European Neuropsychopharmacology最新文献

{"title":"THE PGC-PSTD ANCESTRY WORKING GROUP: IMPROVING THE INCLUSION OF ADMIXED INDIVIDUALS IN PSYCHIATRIC GWAS","authors":"Marcos Santoro ,&nbsp;Jessica Mauer ,&nbsp;Adam Maihofer ,&nbsp;Nirav Shah ,&nbsp;Caroline Nievergelt ,&nbsp;Elizabeth Atkinson","doi":"10.1016/j.euroneuro.2024.08.016","DOIUrl":"10.1016/j.euroneuro.2024.08.016","url":null,"abstract":"<div><div>The latest PGC-PTSD GWAS achieved a considerable increase in the sample sizes of non-European populations, including more than 50,000 African American (AA) and 13,000 Latin American (LA) individuals. One of the difficulties in analyzing these samples is that they are usually very admixed, with different patterns of admixture according to the region they have been collected. The PGC-PTSD Ancestry working group is focused on developing new tools to allow proper inclusion of admixed individuals in GWAS and to facilitate the use of these tools for LMIC collaborators. Previously, we developed Tractor, a gene discovery tool for admixed populations that uses Local Ancestry Inference (LAI) to allow the well-calibrated inclusion of these individuals in GWAS studies. Currently, one of the primary efforts is to comprehensively test strategies for LAI to provide guidelines for parameter setting and reference panel composition. For this, we have simulated admixed individuals considering different patterns of admixture (AA-2 way and LA-3 way), demographic models, software settings, genomic data types, and reference panels. These simulations allow us to define best practice guidelines for researchers to use when analyzing diverse populations to produce the highest accuracy results across ancestries.</div><div>In our tests, we observe that Amerindigenous ancestry tracts suffer from notably reduced accuracy as compared to European and African tracts. When miscalls occur, LAI error rates are most frequently in the direction of calling European ancestry in true Amerindigenous sites than other error modes. Though our investigations are directly responsive to realistic admixed Latin American cohort compositions, the trends we characterize are broadly useful to inform best practice for local ancestry inference across diverse admixed populations. In parallel with this initiative of improving LAI analysis accuracy, our working group is developing a friendly pipeline for Tractor so other consortia can apply this approach for large sample sizes. As a future perspective, the PGC-PTSD ancestry working group will also work on the development of new tools for post GWAS approaches as polygenic scores.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 4"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441741","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}

{"title":"EXPLORING THE IMMUNOGENETIC BASIS OF POST-TRAUMATIC STRESS DISORDER","authors":"Alice Braun ,&nbsp;Adam X Maihofer ,&nbsp;Seyma Katrinli ,&nbsp;Georgia Panagiotaropoulou ,&nbsp;Daniel Levey ,&nbsp;Stephan Ripke ,&nbsp;Joel Gelernter ,&nbsp;Caroline Nievergelt ,&nbsp;PGC PTSD Working Group","doi":"10.1016/j.euroneuro.2024.08.017","DOIUrl":"10.1016/j.euroneuro.2024.08.017","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Post-Traumatic Stress Disorder (PTSD) is a complex psychiatric condition that develops following exposure to traumatic experiences. Its core symptoms include intrusive thoughts, avoidant behavior, and a persistent state of hyperarousal. Although it is widely recognized that stress exacerbates inflammation across tissues, a growing body of evidence suggests a reciprocal relationship, with immune function influencing susceptibility to PTSD. This relationship may be driven by shared underlying biology, such as from pleiotropy. The most recent genome-wide association study (GWAS) of PTSD identified 95 risk loci, including endocrine and immune regulators, such as the major histocompatibility complex (MHC). The MHC harbors numerous genetic variants such as human leukocyte antigen (HLA) alleles that are crucial for immune function. However, the complex linkage disequilibrium structure of the MHC poses challenges in isolating individual signals through SNP-based imputation. Here, we present a large-scale cross-ancestry analysis assessing the association of HLA alleles with PTSD.