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":null,"pages":null},"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}
Pub Date : 2024-10-01DOI: 10.1016/j.euroneuro.2024.08.042
Genome-wide association and the analysis of rare genetic variants has provided great insights into the genetic basis of schizophrenia, with over 250 variants now identified. Evidence suggests that genetic evidence for association between a gene and disease (even for low risk, common variants) increased the probability of success as a drug target by two-fold or more (Minikel et al., 2024). However, there are several barriers to drug development using this information, including variant-to-gene mapping, target prioritisation, the validity of disease models, target tractability and the development of a therapeutic hypothesis. On the plus side, mapping of the genes within these loci have identified the dopamine D2 receptor (DRD2) gene, a major target of typical antipsychotic drugs, as well as a number of other genes that produce druggable or potentially druggable proteins (Kraft et al., 2024). In this presentation, potential pathways to drug development and stratification using genetics and genomics will be explored.
{"title":"Drug Discovery and the Genetic and Biological Underpinnings of Schizophrenia","authors":"","doi":"10.1016/j.euroneuro.2024.08.042","DOIUrl":"10.1016/j.euroneuro.2024.08.042","url":null,"abstract":"<div><div>Genome-wide association and the analysis of rare genetic variants has provided great insights into the genetic basis of schizophrenia, with over 250 variants now identified. Evidence suggests that genetic evidence for association between a gene and disease (even for low risk, common variants) increased the probability of success as a drug target by two-fold or more (Minikel et al., 2024). However, there are several barriers to drug development using this information, including variant-to-gene mapping, target prioritisation, the validity of disease models, target tractability and the development of a therapeutic hypothesis. On the plus side, mapping of the genes within these loci have identified the dopamine D2 receptor (DRD2) gene, a major target of typical antipsychotic drugs, as well as a number of other genes that produce druggable or potentially druggable proteins (Kraft et al., 2024). In this presentation, potential pathways to drug development and stratification using genetics and genomics will be explored.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442308","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.2024.08.039
{"title":"NEW INSIGHTS INTO THE GENETIC ETIOLOGY AND THERAPEUTIC TARGETS OF SCHIZOPHRENIA","authors":"","doi":"10.1016/j.euroneuro.2024.08.039","DOIUrl":"10.1016/j.euroneuro.2024.08.039","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442313","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.2024.08.020
<div><div>The High Risk paradigm is inherently a genetic epidemiologic study, similar to twin studies, adoption studies, and family studies. The questions posed are: What does the disorder look like before its onset? and What determines the transition between the risk state and onset of illness? These questions relate to the developmental expression of the risk genotype and interactions between risk and resilience.</div><div>Many studies have been done using this paradigm in bipolar disorder (BD). The particular sample we have been following comprises 307 young people at risk (first-degree relative of a proband with BD) and 166 controls, followed over the past 15 years. Ascertainment sites in the US are Indiana University School of Medicine, Johns Hopkins University, the University of Michigan and Washington University in St. Louis. We have collaborated with the University of New South Wales in Sydney, Australia. Similar methods of assessment (KSADS-BP and DIGS) have been used in all sites, along with a battery of self-assessment instruments. All participants have provided blood for DNA. All have had GWAS completed and polygenic risk scores calculated and 103 have DNA methylation data. A series of follow-up assessments were carried out over 2007-2020.