Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.055
{"title":"HARNESSING GENOMIC DATA FOR PRECISION MEDICINE IN ALZHEIMER'S DISEASE: CHALLENGES AND OPPORTUNITIES","authors":"","doi":"10.1016/j.euroneuro.2024.08.055","DOIUrl":"10.1016/j.euroneuro.2024.08.055","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 21"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441953","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.2024.08.040
Yamin Zhang , Tong Li , Shaozhong Yang , Zhi Xie , Tao Li
<div><h3>Backgrounds</h3><div>Genetic liability to schizophrenia involves various types of mutations from across the allele frequency spectrum and distributed across the genome. Findings from studies focusing on different types of mutations in schizophrenia converge partially on the same biological processes, while also providing complementary insights. This underscores the importance of studying the full spectrum of mutation. However, currently widely used genotyping technologies, microarrays and short read sequencing (SRS), have limited ability in detecting medium-sized structural variations (SVs) (e.g. 50-2000bp) compared to long-read sequencing (LRS), which is relatively new and has been rarely applied to genetic studies of schizophrenia so far, suggesting an opportunity to leverage this more comprehensive approach to uncover additional sources of genetic variation that may contribute to the disorder.</div></div><div><h3>Methods</h3><div>Utilizing both 20X LRS and 30X SRS, we performed comprehensive whole-genome analysis on 40 Han Chinese parent-offspring trios. We called single nucleotide variants (SNVs), insertions and deletions (indels), and SVs utilizing multiple algorithms. Our primary focus was on the detection and validation of de novo mutations (DNMs). Comparative analysis between LRS and SRS was conducted to assess their respective abilities in detecting SVs and de novo SVs. Subsequently, we annotated the de novo mutations and delved into their potential mechanisms in schizophrenia through mining public databases and conducting functional experiments. Finally, we compared the diagnostic yield of our approach to previous studies employing whole exome sequencing or whole genome sequencing using SRS.</div></div><div><h3>Results</h3><div>Our analysis identified an average of 71.55 DNMs per proband, including 12 de novo SVs. Notably, four of these de novo SVs were detected by more than three out of four algorithms employed for LRS, whereas none were detected by any of the four algorithms utilized for SRS. In addition, our analysis revealed a 2.8Mb region exclusively accessible via by LRS and not SRS. LRS demonstrated exceptional performance in phasing, while the call sets derived from both LRS and SRS exhibited comparable levels of Mendelian consistency. Of particular interest in our study is a de novo 11kb deletion encompassing the last intron, last exon, and 3’ UTR of PPP3CA. Through experimental investigations, we discovered a significant reduction in PPP3CA protein levels in blood cells from the schizophrenia patient harboring this DNM. Similar reductions in PPP3CA protein levels were also observed in HEK293T cell lines carrying a comparable mutation, indicating that the down regulation of PPP3CA results from the identified de novo SV. Subsequently, in mice model with targeted knockdown of PPP3CA in excitatory neurons within the hippocampus, we observed alterations indicative of schizophrenia-like behavior and impaired cognitive funct
{"title":"UNRAVELING THE ROLE OF DE NOVO STRUCTURAL VARIANTS IN SCHIZOPHRENIA THROUGH COMPREHENSIVE WHOLE GENOME SEQUENCING WITH LONG-READ AND SHORT-READ TECHNOLOGIES","authors":"Yamin Zhang , Tong Li , Shaozhong Yang , Zhi Xie , Tao Li","doi":"10.1016/j.euroneuro.2024.08.040","DOIUrl":"10.1016/j.euroneuro.2024.08.040","url":null,"abstract":"<div><h3>Backgrounds</h3><div>Genetic liability to schizophrenia involves various types of mutations from across the allele frequency spectrum and distributed across the genome. Findings from studies focusing on different types of mutations in schizophrenia converge partially on the same biological processes, while also providing complementary insights. This underscores the importance of studying the full spectrum of mutation. However, currently widely used genotyping technologies, microarrays and short read sequencing (SRS), have limited ability in detecting medium-sized structural variations (SVs) (e.g. 50-2000bp) compared to long-read sequencing (LRS), which is relatively new and has been rarely applied to genetic studies of schizophrenia so far, suggesting an opportunity to leverage this more comprehensive approach to uncover additional sources of genetic variation that may contribute to the disorder.