&lt;/div&gt;&lt;div&gt;We conducted HLA imputation and association analysis in a genotyped sample of individuals of African, European, or Latin American ancestry from 38 studies included in the latest PTSD GWAS published by the Psychiatric Genomics Consortium. The outcome phenotype was assessed as either case-control or on a continuous scale (e.g. the PTSD Checklist for DSM-IV or V). The 1000 Genomes Reference Panel, comprised of individuals from African, East Asian, European, South Asian, and American populations was employed to impute around 350 HLA alleles via SHAPEIT5 and MINIMAC4. Additionally, we introduced 21 long-range HLA haplotypes into the reference. Regression analyses were conducted using PLINK 2.0, while the first five principal components were included as covariates to adjust for population stratification. Finally, we employed METAL, using the sample-size weighting approach, to meta-analyze results from dichotomous and continuous outcomes.&lt;/div&gt;&lt;div&gt;We have generated preliminary results in a multi-ancestry sample (N = 60,159) that highlight HLA-DRB1*01:01 as the top risk-conferring allele across three ancestries (Z = 3.255, P = 1.14e-03). HLA-DRB1*01:01 was also the most significant HLA allele (Z = 2.380, P = 1.73e-02) in the Latin American sample (n = 7,072). In the African sample (n = 14,883), HLA-B*51:01 (Z = 3.553, P = 3.82e-04) emerged as the most significant HLA allele, while in Europeans (n = 38,204), the most significant allele HLA-B*08:01 showed a negative association with PTSD (Z = -2.555, P = 1.06e-02).&lt;/div&gt;&lt;div&gt;Our association analysis has identified multiple HLA alleles nominally associated with PTSD, with HLA-DRB1*01:01 emerging as the most significant possibly risk-conferring variant across ancestries. Notably, a protective effect of HLA-B*08:01 has previously been observed in schizophrenia and bipolar disorder. In the next steps, we will conduct imput","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 4-5"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441742","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}

{"title":"COORDINATED EPISTASIS DETECTS HETEROGENOUS PATHWAYS ACROSS PSYCHIATRIC DISORDERS AND COMORBIDITIES","authors":"Jolien Rietkerk ,&nbsp;Morten Krebs ,&nbsp;Lianyun Huang ,&nbsp;Kajsa-Lotta Georgii Hellberg ,&nbsp;IPSYCH Consortium ,&nbsp;Thomas Werge ,&nbsp;Andrew Schork ,&nbsp;Andy Dahl ,&nbsp;Na Cai","doi":"10.1016/j.euroneuro.2024.08.077","DOIUrl":"10.1016/j.euroneuro.2024.08.077","url":null,"abstract":"<div><div>Cross-disorder analyses in psychiatry often center around genetic correlation, which quantifies the average similarity of genetic effects across two disorders. For a long time, this has been the only feasible approach, as most cohorts only collect data on a single disorder. However, few studies have examined the genetic architecture of comorbidity itself or how it relates to the genetic architecture of the individual disorders involved. In this study we set out to investigate the genetic architecture of comorbidity between psychiatric disorders in the iPSYCH2015 case-cohort study. This Danish register-based study contains comorbid cases for 10 pairs of five psychiatric disorders (schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), autism (AUT) and attention deficit hyperactivity disorder (ADHD)), making it ideal for understanding comorbidity. We develop a novel framework to model both cross-disorder genetic sharing and the genetics of comorbidity based on the concept of Coordinated Epistasis (CE). Within this framework, we can identify synergistic and antagonistic interactions of Polygenic Risk Scores (PRS) across each disorder pair. We can also identify how these interactions impact individual disorders involved and delineate established theoretical models of comorbidity. In particular, we test one model of comorbidity where genetic effects distinguish comorbid cases from cases with only one disorder, which shows synergistic PRS interactions between ADHD-AUT comorbid cases and cases of either AUT or ADHD, which replicates in both iPSYCH2015 sub-cohorts: 2012 (P = 1.3E-02) and 2015i (P = 2.9E-02). We next apply our framework to family-based genetic scores (PA-FGRS), using recorded diagnoses from an average of 20 genetic relatives from the Danish medical registry. We find synergistic PA-FGRS interactions in comorbid ADHD-AUT (P = 1.1E-05), validating our PRS results. In summary, we perform the first comprehensive study on the genetics of comorbidity by extending the CE framework using a combination of PRS and PA-FGRS, and for the first time identify coordinated polygenic interactions contributing to cross-disorder genetic sharing and comorbidity among five psychiatric disorders.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 30-31"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442231","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}