</div><div>Diagnostic outcome is related to polygenic risk (Fullerton et al, 2015 PMID <span><span>26178159</span><svg><path></path></svg></span>; Zwicker et al, 2023 PMID <span><span>36856707</span><svg><path></path></svg></span>, Freeman et al, unpublished). Polygenic risk interacts with history of trauma to increase the chances of attempted suicide in high-risk offspring (Wilcox et al, 2017 PMID <span><span>29173741</span><svg><path></path></svg></span>). Polygenic risk also interacts dramatically with perceived pattern of family interaction (Stapp et al, 2023 PMID <span><span>37378048</span><svg><path></path></svg></span>).</div><div>Different patterns of comorbidity predicted major mood disorder in high-risk offspring, including both internalizing and externalizing disorders during childhood and early adolescence. These patterns of comorbidity are related to distinct polygenic signatures (Fullerton et al, unpublished).</div><div>In the literature, studies focused specifically on the emergence of BD have implicated subthreshold hypomanic/manic symptomatology as a premorbid indicator of developing illness (Hafeman et al, 2017 PMID <span><span>28678992</span><svg><path></path></svg></span>). Study of early symptomatic indicators in high-risk offspring have also implicated sleep disorders (Duffy et al, 2019 PMID <span><span>30525908</span><svg><path></path></svg></span>) and this may relate to premorbid disruption of circadian rhythms.</div><div>Although BD presents clinically as a distinctive syndrome, the genetic predisposition and developmental course of the disorder is complex. Risk for BD may be expressed phenotypically as an internalizing disorder, an externalizing disorder, or a disruption of
{"title":"WHAT DO WE KNOW ABOUT OFFSPRING AT RISK FOR BIPOLAR DISORDER AND WHAT REMAINS TO BE DISCOVERED","authors":"","doi":"10.1016/j.euroneuro.2024.08.020","DOIUrl":"10.1016/j.euroneuro.2024.08.020","url":null,"abstract":"<div><div>The High Risk paradigm is inherently a genetic epidemiologic study, similar to twin studies, adoption studies, and family studies. The questions posed are: What does the disorder look like before its onset? and What determines the transition between the risk state and onset of illness? These questions relate to the developmental expression of the risk genotype and interactions between risk and resilience.</div><div>Many studies have been done using this paradigm in bipolar disorder (BD). The particular sample we have been following comprises 307 young people at risk (first-degree relative of a proband with BD) and 166 controls, followed over the past 15 years. Ascertainment sites in the US are Indiana University School of Medicine, Johns Hopkins University, the University of Michigan and Washington University in St. Louis. We have collaborated with the University of New South Wales in Sydney, Australia. Similar methods of assessment (KSADS-BP and DIGS) have been used in all sites, along with a battery of self-assessment instruments. All participants have provided blood for DNA. All have had GWAS completed and polygenic risk scores calculated and 103 have DNA methylation data. A series of follow-up assessments were carried out over 2007-2020.</div><div>Diagnostic outcome is related to polygenic risk (Fullerton et al, 2015 PMID <span><span>26178159</span><svg><path></path></svg></span>; Zwicker et al, 2023 PMID <span><span>36856707</span><svg><path></path></svg></span>, Freeman et al, unpublished). Polygenic risk interacts with history of trauma to increase the chances of attempted suicide in high-risk offspring (Wilcox et al, 2017 PMID <span><span>29173741</span><svg><path></path></svg></span>). Polygenic risk also interacts dramatically with perceived pattern of family interaction (Stapp et al, 2023 PMID <span><span>37378048</span><svg><path></path></svg></span>).</div><div>Different patterns of comorbidity predicted major mood disorder in high-risk offspring, including both internalizing and externalizing disorders during childhood and early adolescence. These patterns of comorbidity are related to distinct polygenic signatures (Fullerton et al, unpublished).</div><div>In the literature, studies focused specifically on the emergence of BD have implicated subthreshold hypomanic/manic symptomatology as a premorbid indicator of developing illness (Hafeman et al, 2017 PMID <span><span>28678992</span><svg><path></path></svg></span>). Study of early symptomatic indicators in high-risk offspring have also implicated sleep disorders (Duffy et al, 2019 PMID <span><span>30525908</span><svg><path></path></svg></span>) and this may relate to premorbid disruption of circadian rhythms.</div><div>Although BD presents clinically as a distinctive syndrome, the genetic predisposition and developmental course of the disorder is complex. Risk for BD may be expressed phenotypically as an internalizing disorder, an externalizing disorder, or a disruption of","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441625","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.2024.08.068
