，在同一家族有多代人的情况下，这种突变可能是可识别的。此外，家族也不会受到人群分层的影响，也不会受到人群水平上存在的其他干扰因素的影响。本研讨会将介绍 ASD 研究的最新进展，在 ASD 研究中，人们对遗传结构和疾病生物学有了更深入的了解，这部分归功于基于三代和四代的研究方法。我们将回顾 PGC Pedigree Sequencing Group 取得的进展，并举例说明对个体数量较少的单个家庭进行测序如何发现相关的风险突变，而只有使用病例对照方法对成千上万的样本进行测序才能发现这些突变。我们还介绍了国际 "情感和精神障碍基于谱系的全基因组测序 "联盟在其他成人疾病方面取得的进展。最后，我们回顾了在印度工作的同事的研究成果，他们将基于 pedigree 的测序研究方法应用于各种疾病。在所有发言中，我们都会考虑招募问题，以及新出现的研究结果如何表明需要比传统上考虑的更广泛的家庭纳入标准。本次会议还将介绍在全基因组测序时代调查家系的新方法。
{"title":"FAMILY-BASED STUDIES IN PSYCHIATRIC GENOMICS: PROGRESS AND RELEVANCE IN 2024","authors":"Aiden Corvin (Chair) , Andrew McIntosh (Co-chair) , Niamh Ryan (Discussant)","doi":"10.1016/j.euroneuro.2024.08.079","DOIUrl":"10.1016/j.euroneuro.2024.08.079","url":null,"abstract":"<div><div>To our knowledge it is ten years since the last symposium on pedigree-based analyses at the WCPG. In the era of whole genome sequencing a review is timely. As costs fall, the field of psychiatric genomics is transitioning from GWAS to next generation sequencing, with power to expand our understanding of the contribution of rare mutations to genetic burden across disorders. Identified rare pathogenic variants may be more informative in understanding disease biology than the common variants of small effect that represent the majority of discovery to date.</div><div>Rare variant association studies require sample sizes an order of magnitude larger than GWAS studies. This is because rare mutations tend to be selected against in populations over a few generations. However, such mutations may be identifiable where multiple generations of the same family are available. Moreover, families do not suffer the same population stratification or other confounds that are present at a population level. This approach, with small sample numbers in a family, allows for detailed phenotypic assessment and is accessible to clinicians and researchers with limited resources who want to contribute to the field.</div><div>This symposium will provide an update on progress made in ASD, where significant understanding of the genetic architecture and disease biology is emerging, in part due to trio- and quad-based approaches. We review progress from the PGC Pedigree Sequencing Group with an example of how sequencing individual families, with small numbers of individuals can identify relevant risk mutations only identifiable with thousands of samples using case-control approaches. We describe progress in other adult disorders from the international \"Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders\" consortium. Finally, we review the findings from colleagues working in India who are applying pedigree-based sequencing study approaches across disorders. Across presentations we consider recruitment, and how emerging findings indicate a need for broader inclusion criteria within families than might traditionally have been considered. This session will also present new methods for investigating pedigrees in the era of whole genome sequencing.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 31-32"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.086
{"title":"SENSITIVE PERIODS FOR CHILDHOOD ADVERSITY AND DNA METHYLATION: META-ANALYSIS RESULTS AND DNA METHYLATION RISK SCORES","authors":"","doi":"10.1016/j.euroneuro.2024.08.086","DOIUrl":"10.1016/j.euroneuro.2024.08.086","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 35"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.104
Michaela Pettie
We are all embedded within societies, communities, families, and institutions. But how do we ensure our research, methodologies, findings, and implications are accessible and meaningful for those who need the knowledge? As a Māori (Indigenous) researcher from New Zealand and a researcher within the NIH-funded International Eating Disorder Genetics Initiative (EDGI) study led by Professor Cynthia Bulik, I am acutely aware of the pivotal role language plays in bridging the gap between scientific communication and societal understanding.
My symposia presentation delves into the importance of a researcher's role as a knowledge creator to craft accessible and culturally sensitive narratives from complex scientific concepts. Researchers are responsible for spreading the knowledge of genetic findings beyond the confines of scholarly journals so that our work reaches and resonates with communities far and wide. It is imperative to embrace diverse modalities of dissemination and recognise that peer-reviewed articles are but one conduit through which knowledge can flow. I will cover opportunities for various dissemination modalities, including the use wānanga by our Māori communities in New Zealand. Wānanga (forum or seminar) is a way of sharing knowledge, discussing, exploring and making meaning of the content, and using the associated concepts can present new opportunities for knowledge dissemination in various contexts.
Ultimately, my presentation serves as a call to action for researchers and communicators alike. The true measure of research impact lies not solely in scholarly publications but in the tangible difference we make in the lives of people and communities through accessible, inclusive, and culturally resonant knowledge dissemination practices.
