European Neuropsychopharmacology最新文献

{"title":"WHAT IS THE IMPACT OF COMPOUND HETEROZYGOUS EVENTS INVOLVING DELETIONS AND SEQUENCE-LEVEL VARIANTS IN AUTISM?","authors":"Worrawat Engchuan , Brett Trost , Marla Mendes de Aquino , David Mager , Mehdi Zarrei , Rulan Shaath , Rayssa de Melo Wanderley , Faraz Ali , Nickie Safarian , Alex Chan , Shania Wu , Stephen W. Scherer , Elemi Breetvelt , Jacob Vorstman","doi":"10.1016/j.euroneuro.2024.08.080","DOIUrl":"10.1016/j.euroneuro.2024.08.080","url":null,"abstract":"<div><div>The majority of human genes maintain normal biological function when they become haploid due to a genomic deletion. However, pathogenicity may still arise when the remaining allele is affected by additional functional variation. Here, we describe analytical strategies for examining a specific type of compound heterozygosity, namely the co-occurrence of a deletion and a sequence-level variant affecting the other allele, hereafter referred to as deletion compound heterozygosity (DelCH). We report preliminary results in using these strategies to assess DelCH in Autism Spectrum Disorder (ASD).</div><div>We analyzed whole-genome sequencing data from MSSNG, Simons Simplex Collection, and SPARK cohorts (collectively 11,636 autistic individuals and 22,962 family members).</div><div>We developed multiple analytical strategies to examine rare (event rate < 1%) DelCH:<ul><li><span>1)</span><span><div>The burden analysis uses conditional logistic regression for group-level comparisons of DelCH rates between a) probands and their deletion-transmitting parents, with inherited deletion as a random effect variable, or b) probands and their family members, with family ID as a random effect variable;</div></span></li><li><span>2)</span><span><div>The transmission disequilibrium test (TDT) compares the rates with which deletion-non-transmitting parents transmit sequence-level variants within genes affected by deletions to their autistic offspring. Association is indicated by transmission of non-synonymous variants at a rate higher than predicted by chance. This approach was repeated in unaffected siblings as an additional control analysis.</div></span></li></ul></div><div>Each strategy has different strengths and weaknesses. The first burden analysis (1a) achieves perfect matching of deleted sequence and unambiguous phasing of variants but is restricted to proband-parent pairs. The second burden analysis (1b) benefits from a larger sample size but cannot distinguish between de novo and inherited variation. In addition, unambiguous phasing is possible only for SNVs within deletion boundaries. In contrast, while the TDT (2) can include SNVs outside deletion boundaries, thereby increasing statistical power, de novo events are not analyzed.</div><div>Our preliminary findings show variability in results as a function of the analytical strategy. Findings from the burden analysis suggest a modest enrichment of DelCH in ASD which was inversely proportional to the variant frequency thresholds applied.</div><div>Given that the mechanism consists of two rare events at the same locus, on the population level the role of DelCH in ASD etiology is likely modest, requiring large samples sizes for sufficient statistical power. In addition to this “lightning striking twice”, data preparation is demanding, as every subject has unique deletion regions in which sequence-level variants on the other allele are tallied. Variant selection metrics include allele frequency thres","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 32"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442143","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":"THE POLYGENETIC ARCHITECTURE OF AUTISM","authors":"Jing Zhang ,&nbsp;Jakob Grove ,&nbsp;Caitlin Carey ,&nbsp;Jack Fu ,&nbsp;F. Kyle Satterstrom ,&nbsp;Susan Kuo ,&nbsp;Ajay Nadig ,&nbsp;Swapnil Awasthi ,&nbsp;Kaitlin Samocha ,&nbsp;Anders Børglum ,&nbsp;Elise Robinson","doi":"10.1016/j.euroneuro.2024.08.045","DOIUrl":"10.1016/j.euroneuro.2024.08.045","url":null,"abstract":"<div><div>Autism is highly heritable and has been associated with multiple classes of genetic variation. Common genetic variation contributes substantially to autism. Previously, with 18,381 autistic individuals and 27,969 non-autistic individuals, five genome-wide significant loci were identified. Now with 38,717 autistic individuals and 232,725 non-autistic individuals, we report an updated genome-wide association study (GWAS) of autism with 12 genome-wide significant