<div><div>Copy number variation (CNV) is a key component of psychiatric risk and it is imperative to study their effects in the general population, yet CNV studies for psychiatric traits have primarily focused on European (EUR) populations and have neglected other ancestry groups. Previous genome-wide association studies (GWAS) for single nucleotide polymorphisms (SNP) have shown evidence that including samples from diverse ancestries can boost power for genetic association with psychiatric traits as well as identify cross-ancestry and ancestry-specific loci. This underscores the importance of expanding population diversity in CNV analyses of psychiatric traits, prompting the CNV group of the Psychiatric Genomics Consortium (PGC) to extend their analyses to include large amounts of diverse samples.</div><div>Recently, the expansion of sample sizes has significantly enhanced our ability to understand the genetic impact of CNVs on psychiatric disorders. We performed CNV analyses in six psychiatric disorders including autism (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia (SCZ), post-traumatic stress disorder (PTSD), major depression (MDD), bipolar disorder (BD), and a cross-disorder sample of all disorders (N=537,466). This allowed us to identify novel risk loci, gene dosage effects in pathways and brain regions, and how polygenic risk scores moderate phenotypes for carriers of recurrent CNV loci. We will discuss how the inclusion of diverse ancestry enhances our ability to detect new associations and compare the difference or similarity of genetic effects between populations.</div><div>The first presentation will be given by Max Lam, who will introduce the largest study of rare CNVs in SCZ for individuals in the East Asian (EAS) population (N=20,903 cases; 23,258 controls). We will show a meta-analysis of this EAS CNV study with a EUR CNV study of comparable sample size (N=17,506 cases; 16,751 controls), which allows us to measure the proportion of variance explained by each population at both novel and previously reported loci. Omar Shanta will then present a rare CNV-GWAS meta-analysis of cross disorder samples within multiple ancestry groups (N=571,803) including 17,474 African/African-American (AFR/AFAM) and 16,863 Asian/Asian-American (ASN/ASAM) samples. He will highlight how the inclusion of different ancestries influences the association at specific loci. Using the same cross-ancestry samples, Worrawat Engchuan will introduce a cross-ancestry CNV meta-analysis for a comparative gene-set analysis that includes gene-sets for cortical brain regions, neural cell types, developmental periods, and molecular pathways in multiple disorders. This approach achieves a more granular understanding of how gene dosage influences risk towards one diagnosis or another. Molly Sacks will then discuss how phenotypic variability between carriers of recurrent CNV loci can be influenced by genetic background, providing insight into how rare
{"title":"LEVERAGING ANCESTRAL DIVERSITY IN CNV STUDIES: IMPROVING POWER AND GAINING NEW INSIGHT INTO THE GENETIC ETIOLOGY OF PSYCHIATRIC DISORDERS","authors":"","doi":"10.1016/j.euroneuro.2024.08.068","DOIUrl":"10.1016/j.euroneuro.2024.08.068","url":null,"abstract":"<div><div>Copy number variation (CNV) is a key component of psychiatric risk and it is imperative to study their effects in the general population, yet CNV studies for psychiatric traits have primarily focused on European (EUR) populations and have neglected other ancestry groups. Previous genome-wide association studies (GWAS) for single nucleotide polymorphisms (SNP) have shown evidence that including samples from diverse ancestries can boost power for genetic association with psychiatric traits as well as identify cross-ancestry and ancestry-specific loci. This underscores the importance of expanding population diversity in CNV analyses of psychiatric traits, prompting the CNV group of the Psychiatric Genomics Consortium (PGC) to extend their analyses to include large amounts of diverse samples.