</div></div><div><h3>Methods</h3><div>Utilizing both 20X LRS and 30X SRS, we performed comprehensive whole-genome analysis on 40 Han Chinese parent-offspring trios. We called single nucleotide variants (SNVs), insertions and deletions (indels), and SVs utilizing multiple algorithms. Our primary focus was on the detection and validation of de novo mutations (DNMs). Comparative analysis between LRS and SRS was conducted to assess their respective abilities in detecting SVs and de novo SVs. Subsequently, we annotated the de novo mutations and delved into their potential mechanisms in schizophrenia through mining public databases and conducting functional experiments. Finally, we compared the diagnostic yield of our approach to previous studies employing whole exome sequencing or whole genome sequencing using SRS.</div></div><div><h3>Results</h3><div>Our analysis identified an average of 71.55 DNMs per proband, including 12 de novo SVs. Notably, four of these de novo SVs were detected by more than three out of four algorithms employed for LRS, whereas none were detected by any of the four algorithms utilized for SRS. In addition, our analysis revealed a 2.8Mb region exclusively accessible via by LRS and not SRS. LRS demonstrated exceptional performance in phasing, while the call sets derived from both LRS and SRS exhibited comparable levels of Mendelian consistency. Of particular interest in our study is a de novo 11kb deletion encompassing the last intron, last exon, and 3’ UTR of PPP3CA. Through experimental investigations, we discovered a significant reduction in PPP3CA protein levels in blood cells from the schizophrenia patient harboring this DNM. Similar reductions in PPP3CA protein levels were also observed in HEK293T cell lines carrying a comparable mutation, indicating that the down regulation of PPP3CA results from the identified de novo SV. Subsequently, in mice model with targeted knockdown of PPP3CA in excitatory neurons within the hippocampus, we observed alterations indicative of schizophrenia-like behavior and impaired cognitive funct","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 13-14"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442314","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.2024.08.102
José J. Morosoli , Lucia Colodro-Conde , Fiona K. Barlow , Sarah E. Medland
<div><div>From my perspective, science communication goes beyond the mere transmission of information from experts to non-experts. Science communication is dynamic and influenced by personal characteristics and sociopolitical context. As scientists, we not only need to know our audience but also understand ourselves better. The main topics of this presentation are (i) literacy and the use of jargon when talking about genetics; and (ii) specific cognitive biases in how we process information about genetics, including how personal values and experiences can influence how we understand scientific information.</div><div>The talk will be structured in two sections: The first section synthesises our previous work on public understanding of genetics. First, I will discuss a survey study on genetic literacy and public attitudes towards genetic testing in mental health. In this study, we surveyed families that had previously participated in genetic research studies at QIMR Berghofer, Australia (N=3,974), and the general population from the U.K. (N=501) and the U.S. (N=500). Results showed a high interest in psychiatric genetic testing, but the potential for negative impact of such information is also high, with more than a third of the participants showing serious concerns relating to learning about personal genetic predisposition. Concerns were mitigated by higher levels of genetic literacy, leading to less worry about coping with learning about a high genetic predisposition for several mental health problems and less prejudice against people with a high genetic predisposition. Second, I will discuss our recent review on online media articles covering genome-wide association studies (GWAS). We show that we might be missing a major opportunity for increasing general knowledge about genetic findings. Indeed, ∼95% of the news sites and blogs on GWAS used a language too complex to be understood by most adults. Most news articles used the terms ‘RNA’, ‘risk’, ‘gene’, ‘genome’, and ‘DNA’, while the terms ‘marker, ‘polymorphism’, or ‘allele’, rarely appeared. To contextualise these results, I will present new data from our survey showing the results from a modified version of the Rapid Estimate of Adult Literacy in Genetics (REAL-G), which evaluates how familiar the public is with the terms ‘genetics’, ‘chromosome’, ‘susceptibility’, ‘mutation’, ‘genetic variant’, ‘heredity’, and ‘polygenic’. I will briefly touch on the concept of ‘framing’, or how interpretation of information can be influenced by the presence or absence of certain words or images. For example, media on GWAS tends to focus on ‘risk’ (mentioned in 63.7% of articles) versus ‘susceptibility’ (12.2%) or ‘protect’ (11.3%) – the stem of words such as ‘protective’.