{"title":"SCIENCE COMMUNICATION: THE IMPORTANCE OF LANGUAGE IN A DIVERSE WORLD","authors":"Helena Davies (Chair) ,&nbsp;Abigail ter Kuile (Co-chair) ,&nbsp;Helena Davies (Discussant)","doi":"10.1016/j.euroneuro.2024.08.100","DOIUrl":"10.1016/j.euroneuro.2024.08.100","url":null,"abstract":"<div><div>Our aim as the PGC Outreach Committee is to improve visibility, accessibility, and understanding of psychiatric genetics amongst both the general public and the wider scientific community. But how accessible are we really? How easily interpreted is the information we share to non-scientists? And how can we improve?</div><div>A systematic review of media coverage and readability in genome-wide association studies, published earlier this year, concluded that the language used to describe genetics research is too complex to be understood by the public. Over 95% of the online news sites examined would require more than twelve years of formal education for a full understanding of their content. The importance of language, particularly in genetics research, can extend beyond ‘readability’ to even more fundamental issues. For instance, another recent systematic review emphasised the need for defining ancestry based on the type of data used for its measurement (e.g., “genetic ancestry”), as failure to do so can result in reduced clarity concerning the distinction between genetic and social identities.</div><div>This symposium will delve into the critical role of language in the effective communication of scientific concepts to diverse audiences. Our presenters will first each discuss what the importance of language in a diverse world means from their own unique perspective (10 minutes each). They will cover topics such as the importance of the choice of words in relation to genetic ancestry and other complex concepts in psychiatric genetics such as heritability, and the impact of language in discussions surrounding the lived experience of those with psychiatric disorders. Broadly, the presentations will highlight how we can bridge the gap between technical jargon and layman's terms, making complex ideas accessible to a broader audience including those living with psychiatric conditions and their families, as well as how we can more accurately use language in our communications within the scientific community.</div><div>We will then have a panel discussion (30 minutes) in which the presenters will share insights into, for example, some of the challenges they have faced in science communication, such as combating misinformation, and what they believe the consequences for our field will be if we do not carefully consider the role of accurate and responsible communication in psychiatric genetics. We will conclude the session with questions from the audience (15 minutes).</div><div>Ultimately, the symposium will demonstrate that effective science communication is a dynamic interplay of language, empathy, and engagement, and will encourage attendees to consider the impact of their words in shaping public perceptions and attitudes towards psychiatric genetics.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 40-41"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442266","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}

{"title":"EVALUATING THE IMPACT OF BIOLOGICAL SEX ON ADHD PRESENTATION, PREVALENCE, AND GENETIC RISK","authors":"Sarah Guagliardo ,&nbsp;Mischa Lundberg ,&nbsp;Andrew Schork ,&nbsp;Nancy Cox ,&nbsp;Megan Shuey","doi":"10.1016/j.euroneuro.2024.08.076","DOIUrl":"10.1016/j.euroneuro.2024.08.076","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs executive functioning, vigilance-attention, and motivation. Due to this, individuals with ADHD are at higher risk of addiction, poor academic and professional outcomes, and social deficits. Heterogeneity in presenting symptoms is well-established and may result in a delayed or missed diagnosis. The prevalence of ADHD is reported from two to seven times higher for males than females. The prevalence of ADHD appears consistent in childhood and adulthood. Only half of those diagnosed in childhood report persisting symptoms, implying many are first diagnoses as adults and those first diagnosed in adulthood tend towards a different symptom profile. Such