{"title":"INNOVATING KNOWLEDGE DISSEMINATION FOR CULTURAL RELEVANCE AND ACCESSIBILITY","authors":"Michaela Pettie","doi":"10.1016/j.euroneuro.2024.08.104","DOIUrl":"10.1016/j.euroneuro.2024.08.104","url":null,"abstract":"<div><div>We are all embedded within societies, communities, families, and institutions. But how do we ensure our research, methodologies, findings, and implications are accessible and meaningful for those who need the knowledge? As a Māori (Indigenous) researcher from New Zealand and a researcher within the NIH-funded International Eating Disorder Genetics Initiative (EDGI) study led by Professor Cynthia Bulik, I am acutely aware of the pivotal role language plays in bridging the gap between scientific communication and societal understanding.</div><div>My symposia presentation delves into the importance of a researcher's role as a knowledge creator to craft accessible and culturally sensitive narratives from complex scientific concepts. Researchers are responsible for spreading the knowledge of genetic findings beyond the confines of scholarly journals so that our work reaches and resonates with communities far and wide. It is imperative to embrace diverse modalities of dissemination and recognise that peer-reviewed articles are but one conduit through which knowledge can flow. I will cover opportunities for various dissemination modalities, including the use wānanga by our Māori communities in New Zealand. Wānanga (forum or seminar) is a way of sharing knowledge, discussing, exploring and making meaning of the content, and using the associated concepts can present new opportunities for knowledge dissemination in various contexts.</div><div>Ultimately, my presentation serves as a call to action for researchers and communicators alike. The true measure of research impact lies not solely in scholarly publications but in the tangible difference we make in the lives of people and communities through accessible, inclusive, and culturally resonant knowledge dissemination practices.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 42"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.015
Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler
Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of PTSD and MDD patients, compared to neurotypical controls, reveal genetic overlaps, sex disparities, and immune and interneuron signaling involvement, yet lack integrative analyses. To address this gap, we established a brain multi-omic, multi-region database comprising individuals with PTSD, MDD, and NCs (77/group, n = 231). We analyzed molecular changes across the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at transcriptomic, methylomic, and proteomic levels. Our approach is supplemented by single-nucleus RNA sequencing (snRNA-seq), genetics, and blood proteomics, aiming for a comprehensive systems perspective. Our findings highlight predominant molecular
changes in the mPFC, with differentially expressed genes (DEGs) and exons carrying disease signals. Notably, methylation alterations were concentrated in the DG for PTSD and CeA for MDD. Findings supported by replication analyses across two cohorts (n = 114). We observed a moderate overlap between disorders, with childhood trauma and suicide driving molecular variations, and sex-specificity was more notable in MDD. Pathway analyses link disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, and stress hormone signaling, albeit with low concordance across omics. Top upstream regulators include IL1B, GR, STAT3, and TNF. Multi-omic factor and gene network analyses suggest latent factors and modules related to aging, inflammation, vascular processes, and stress.
Complementing multi-omics, our snRNA-seq in the dorsolateral PFC reveals dysregulated pathways and upstream regulators in neuronal and non-neuronal cell types, including stress-related genes. Examining brain multi-omics with blood proteins in the large UK Biobank cohort shows significant correlation, overlap, and directional similarity, implying potential blood-based biomarkers. Fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.
Ultimately, prioritized genes with multi-omic, multi-region, or multi-trait associations are implicated in pathways/networks, exhibit cell-type specificity, demonstrate blood biomarker potential, or are linked to genetic risk for PTSD and MDD.
In conclusion, our study unveils shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for blood-based biomarker development. These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.
{"title":"SYSTEMS BIOLOGY OF PTSD REVEALS MECHANISMS OF RISK AND DISEASE PROCESSES AT BRAIN MULTI-OMIC, BRAIN CELL TYPE, AND BLOOD LEVELS","authors":"Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler","doi":"10.1016/j.euroneuro.2024.08.015","DOIUrl":"10.1016/j.euroneuro.2024.08.015","url":null,"abstract":"<div><div>Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of PTSD and MDD patients, compared to neurotypical controls, reveal genetic overlaps, sex disparities, and immune and interneuron signaling involvement, yet lack integrative analyses. To address this gap, we established a brain multi-omic, multi-region database comprising individuals with PTSD, MDD, and NCs (77/group, n = 231). We analyzed molecular changes across the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at transcriptomic, methylomic, and proteomic levels. Our approach is supplemented by single-nucleus RNA sequencing (snRNA-seq), genetics, and blood proteomics, aiming for a comprehensive systems perspective. Our findings highlight predominant molecular</div><div>changes in the mPFC, with differentially expressed genes (DEGs) and exons carrying disease signals. Notably, methylation alterations were concentrated in the DG for PTSD and CeA for MDD. Findings supported by replication analyses across two cohorts (n = 114). We observed a moderate overlap between disorders, with childhood trauma and suicide driving molecular variations, and sex-specificity was more notable in MDD. Pathway analyses link disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, and stress hormone signaling, albeit with low concordance across omics. Top upstream regulators include IL1B, GR, STAT3, and TNF. Multi-omic factor and gene network analyses suggest latent factors and modules related to aging, inflammation, vascular processes, and stress.</div><div>Complementing multi-omics, our snRNA-seq in the dorsolateral PFC reveals dysregulated pathways and upstream regulators in neuronal and non-neuronal cell types, including stress-related genes. Examining brain multi-omics with blood proteins in the large UK Biobank cohort shows significant correlation, overlap, and directional similarity, implying potential blood-based biomarkers. Fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.</div><div>Ultimately, prioritized genes with multi-omic, multi-region, or multi-trait associations are implicated in pathways/networks, exhibit cell-type specificity, demonstrate blood biomarker potential, or are linked to genetic risk for PTSD and MDD.</div><div>In conclusion, our study unveils shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for blood-based biomarker development. These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 3-4"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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