</div><div>In the second section, I will discuss previous research on genetic determinism as a cognitive bias, as well as the role of motivated cognition. That is, we are not passive or even objective recipients of scientific information, b
{"title":"WHEN YOU ASSUME: RESULTS AND REFLECTIONS FROM STUDIES ON PUBLIC UNDERSTANDING OF GENETICS","authors":"José J. Morosoli , Lucia Colodro-Conde , Fiona K. Barlow , Sarah E. Medland","doi":"10.1016/j.euroneuro.2024.08.102","DOIUrl":"10.1016/j.euroneuro.2024.08.102","url":null,"abstract":"<div><div>From my perspective, science communication goes beyond the mere transmission of information from experts to non-experts. Science communication is dynamic and influenced by personal characteristics and sociopolitical context. As scientists, we not only need to know our audience but also understand ourselves better. The main topics of this presentation are (i) literacy and the use of jargon when talking about genetics; and (ii) specific cognitive biases in how we process information about genetics, including how personal values and experiences can influence how we understand scientific information.</div><div>The talk will be structured in two sections: The first section synthesises our previous work on public understanding of genetics. First, I will discuss a survey study on genetic literacy and public attitudes towards genetic testing in mental health. In this study, we surveyed families that had previously participated in genetic research studies at QIMR Berghofer, Australia (N=3,974), and the general population from the U.K. (N=501) and the U.S. (N=500). Results showed a high interest in psychiatric genetic testing, but the potential for negative impact of such information is also high, with more than a third of the participants showing serious concerns relating to learning about personal genetic predisposition. Concerns were mitigated by higher levels of genetic literacy, leading to less worry about coping with learning about a high genetic predisposition for several mental health problems and less prejudice against people with a high genetic predisposition. Second, I will discuss our recent review on online media articles covering genome-wide association studies (GWAS). We show that we might be missing a major opportunity for increasing general knowledge about genetic findings. Indeed, ∼95% of the news sites and blogs on GWAS used a language too complex to be understood by most adults. Most news articles used the terms ‘RNA’, ‘risk’, ‘gene’, ‘genome’, and ‘DNA’, while the terms ‘marker, ‘polymorphism’, or ‘allele’, rarely appeared. To contextualise these results, I will present new data from our survey showing the results from a modified version of the Rapid Estimate of Adult Literacy in Genetics (REAL-G), which evaluates how familiar the public is with the terms ‘genetics’, ‘chromosome’, ‘susceptibility’, ‘mutation’, ‘genetic variant’, ‘heredity’, and ‘polygenic’. I will briefly touch on the concept of ‘framing’, or how interpretation of information can be influenced by the presence or absence of certain words or images. For example, media on GWAS tends to focus on ‘risk’ (mentioned in 63.7% of articles) versus ‘susceptibility’ (12.2%) or ‘protect’ (11.3%) – the stem of words such as ‘protective’.</div><div>In the second section, I will discuss previous research on genetic determinism as a cognitive bias, as well as the role of motivated cognition. That is, we are not passive or even objective recipients of scientific information, b","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 41-42"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442315","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.2024.08.088
Isabel Schuurmans , Esther Walton , Charlotte Cecil , MIND Consortium
Epigenetic processes, such as DNA methylation (DNAm), show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of psychiatric and other brain-based phenotypes. However, we still know surprisingly little about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research is almost entirely comprised of cross-sectional studies in adults, with modest sample sizes (median N = 80) and a lack of replication.