sex and age trends may reflect protective effects of “female sex”, children “growing out of” ADHD, or adults experiencing a different clinical entity. However, others argue that the high heritability of ADHD (0.6-0.85) and similar genetic risk in females suggests that these trends may be due to a heterogenous expression of symptoms in response to the environment (e.g., modulated by the female or adult experience). We use Vanderbilt University Medical Center's (VUMC) biobank (n=3,285,882 electronic health records (EHR) and 119,750 genotyped samples) to analyze ADHD prevalence and genetic architecture. We observed the ADHD-associated ICD codes (n=38,419) were less frequent in EHR-recorded females relative to males (n=14,395 vs. 24,024) and the median age at first diagnosis was substantially older (21.72 years, IQR=20.96 vs.15.05 years, IQR=9.1). Among subset of European ancestry patient genotyped in VUMC (n=69,397), we observed an ADHD polygenic risk scores (PRS) was significant independent predictor of diagnosis, with stronger effects on females (males, beta= 13.47, p=0.03; females, beta=16.90, p=7.4e-7), and female cases having higher average PRS than male cases (p=0.04). In a sex-specific phenome-wide association study (PheWAS), the ADHD PRS was associated with similar phenotypes regardless of sex, including substance/tobacco use, other psychiatric disorders, obesity, diabetes mellitus, and respiratory problems. Our findings that female patients with ADHD appear to have higher genetic liability for the condition despite lower rates of diagnosis are consistent with previous studies. Additionally, ADHD PRS did not demonstrate differential comorbidity structures based on sex in VUMC. One explanation for this is that established genetic proxies of disease inadequately reflect the nuances of particular behaviors of ADHD subtypes, including but not limited to exhibition of externalizing hyperactive subtype (ADHD-H) opposed to internalizing inattentive subtype (ADHD-I), which is reported more frequently in females. Therefore, obtaining clinical diagnoses in females may require symptom manifestations that are largely overlapping with their male counterparts. Additional work in various EHR resources may shed ","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 30"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441954","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}

{"title":"JOINT MULTI-FAMILY HISTORY AND MULTI-POLYGENIC SCORE PREDICTION OF MAJOR DEPRESSIVE DISORDER","authors":"Rujia Wang ,&nbsp;Helena Davies ,&nbsp;Sanghyuck Lee ,&nbsp;Jonathan Coleman ,&nbsp;Raquel Iniesta ,&nbsp;Thalia Eley ,&nbsp;Gerome Breen","doi":"10.1016/j.euroneuro.2024.08.064","DOIUrl":"10.1016/j.euroneuro.2024.08.064","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a complex psychiatric disorder influenced by genetic, social, and environmental factors. Family history and polygenic risk scores of MDD and related psychiatric disorders are strong predictors for MDD, while childhood trauma (CT) also plays a crucial role. This study aimed to jointly model the predictive effect of multi-family history (mFH), multi-PRS (mPRS), and childhood trauma on the development of MDD and the number of MDD episodes experienced. Our aim was to identify predictive model useful for stratification to more or less intensive treatment plans and interventions.</div><div>Data were obtained from the NIHR BioResource Genetic Links to Anxiety and Depression (GLAD) study and UK Biobank (UKB). MDD diagnosis followed DSM-V criteria using the same online mental health questionnaire data in GLAD and UKB. Family history (Yes/No) was reported for up to 22 psychiatric disorders. MegaPRS was used to calculate PRSs based on large genome-wide association studies. Reported childhood trauma was identified via the5-item childhood trauma screener questionnaire. Elastic net regression with nested cross-validation was applied.