</div><div>Recently, the expansion of sample sizes has significantly enhanced our ability to understand the genetic impact of CNVs on psychiatric disorders. We performed CNV analyses in six psychiatric disorders including autism (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia (SCZ), post-traumatic stress disorder (PTSD), major depression (MDD), bipolar disorder (BD), and a cross-disorder sample of all disorders (N=537,466). This allowed us to identify novel risk loci, gene dosage effects in pathways and brain regions, and how polygenic risk scores moderate phenotypes for carriers of recurrent CNV loci. We will discuss how the inclusion of diverse ancestry enhances our ability to detect new associations and compare the difference or similarity of genetic effects between populations.</div><div>The first presentation will be given by Max Lam, who will introduce the largest study of rare CNVs in SCZ for individuals in the East Asian (EAS) population (N=20,903 cases; 23,258 controls). We will show a meta-analysis of this EAS CNV study with a EUR CNV study of comparable sample size (N=17,506 cases; 16,751 controls), which allows us to measure the proportion of variance explained by each population at both novel and previously reported loci. Omar Shanta will then present a rare CNV-GWAS meta-analysis of cross disorder samples within multiple ancestry groups (N=571,803) including 17,474 African/African-American (AFR/AFAM) and 16,863 Asian/Asian-American (ASN/ASAM) samples. He will highlight how the inclusion of different ancestries influences the association at specific loci. Using the same cross-ancestry samples, Worrawat Engchuan will introduce a cross-ancestry CNV meta-analysis for a comparative gene-set analysis that includes gene-sets for cortical brain regions, neural cell types, developmental periods, and molecular pathways in multiple disorders. This approach achieves a more granular understanding of how gene dosage influences risk towards one diagnosis or another. Molly Sacks will then discuss how phenotypic variability between carriers of recurrent CNV loci can be influenced by genetic background, providing insight into how rare ","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442044","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.2024.08.071
Associating rare variants with disease risk has been limited by the lack of statistical power. Meta-analysis across different populations or different genetically correlated disorders have shown to successfully improve the statistical power in common variant studies. Such approaches have not been explored in the analyses of rare variants.
This study investigated the association of rare CNVs aggregated at the functional level with 6 major psychiatric disorders including schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD), in 571,803 individuals of European, African, and East Asian descent. Functional gene-set burden analyses, followed by cross-ancestry meta-analysis was conducted across 16 brain regions, 32 neural cell types, and 2,453 molecular functions. This approach aimed to comprehensively capture the impact of genetic risk variants.
Our preliminary findings from the European subset revealed distinct dosage sensitivity patterns across the 6 disorders. The effect sizes of DEL and DUP on SCZ were negatively correlated, while their effects on ASD risk were positively correlated. Our results suggest that multiple major psychiatric disorders share common etiologic pathways, but diagnostic outcome varies according to how gain and loss of function of neurodevelopmental and synaptic processes are spatially distributed in the developing brain. We hypothesized that even if the associated variants might differ in population frequency in different populations, the associations at functional level would agree across populations. Thus, cross-ancestry meta-analysis would strengthen the findings we had from the European subset. In this talk, we will present more on how the inclusion of African and East Asian samples influences the findings from the analysis of the European subset. We will also be discussing the dosage sensitivity patterns and genetic correlation at functional levels among the 6 major psychiatric disorders and across three populations.