To bridge this gap, we present here the new Methylation, Imaging and NeuroDevelopment (MIND) Consortium. MIND aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies.
MIND currently brings together 14 cohorts worldwide, comprising samples from North and South America, Europe, Africa and Australia, with (repeated) measures of DNAm in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging (MRI) across up to five time points across development (Npooled DNAm = 11,791; Npooled neuroimaging = 9,350; Npooled combined = 5,249). The MIND Consortium operates as an open network, welcoming researchers who have access to neuroimaging and epigenetic data (collected at 1+ time points before 18 years) to join.
In this talk, we introduce the consortium, presenting key characteristics of the samples and data types included. We discuss main considerations, challenges and opportunities in collaborative research on developmental neuroimaging epigenetics, including: (i) separating developmental from technical variability, (ii) modeling time-varying DNAm-brain associations in multi-cohort analyses, and (iii) addressing the dimensionality of neuroimaging epigenetic data. We conclude with key priorities for the consortium, current plans and future directions.
By triangulating associations across multiple developmental time points and study types, we aim to generate new insights about the dynamic relationship between peripheral DNA methylation and the brain, and to improve understanding of how these ultimately relate to neurodevelopmental and psychiatric phenotypes.
{"title":"INTRODUCING MIND: THE METHYLATION, IMAGING AND NEURODEVELOPMENT CONSORTIUM","authors":"Isabel Schuurmans , Esther Walton , Charlotte Cecil , MIND Consortium","doi":"10.1016/j.euroneuro.2024.08.088","DOIUrl":"10.1016/j.euroneuro.2024.08.088","url":null,"abstract":"<div><div>Epigenetic processes, such as DNA methylation (DNAm), show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of psychiatric and other brain-based phenotypes. However, we still know surprisingly little about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research is almost entirely comprised of cross-sectional studies in adults, with modest sample sizes (median N = 80) and a lack of replication.</div><div>To bridge this gap, we present here the new Methylation, Imaging and NeuroDevelopment (MIND) Consortium. MIND aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies.</div><div>MIND currently brings together 14 cohorts worldwide, comprising samples from North and South America, Europe, Africa and Australia, with (repeated) measures of DNAm in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging (MRI) across up to five time points across development (Npooled DNAm = 11,791; Npooled neuroimaging = 9,350; Npooled combined = 5,249). The MIND Consortium operates as an open network, welcoming researchers who have access to neuroimaging and epigenetic data (collected at 1+ time points before 18 years) to join.</div><div>In this talk, we introduce the consortium, presenting key characteristics of the samples and data types included. We discuss main considerations, challenges and opportunities in collaborative research on developmental neuroimaging epigenetics, including: (i) separating developmental from technical variability, (ii) modeling time-varying DNAm-brain associations in multi-cohort analyses, and (iii) addressing the dimensionality of neuroimaging epigenetic data. We conclude with key priorities for the consortium, current plans and future directions.</div><div>By triangulating associations across multiple developmental time points and study types, we aim to generate new insights about the dynamic relationship between peripheral DNA methylation and the brain, and to improve understanding of how these ultimately relate to neurodevelopmental and psychiatric phenotypes.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 35-36"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442150","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.2024.08.048
Niamh Mullins (Chair) , Anna Docherty (Co-chair) , Brenda Cabrera-Mendoza (Discussant)
Suicide accounts for more than 700,000 preventable deaths worldwide per year, and suicide attempts (SAs) - defined as non-fatal self-injurious behaviors with intent to die - are up to 25 times more common. SAs are associated with disability, poor quality of life, and social and economic burden, and are the single strongest predictor of future suicide deaths (SDs). Suicidal ideation (SI), the contemplation of taking one's own life, occurs at even higher rates, with a cross-national lifetime prevalence of > 9%. Currently, effective treatment options for alleviating suicidality in diverse populations are lacking, and the ability to predict risk remains poor.