</div><div>In GLAD (9,927 MDD cases, 4,452 controls), mFH explained 16.85% of MDD variance, followed by CT (10.62%), demographics (9.92%), and mPRS (7.73%). All predictors together explained 33.87% of MDD variance, with corresponding areas under the receiver operating characteristic curve (AUC) of 0.84 and a positive predictive value (PPV) of 0.81. In UKB (40,667 MDD cases, 70,755 controls), mFH explained 13.56% of MDD variance, followed by demographics (5.95%), CT (5.87%), and mPRS (3.69%). Together, all predictors explained 23.68% of variance (AUC=0.74, PPV=0.66). The strongest individual predictor in both cohorts is family history of depression, followed by CT, sex, family history of anxiety, and PRS for depression. The modal number of MDD episodes among MDD cases is ≥ 13 episodes in GLAD, compared to 1 episode in UKB. Additionally, the mean age of onset is 21 years in GLAD and 33 years in UKB. When the model was applied to other MDD phenotypes, all predictors accounted for 25.80% of the variances for the number of MDD episodes and 8.41% for age of onset in GLAD, and 11.92% and 6.01% in UKB, respectively.</div><div>Integrating multi-family history, multi-PRS, childhood trauma, and demographics enhances MDD prediction. The prediction model performs effectively in both severe MDD cohort (GLAD) and population-based cohort (UKB), suggesting its potential generalizability to broader populations. The strongest predictors are family history of depression and childhood trauma, both of which are easily measurable in clinical settings. Furthermore, the model trained for MDD prediction also proves to be a strong predictor for the number of MDD episodes and age of onset, indicating its effectiveness in predicting the severity of MDD.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 24-25"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442040","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}

{"title":"COLLABORATIVE STUDY OF THE COMBINED EFFECTS OF RARE CNVS AND POLYGENIC RISK ON PSYCHIATRIC TRAITS","authors":"Molly Sacks ,&nbsp;Marieke Klein ,&nbsp;Omar Shanta ,&nbsp;Mohammad Ahangari ,&nbsp;Oanh Hong ,&nbsp;Jeff MacDonald ,&nbsp;Bhooma Thiruvahindrapuram ,&nbsp;Sebastien Jacquemont ,&nbsp;Tim Bigdeli ,&nbsp;Matthew Oetjens ,&nbsp;Mart Kals ,&nbsp;Stephen H. Scherer ,&nbsp;Jonathan Sebat ,&nbsp;The Bipolar Disorder, Schizophrenia, Post-Traumatic Stress Disorder, Attention-Deficit/Hyperactivity Disorder, Major Depressive Disorder, Autism Spectrum Disorder and Copy Number Variation working groups of the Psychiatric Genomics Consortium ,&nbsp;Genes to Mental Health Network","doi":"10.1016/j.euroneuro.2024.08.072","DOIUrl":"10.1016/j.euroneuro.2024.08.072","url":null,"abstract":"<div><div>Recurrent CNVs are known to be major risk factors in neuropsychiatric disorders, yet phenotypic variability between carriers of the same CNV remains unexplained. A possible explanation is that the effect of a CNV depends on genetic background, which can be quantified by a polygenic risk score (PRS). Using data from the PGC and UKBB (combined n=543,111), this project aims to characterize the individual and combined effects of recurrent CNVs and PRS on six major psychiatric disorders: ADHD, ASD, BD, PTSD, MDD, and SCZ.</div><div>We first quantified the effects of 42 recurrent CNV loci across all 6 disorders using logistic regression. After Bonferroni correction, 24 loci had a significant association with at least one disorder in either the deletion or duplication. We next documented evidence for the traditional liability threshold model of disease risk; cases carrying CNVs with weak main effects had higher PRS than cases carrying CNVs with strong main effects. This pattern was strongest for SCZ (p=2.13e-4) but was evident in BD as well. Additionally, we tested a composite CNV-PRS model, which demonstrates how PRS can be a useful tool for predicting outcomes in CNV carriers. For example, a carrier of 16p11.2 proximal duplication (a well-known SCZ association) is not at increased risk for SCZ if they have a low PRS-SCZ.</div><div>To increase power to detect statistical interactions between CNVs and PRS, we conducted a meta-analysis of CNVxPRS effects on BMI and height in four biobanks: UK Biobank, Estonian Biobank, Geisinger Health, and Million Veterans Program, (n=975,408). Of the 32 CNVs that were sufficiently powered for this analysis (n &gt; 225), 3 had nominally significant (p &lt; .05) interactions with PRS on BMI. In all three cases, the sign on the interaction was the same as the main effect of the CNV, suggesting that these interactions are synergistic. When we collapsed CNVs by their main effect direction, we saw a significant negative interaction between the BMI decreasing CNVs and PRS (p=9.98e-4). These interactions were robust to rescaling of the BMI response variable via inverse normalization or Box-Cox. We observed no significant interactions for Height.</div><div>Taken together, these analyses demonstrate that the effect of recurrent CNVs is moderated by PRS. In addition to emphasizing the importance of considering genetic background when studying the effects of rare variants, this study also demonstrates that genetic factors may have non-additive effects on complex traits.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 28-29"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442048","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}