{"title":"FUNCTIONAL-BASED ASSOCIATION STUDY OF RARE CNVS ACROSS SIX PSYCHIATRIC DISORDERS IN EUROPEAN, AFRICAN, AND EAST ASIAN POPULATIONS","authors":"","doi":"10.1016/j.euroneuro.2024.08.071","DOIUrl":"10.1016/j.euroneuro.2024.08.071","url":null,"abstract":"<div><div>Associating rare variants with disease risk has been limited by the lack of statistical power. Meta-analysis across different populations or different genetically correlated disorders have shown to successfully improve the statistical power in common variant studies. Such approaches have not been explored in the analyses of rare variants.</div><div>This study investigated the association of rare CNVs aggregated at the functional level with 6 major psychiatric disorders including schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD), in 571,803 individuals of European, African, and East Asian descent. Functional gene-set burden analyses, followed by cross-ancestry meta-analysis was conducted across 16 brain regions, 32 neural cell types, and 2,453 molecular functions. This approach aimed to comprehensively capture the impact of genetic risk variants.</div><div>Our preliminary findings from the European subset revealed distinct dosage sensitivity patterns across the 6 disorders. The effect sizes of DEL and DUP on SCZ were negatively correlated, while their effects on ASD risk were positively correlated. Our results suggest that multiple major psychiatric disorders share common etiologic pathways, but diagnostic outcome varies according to how gain and loss of function of neurodevelopmental and synaptic processes are spatially distributed in the developing brain. We hypothesized that even if the associated variants might differ in population frequency in different populations, the associations at functional level would agree across populations. Thus, cross-ancestry meta-analysis would strengthen the findings we had from the European subset. In this talk, we will present more on how the inclusion of African and East Asian samples influences the findings from the analysis of the European subset. We will also be discussing the dosage sensitivity patterns and genetic correlation at functional levels among the 6 major psychiatric disorders and across three populations.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442047","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.2024.08.073
Genomics research on sensitive traits such as neurodevelopmental, psychiatric, and behavioral traits poses numerous conceptual, methodological, ethical, legal, and social challenges. Community engagement and participatory research have been proposed as tools to increase the relevance, rigor, and acceptability of research, including genetic and biomedical studies. Informed by a growing body of research and lessons learned from recent and ongoing efforts to engage communities affected by genomics studies, I set a vision for more just, equitable, and collaborative genomics where primary stakeholders are included in research and decision-making as peers and collaborators, not solely as objects of study. Further, considering recent debates, lapses, and successes, I propose frameworks to promote respectful and productive engagement, communication, and collaboration between diverse stakeholders.
{"title":"TOWARDS JUSTICE, EQUITY, AND COMMUNITY EMPOWERMENT IN GENOMICS STUDIES ON BEHAVIORAL, PSYCHIATRIC AND NEURODEVELOPMENTAL TRAITS","authors":"","doi":"10.1016/j.euroneuro.2024.08.073","DOIUrl":"10.1016/j.euroneuro.2024.08.073","url":null,"abstract":"<div><div>Genomics research on sensitive traits such as neurodevelopmental, psychiatric, and behavioral traits poses numerous conceptual, methodological, ethical, legal, and social challenges. Community engagement and participatory research have been proposed as tools to increase the relevance, rigor, and acceptability of research, including genetic and biomedical studies. Informed by a growing body of research and lessons learned from recent and ongoing efforts to engage communities affected by genomics studies, I set a vision for more just, equitable, and collaborative genomics where primary stakeholders are included in research and decision-making as peers and collaborators, not solely as objects of study. Further, considering recent debates, lapses, and successes, I propose frameworks to promote respectful and productive engagement, communication, and collaboration between diverse stakeholders.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442049","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.2024.08.058
This will be the Symposium presented by the Ethics, Positions, and Public Policy Committee.
这将是伦理、立场和公共政策委员会举办的专题讨论会。
{"title":"ETHICAL AND POLICY ISSUES IN A DIVERSE WORLD","authors":"","doi":"10.1016/j.euroneuro.2024.08.058","DOIUrl":"10.1016/j.euroneuro.2024.08.058","url":null,"abstract":"<div><div>This will be the Symposium presented by the Ethics, Positions, and Public Policy Committee.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442134","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.2024.08.050
Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the genetic factors underlying these behaviors has been challenging. A recent genome-wide association study for suicide and suicide attempt identified an intergenic SNP on chromosome 7, rs62474683, which was significantly associated with suicide attempt, independently of psychiatric disorders.
In order to determine the potential functional effects of rs62474683 genotype, and how it may be related to suicide, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two different brain regions and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility.
We found differential expression of Forkhead box P2 (FOXP2), transcription factor EC (TFEC), and Testin LIM domain protein (TES) in the brains of individuals who died by suicide and found that FOXP2 and MyoD family inhibitor domain containing (MDFIC) expression was related to rs62474683. Additionally, the relationship between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for direct relationships between the region containing rs62474683 and FOXP2, MDFIC, and TES.