Heritability estimates for SI, SA and SD are in the range of 30-55%, and recent large-scale genome-wide association studies (GWAS) have yielded the first replicable genome-wide significant (GWS) loci, and novel insights into the underlying biology. For example, GWAS by the Psychiatric Genomics Consortium Suicide Working Group (PGC SUI) of up to 43,871 SA cases, have identified 12 GWS loci, including an intergenic risk locus on chromosome 7, which remained GWS after conditioning on psychiatric disorders, and replicated in an independent cohort. The study also demonstrated a genetic liability to SA that is not mediated by associated psychiatric disorders, as well as pleiotropy between SA and psychiatric disorders, particularly major depression, and risk factors such as pain, smoking, risk-taking behavior, sleep disturbances, and poorer general health.
In this symposium, we will showcase recent highlights in suicide genomics research, covering the spectrum of suicide phenotypes, common genetic variation, diverse ancestry studies, a variety of ‘omics data and electronic health records. Sarah Colbert, PhD student, will present new unpublished GWAS by PGC SUI comprising >259,000 SI cases, > 73,000 SA cases and > 6,000 SD cases from 46 cohorts of diverse genetic ancestries. Gustavo Turecki, MD PhD will share a detailed investigation of the intergenic chromosome 7 locus specific to SA, using a suite of ‘omics data, to uncover relevant genes and molecular mechanisms. Chittaranjan Behera, MD will discuss the first population-based collection of postmortem blood and brain tissue from non-European ancestry suicide decedents in India. Hilary Coon, PhD will present an analysis of the clinical and genetic profiles of SD cases with and without prior SA, through linking the Utah Suicide Mortality Risk Study with electronic health records and leveraging natural language processing of clinical notes. Finally, our Discussant Brenda Cabrera-Mendoza, MD, PhD will summarize the current state of the field of suicide genomics and provide perspectives on future research and the necessary next steps to translate findings to clinical prediction, treatment, and prevention.
全世界每年有 70 多万人死于可预防的自杀，而自杀未遂（SAs）--定义为意图致死的非致命性自伤行为--的发生率高达自杀未遂的 25 倍。自杀未遂与残疾、生活质量低下、社会和经济负担有关，是未来自杀死亡（SD）的最有力预测因素。自杀意念（SI），即考虑自杀，发生率更高，跨国终生发生率为 9%。SI、SA和SD的遗传率估计在30-55%之间，最近的大规模全基因组关联研究（GWAS）首次发现了可复制的全基因组重要（GWS）位点，并对潜在的生物学有了新的认识。例如，精神病基因组学联合会自杀工作组（PGC SUI）对多达 43 871 个 SA 病例进行了全基因组关联研究，发现了 12 个 GWS 位点，其中包括 7 号染色体上的一个基因间风险位点。这项研究还证明了自杀风险基因组学的遗传易感性，这种易感性不受相关精神障碍的介导，而且自杀风险基因组学与精神障碍（尤其是重度抑郁症）以及疼痛、吸烟、冒险行为、睡眠障碍和较差的一般健康状况等风险因素之间存在多重效应。博士生莎拉-科尔伯特（Sarah Colbert）将介绍 PGC SUI 未发表的新的 GWAS，包括来自 46 个不同遗传祖先队列的 259,000 个 SI 病例、73,000 个 SA 病例和 6,000 个 SD 病例。医学博士 Gustavo Turecki 将与大家分享一项详细研究，该研究利用一整套'omics'数据，发现了与 SA 相关的基因和分子机制，并对 7 号染色体基因间位点进行了特异性研究。Chittaranjan Behera 医学博士将讨论首次以人群为基础收集印度非欧洲血统自杀死者的死后血液和脑组织。希拉里-库恩（Hilary Coon）博士将介绍通过将犹他州自杀死亡率风险研究与电子健康记录联系起来，并利用临床笔记的自然语言处理，对有和无SA的SD病例的临床和遗传特征进行分析。最后，我们的讨论者、医学博士布伦达-卡布雷拉-门多萨（Brenda Cabrera-Mendoza）将总结自杀基因组学领域的现状，并对未来的研究以及将研究成果转化为临床预测、治疗和预防所需的下一步工作提出看法。
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Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.091
Poppy Grimes , Mark Adams , Anita Thapar , Christel M. Middeldorp , Andrew McIntosh , Heather Whalley , Alex S.F. Kwong
<div><div>Depression is a complex trait disease which emerges most often and most severely during adolescence. Early-onset depression correlates with late-onset depression and has a three-fold higher single nucleotide polymorphism (SNP)-heritability. Early or adolescent depression is also well-predicted by polygenic risk scores (PRS) of adult major depressive disorder (MDD). Though genetic signal likely exists, attempts to determine variants associated with adolescent depression have been unfruitful due to phenotype heterogeneity and the lack of power available in prospective adolescent cohort sample sizes. To overcome the power problem whilst maintaining a stable phenotype, our study proposes to, i) leverage genetic data from both prospective and retrospective cohorts and, ii) restrict the phenotype to self-report symptoms only.