{"title":"USING REPEATED MEASURES TO IMPROVE THE PRECISION AND POWER OF GENOME-WIDE ASSOCIATION STUDIES (GWAS)","authors":"Alex Kwong ,&nbsp;Mark Adams ,&nbsp;Poppy Grimes ,&nbsp;Gareth Griffith ,&nbsp;Tim Morris ,&nbsp;Kate Tilling ,&nbsp;Andrew McIntosh","doi":"10.1016/j.euroneuro.2024.08.090","DOIUrl":"10.1016/j.euroneuro.2024.08.090","url":null,"abstract":"<div><div>Genome Wide Association Studies (GWAS) have been vital to understanding the genetics of complex traits. However, the majority of GWAS use data from only one occasion, even in longitudinal studies with repeated assessments. Traits like depression are often subject to measurement error. Using a more precise and longitudinal phenotype of depression could reduce measurement error and increase power and precision in depression GWAS, further enhancing understanding of the genetics of depression.</div><div>We used data from the UK Biobank (max n=462,566) on the PHQ-2, a measure of depressive symptoms assessed up to 8 occasions over approximately 17 years. We tested a GWAS baseline model (a traditional cross-sectional GWAS that took the first observed assessment) against four other longitudinal GWAS models: 1) the mean of all the assessments, 2) a structural equation model (common factor model), 3) a precision-weighted shrinkage model and 4) a genomicSEM model. We also conducted analysis across multiple ancestries and performed out of sample polygenic prediction.</div><div>All longitudinal GWAS models outperformed the GWAS baseline model in European ancestries, with the most powerful model being the precision-weighted shrinkage model which identified 169 genome wide significant single nucleotide polymorphisms (SNPs). Importantly, this precision-weighted shrinkage method had an increase of 34 more lead SNPs (121% increase), 107 more independent significant SNPs (173% increase), 50 more mapped genes (35% increase) and a greater SNP heritability (35% increase), compared to the baseline model. Polygenic prediction into an external cohort also explained a greater proportion of variance (17% increase). There were no GWAS lead SNPs identified in the South Asian and African baseline models, but 2 and 7 novel lead SNPs in the precision-weighted shrinkage methods, respectively.</div><div>Leveraging repeated information within GWAS appears to improve power and precision to detect novel biological underpinnings in depression. This is likely due to a reduction in measurement error and increased power. These methods can be applied to other noisy traits within psychiatric genetics and could be useful for detecting novel loci in smaller studies.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Pages 36-37"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442229","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}

{"title":"ACCELERATING DRUG REPURPOSING IN PSYCHIATRY USING GENETICS","authors":"William Reay (Chair) ,&nbsp;Zachary Gerring (Co-chair)","doi":"10.1016/j.euroneuro.2024.08.095","DOIUrl":"10.1016/j.euroneuro.2024.08.095","url":null,"abstract":"<div><div>New pharmacotherapies in psychiatry would likely reduce the immense burden that mental health conditions place on individuals and society at large. However, the pipeline to discover novel drugs for use in psychiatric disorders has remained unproductive, where a lack of objective biomarkers for psychiatric diagnoses and the assessment of treatment outcomes contributes to clinical trial failure. Therefore, new approaches are urgently needed to identify more suitable drug candidates for clinical trials. One approach is the integration of human genetic and molecular data to identify and prioritize existing drugs for human clinical trials, known as drug repurposing. This approach has previously been successfully applied in psychiatry and offers an avenue for expedited clinical translation compared to traditional drug discovery. For example, valproic acid was originally used for its anticonvulsant properties in epilepsy before its utility in bipolar disorder was uncovered. Despite the promise of drug repurposing in psychiatry, challenges remain arising from