Our study provides evidence for a functional relationship between the most significant suicide attempt loci to date and genes displaying differential expression related to suicide.
{"title":"CHARACTERIZATION OF A SUICIDAL BEHAVIOR GWAS LOCUS ON CHROMOSOME 7","authors":"","doi":"10.1016/j.euroneuro.2024.08.050","DOIUrl":"10.1016/j.euroneuro.2024.08.050","url":null,"abstract":"<div><div>Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the genetic factors underlying these behaviors has been challenging. A recent genome-wide association study for suicide and suicide attempt identified an intergenic SNP on chromosome 7, rs62474683, which was significantly associated with suicide attempt, independently of psychiatric disorders.</div><div>In order to determine the potential functional effects of rs62474683 genotype, and how it may be related to suicide, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two different brain regions and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility.</div><div>We found differential expression of Forkhead box P2 (FOXP2), transcription factor EC (TFEC), and Testin LIM domain protein (TES) in the brains of individuals who died by suicide and found that FOXP2 and MyoD family inhibitor domain containing (MDFIC) expression was related to rs62474683. Additionally, the relationship between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for direct relationships between the region containing rs62474683 and FOXP2, MDFIC, and TES.</div><div>Our study provides evidence for a functional relationship between the most significant suicide attempt loci to date and genes displaying differential expression related to suicide.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442218","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.2024.08.078
Large samples are needed for genome-wide association studies (GWAS) of Major Depressive Disorder (MDD), and, indeed, recent studies aggregate more than a million individuals. Achieving these numbers means relaxing inclusion criteria for cases, often to a single self-report item, which may impact our ability to identify core disease mechanisms. Prior work suggests “shallow” criteria offer a different picture of the genetic architecture of MDD than more careful clinical criteria. Danish health registers, with long follow-ups, provide life-course medical history for those diagnosed with MDD and an ability to ask how representative samples are of the underlying population. Here, we study 50,000 MDD cases and 300,000 controls from three Danish biobanks with linkage to National register data: the iPSYCH2015 case-cohort study, the Danish Blood Donors Study, and the Copenhagen Hospital Biobank. We conduct a systemic analysis of the impact of ascertainment and inclusion/exclusion criteria on the inferred genetic architecture of MDD, seeking to clarify analogues for deeply phenotyped MDD. Among broadest possible MDD (BP-MDD; at least one diagnosis of ICD10: F32-33), we assessed the prevalence of potentially exclusionary diagnoses that reflect enrollment requirements for deeply phenotyped clinical studies (e.g., lifetime exclusions for schizophrenia, bipolar, or intellectual disability; post exclusions for onset of MDD subsequent to dementia or terminal illness diagnosis; event-based exclusions of MDD occurring within one year of an AUD, DUD or MCI diagnosis; and age-based exclusions for onset before 18 or after 50). We compare the genetic architecture of BP-MDD to clinically plausible MDD defined by the above criteria with or without age restrictions (CPA-MDD / CP-MDD) using GWAS and SNP-based variance components analysis. We then use polygenic score (PGS) profiles to test for differences in underlying genetic liability among cases with and without each potential exclusion criterion. Next, we compare the replication sensitivity of 250 index SNPs of previously identified MDD loci to inclusion/exclusion criteria. We observed an impact of exclusion criteria on GWAS power, replication sensitivity, and PGS profiles of individuals diagnosed with MDD. For example, we observed the PGS for MDD trended higher in CP-MDD while the PGS for SCZ and PTSD were significantly lower. Consistent with this, for some variants, effect sizes appear to increase when replicated in the smaller, more strictly defined CP-MDD, while other variants saw effect sizes diminish when moving from shallower BP-MDD to stricter CP-MDD. Our study highlights the impact that considering life-course exclusion criteria in defining MDD cases from biobanks has on the underlying genetic architecture. We believe this motivates important discussions regarding the next steps for MDD GWAS that could help improve the portability of results across cohorts and enable.
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