</div><div>We perform a Genome-Wide Association Study (GWAS) of adolescent-onset depression leveraging approximately 180,000 individuals from over 20 cohorts in the Psychiatric Genomics Consortium (PGC) and Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Cohorts span 10 countries with diverse ancestries (including African, American-admixed, East Asian, European, Middle Eastern, and South Asian). We first analyse prospective and retrospective cohorts independently before combining all cohorts in a meta-analysis. We perform tissue expression analysis and compare results with findings in the GWAS catalogue.</div><div>Current results from 107,721 individuals (14 891 cases and 92 830 controls) have revealed 7 novel independent genome-wide significant SNPs in European ancestry. We determined a SNP-heritability (SE) of 0.053 (0.006). Genetic correlation (SE) between meta-analysed cohorts with the latest MDD GWAS summary statistics was 0.79 (0.04) and between prospective and retrospective cohorts was 0.52 (0.05). Gene-expression analysis determined tissue enrichment in the cortex, cerebellum and hippocampus. Leading SNPs of the association with adolescent-onset depression overlapped with results from previous GWASs of depression, neuroticism and wellbeing in adults.</div><div>Association analyses from the remaining contributing cohorts are ongoing. Current results already provide novel genetic associations, and we expect the addition of approximately 70,000 more individuals to further increase power and discovery across ancestries. Once all samples are received, we will derive PRS for out-of-sample prediction across ancestries, test genetic correlation with other traits, use genomic structural equation modelling to investigate shared architecture, run colocalization for shared trait variants and perform Mendelian randomisation to identify causality. We expect that biological insights, potentially hidden within the larger and more heterogeneous adult population, could be uncovered in the more genetically heritable adolescent-onset group. Investigating the genetic architecture of the adolescent-onset depression subty
{"title":"GENOME-WIDE ASSOCIATION STUDY OF ADOLESCENT-ONSET DEPRESSION","authors":"Poppy Grimes , Mark Adams , Anita Thapar , Christel M. Middeldorp , Andrew McIntosh , Heather Whalley , Alex S.F. Kwong","doi":"10.1016/j.euroneuro.2024.08.091","DOIUrl":"10.1016/j.euroneuro.2024.08.091","url":null,"abstract":"<div><div>Depression is a complex trait disease which emerges most often and most severely during adolescence. Early-onset depression correlates with late-onset depression and has a three-fold higher single nucleotide polymorphism (SNP)-heritability. Early or adolescent depression is also well-predicted by polygenic risk scores (PRS) of adult major depressive disorder (MDD). Though genetic signal likely exists, attempts to determine variants associated with adolescent depression have been unfruitful due to phenotype heterogeneity and the lack of power available in prospective adolescent cohort sample sizes. To overcome the power problem whilst maintaining a stable phenotype, our study proposes to, i) leverage genetic data from both prospective and retrospective cohorts and, ii) restrict the phenotype to self-report symptoms only.</div><div>We perform a Genome-Wide Association Study (GWAS) of adolescent-onset depression leveraging approximately 180,000 individuals from over 20 cohorts in the Psychiatric Genomics Consortium (PGC) and Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Cohorts span 10 countries with diverse ancestries (including African, American-admixed, East Asian, European, Middle Eastern, and South Asian). We first analyse prospective and retrospective cohorts independently before combining all cohorts in a meta-analysis. We perform tissue expression analysis and compare results with findings in the GWAS catalogue.</div><div>Current results from 107,721 individuals (14 891 cases and 92 830 controls) have revealed 7 novel independent genome-wide significant SNPs in European ancestry. We determined a SNP-heritability (SE) of 0.053 (0.006). Genetic correlation (SE) between meta-analysed cohorts with the latest MDD GWAS summary statistics was 0.79 (0.04) and between prospective and retrospective cohorts was 0.52 (0.05). Gene-expression analysis determined tissue enrichment in the cortex, cerebellum and hippocampus. Leading SNPs of the association with adolescent-onset depression overlapped with results from previous GWASs of depression, neuroticism and wellbeing in adults.