the immense biological heterogeneity of these phenotypes. The advent of well powered, genetic association studies and high throughput measurements on diverse molecular data types (e.g., gene expression) represent an opportunity to better understand the biological complexity of these phenotypes and accelerate successfully translating prospective repurposing candidates into clinical practice. In this symposium, we will outline some of the key methodological considerations and progress to date in genetically informed prioritization of repurposing candidates across psychiatric disorders. Specifically, we will discuss how integration of genetic association signals with multiomic data can reveal prospective opportunities for drug repurposing. Approaches to biologically interpret individual target genes in the context of the wider polygenic architecture of these disorders will also be outlined. Shared genetic liability and biological relationships between psychiatric disorders and somatic disorders across the rest of the body treated by existing drugs additionally can present supporting lines of evidence for prospective repurposing candidates. Finally, given the immense variability observed between individuals with the same diagnosis, we will discuss the prospects of using genetics to target drug repurposing opportunities with greater precision at the individual level. This symposium brings together a diverse set of international researchers that are working at the forefront of innovative approaches to identify opportunities for drug repurposing in psychiatry.</div></div>","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":"142442261","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}

{"title":"BRIDGING LINGUISTIC AND CULTURAL DIVIDES IN PSYCHIATRIC GENOMICS RESEARCH: LESSONS FROM UGANDA","authors":"Allan Kalungi ,&nbsp;Segun Fatumo","doi":"10.1016/j.euroneuro.2024.08.101","DOIUrl":"10.1016/j.euroneuro.2024.08.101","url":null,"abstract":"<div><div>Psychiatric genomics research tools frequently depend on terminology and notions that are predominantly derived from Western viewpoints, specifically designed for populations speaking English in Europe and the United States of America. Nevertheless, there is an increasing interest in incorporating African populations into genetic studies, as African genetic data possess significant potential for enhancing discovery in psychiatric genetics research. However, this undertaking has unique difficulties, including inefficiently conveying intricate genetic and psychiatric ideas and terminology to participants using their native African languages. The absence of obvious counterparts for terms such as \"trauma\" or \"genome\" necessitates the need for unique strategies to overcome linguistic barriers.</div><div>In 2011, we established the Uganda Genome Resource (UGR) – a well-characterized genomic database with a range of phenotypes for communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC), a population-based open cohort. The UGR comprises genotype data on ∼5,000 and whole-genome sequence data on ∼2,000 Ugandan GPC individuals from 10 ethno-linguistic groups. We have since extended UGR to include studies focusing primarily on mental health conditions including major depressive disorder, post-traumatic stress disorder, generalized anxiety disorder, alcohol misuse and suicidality, among others.</div><div>To mitigate against the barrier poised by research tools which were developed in a foreign language to the participants, first, we engage the service of a professional linguistic translator to ensure accurate translation of all study materials. Additionally, we provide cultural sensitivity training to researchers to ensure respectful and ethical interactions with participants from diverse ethno-linguistic backgrounds. Secondly, following the translated study material, we set up a series of workshop including mental health experts and leading psychiatric geneticists and local scientists to agree on the translated content. Thirdly, we ask an independent local scientist to conduct a reverse translation of the study materials to ensure accuracy and consistency in the translated versions. This thorough process helps to minimize any potential misunderstandings or misinterpretations that may arise during the research study.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 41"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442267","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}