</div><div>Association analyses from the remaining contributing cohorts are ongoing. Current results already provide novel genetic associations, and we expect the addition of approximately 70,000 more individuals to further increase power and discovery across ancestries. Once all samples are received, we will derive PRS for out-of-sample prediction across ancestries, test genetic correlation with other traits, use genomic structural equation modelling to investigate shared architecture, run colocalization for shared trait variants and perform Mendelian randomisation to identify causality. We expect that biological insights, potentially hidden within the larger and more heterogeneous adult population, could be uncovered in the more genetically heritable adolescent-onset group. Investigating the genetic architecture of the adolescent-onset depression subty","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 37"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442228","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.2024.08.083
{"title":"FAMILY-BASED WHOLE EXOME SEQUENCING IN MULTIPLEX PEDIGREES WITH SCHIZOPHRENIA AND BIPOLAR DISORDER FROM INDIA: FROM VARIANT HITS TO DISEASE MECHANISMS","authors":"","doi":"10.1016/j.euroneuro.2024.08.083","DOIUrl":"10.1016/j.euroneuro.2024.08.083","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 33"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442141","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.2024.08.081
Cathal Ormond , Niamh Ryan , William Byerley , Elizabeth Heron , Aiden Corvin
<div><div><strong>Background:</strong> Examining rare variants in multiplex pedigrees offers a complementary approach to the case-control study design to identify genes robustly associated with psychiatric disorders. Affected individuals within a pedigree are likely influenced by the same rare variant(s), which can simplify the disease-gene discovery process. Also, pedigrees are less sensitive to confounding from population stratification or environmental effects compared to unrelated cohorts. The goal of the Pedigree Sequencing Working Group of the Psychiatric Genomics Consortium (PGC) is to evaluate the contribution of rare variants from whole genome sequencing (WGS) in densely affected pedigrees. To date, we have collated WGS data from 310 individuals in 50 pedigrees across a range of psychiatric diagnoses. Here we give a progress update of the working group as well as describing novel methodologies developed for analysing pedigree-based WGS data.</div><div><strong>Methods:</strong> As an example of the above, we evaluated WGS data from 61 samples across ten pedigrees recruited from Utah multiply affected with schizophrenia or bipolar disorder. For single nucleotide variants (SNVs) and indels, we applied a simple filtering approach to identify plausible causal variants within each pedigree. We prioritised variants with a full co-segregation pattern (carried by all affected samples in-family and absent from unaffected and marry-in samples) or a reduced co-segregation pattern (carried by all but one affected sample in-family and absent from unaffected and marry-in samples). In addition, we applied an in-house Bayesian methodology known as BICEP to further identify variants of interest that would have been lost to the strict filtering. For copy number variants (CNVs), we applied our pedigree-aware consensus framework known as PECAN to call variants from the WGS data. We then applied a simple filtering prioritisation as before.</div><div><strong>Results:</strong> For the SNV/indel analysis, our filtering approach identified an ultra-rare, deleterious variant in ATP2B2 that had a reduced co-segregation pattern with schizophrenia. Recently, this gene was reported as significantly associated with bipolar disorder from a large case-control analysis of ultra-rare variants. Additionally, BICEP identified an ultra-rare variant in TTBK1 that perfectly co-segregated with schizophrenia. De novo pathogenic variants in this gene have been reported for childhood-onset schizophrenia. Finally, PECAN identified a rare, exonic deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults.</div><div><strong>Discussion:</strong> Our results highlight how pedigree-based analyses can provide a useful orthogonal approach to case-control strategies in identifying plausible risk genes for r
{"title":"PROGRESS UPDATE FROM THE PGC PEDIGREE SEQUENCING WORKING GROUP: RESULTS AND NOVEL METHODOLOGIES","authors":"Cathal Ormond , Niamh Ryan , William Byerley , Elizabeth Heron , Aiden Corvin","doi":"10.1016/j.euroneuro.2024.08.081","DOIUrl":"10.1016/j.euroneuro.2024.08.081","url":null,"abstract":"<div><div><strong>Background:</strong> Examining rare variants in multiplex pedigrees offers a complementary approach to the case-control study design to identify genes robustly associated with psychiatric disorders. Affected individuals within a pedigree are likely influenced by the same rare variant(s), which can simplify the disease-gene discovery process. Also, pedigrees are less sensitive to confounding from population stratification or environmental effects compared to unrelated cohorts. The goal of the Pedigree Sequencing Working Group of the Psychiatric Genomics Consortium (PGC) is to evaluate the contribution of rare variants from whole genome sequencing (WGS) in densely affected pedigrees. To date, we have collated WGS data from 310 individuals in 50 pedigrees across a range of psychiatric diagnoses. Here we give a progress update of the working group as well as describing novel methodologies developed for analysing pedigree-based WGS data.</div><div><strong>Methods:</strong> As an example of the above, we evaluated WGS data from 61 samples across ten pedigrees recruited from Utah multiply affected with schizophrenia or bipolar disorder. For single nucleotide variants (SNVs) and indels, we applied a simple filtering approach to identify plausible causal variants within each pedigree. We prioritised variants with a full co-segregation pattern (carried by all affected samples in-family and absent from unaffected and marry-in samples) or a reduced co-segregation pattern (carried by all but one affected sample in-family and absent from unaffected and marry-in samples). In addition, we applied an in-house Bayesian methodology known as BICEP to further identify variants of interest that would have been lost to the strict filtering. For copy number variants (CNVs), we applied our pedigree-aware consensus framework known as PECAN to call variants from the WGS data. We then applied a simple filtering prioritisation as before.</div><div><strong>Results:</strong> For the SNV/indel analysis, our filtering approach identified an ultra-rare, deleterious variant in ATP2B2 that had a reduced co-segregation pattern with schizophrenia. Recently, this gene was reported as significantly associated with bipolar disorder from a large case-control analysis of ultra-rare variants. Additionally, BICEP identified an ultra-rare variant in TTBK1 that perfectly co-segregated with schizophrenia. De novo pathogenic variants in this gene have been reported for childhood-onset schizophrenia. Finally, PECAN identified a rare, exonic deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults.</div><div><strong>Discussion:</strong> Our results highlight how pedigree-based analyses can provide a useful orthogonal approach to case-control strategies in identifying plausible risk genes for r","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 33"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442144","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.2024.08.096
{"title":"PSYCHIATRIC GENOME-WIDE ASSOCIATION STUDY ENRICHMENT SHOWS PROMISE FOR FUTURE PSYCHOPHARMACEUTICAL DISCOVERIES","authors":"","doi":"10.1016/j.euroneuro.2024.08.096","DOIUrl":"10.1016/j.euroneuro.2024.08.096","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 39"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442262","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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