loci. We observe a moderate genetic correlation (0.675, SE=0.0434) between Europe-based (Nautistic=22,643; Nnon-autistic=204,389) and United States-based (Nautistic =16,074; Nnon-autistic=28,346) autism cohorts, which contributes to the decline of the estimated single nucleotide polymorphism (SNP) heritability (from 0.118 (SE=0.010) to 0.068 (SE=0.003)). The genetic correlation between autism with intellectual disability (ID) (Nautistic=6,590; Nnon-autistic= 43,071; h2=0.062; SE=0.012) and autism without ID (Nautistic=23,173; Nnon-autistic= 204,679; h2=0.089; SE=0.005) is 0.658 (SE=0.086). In the United States family-based cohorts, the genetic correlation between autism with ID (Nfamily=3,993; h2=0.159; SE=0.033) and autism without ID (Nfamily=4,357; h2=0.171; SE=0.031) is 0.812 (SE=0.157). Autism without ID was positively genetically correlated with educational attainment (0.163; P=4.84 × 10-11) and intelligence (0.233; P=1.95 × 10-11). Autism with ID genetically correlated with neither educational attainment (0.036; P=0.409) nor intelligence (-0.072; P=0.235). As ID alone is negatively genetically correlated with intelligence, the lack of correlation between autism with ID and intelligence strongly suggests that autism with ID is genetically different from ID alone. This difference has implications for both research and clinical nosology. Rare and de novo variants contribute substantially to autism in some individuals. Through rare variant analyses, 72 genes have been associated with autism at a genome-wide significant level to date. While de novo protein truncating variants (PTVs) and copy number deletions have been associated with autism, we report preliminary findings that the burden of inherited PTVs and copy number deletions among autistic individuals was elevated compared to their non-autistic siblings (P=4.00 × 10-5). Integration of multiple genetic factors will help us better understand the etiology of autism.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 16"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442213","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":"UPDATE FROM THE “PEDIGREE-BASED WHOLE GENOME SEQUENCING OF AFFECTIVE AND PSYCHOTIC DISORDERS\" CONSORTIUM","authors":"","doi":"10.1016/j.euroneuro.2024.08.082","DOIUrl":"10.1016/j.euroneuro.2024.08.082","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":"142442145","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":"FAST AND EFFICIENT MIXED-EFFECTS ALGORITHM (FEMA) FOR LONGITUDINAL GWAS AND SNP × TIME INTERACTION: APPLICATIONS AND OPPORTUNITIES IN MOBA","authors":"","doi":"10.1016/j.euroneuro.2024.08.106","DOIUrl":"10.1016/j.euroneuro.2024.08.106","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 43"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442224","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":"THE ADOLESCENT BRAIN COGNITIVE DEVELOPMENT STUDY: APPLICATIONS FOR PSYCHIATRIC GENETICS RESEARCH","authors":"","doi":"10.1016/j.euroneuro.2024.08.107","DOIUrl":"10.1016/j.euroneuro.2024.08.107","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 43"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442225","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":"THE BASICS OF MENDELIAN RANDOMISATION AND SPECIFIC CONSIDERATIONS FOR MENTAL HEALTH TRAITS","authors":"","doi":"10.1016/j.euroneuro.2024.08.029","DOIUrl":"10.1016/j.euroneuro.2024.08.029","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 10"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441636","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":"PRELIMINARY INVESTIGATIONS INTO THE GUT MICROBIOME'S ROLE IN SCHIZOPHRENIA","authors":"","doi":"10.1016/j.euroneuro.2024.08.041","DOIUrl":"10.1016/j.euroneuro.2024.08.041","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 14"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442310","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":"ANCESTRALLY DIVERSE SAMPLES IMPROVE FINE-MAPPING OF DEPRESSION-ASSOCIATED LOCI","authors":"","doi":"10.1016/j.euroneuro.2024.08.034","DOIUrl":"10.1016/j.euroneuro.2024.08.034","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 11"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442130","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":"IDENTIFYING DRUG TARGETS FOR SCHIZOPHRENIA THROUGH GENE PRIORITIZATION","authors":"Karl Heilbron ,&nbsp;Julia Kraft ,&nbsp;Alice Braun ,&nbsp;Swapnil Awasthi ,&nbsp;Georgia Panagiotaropoulou ,&nbsp;Marijn Schipper ,&nbsp;Nathaniel Bell ,&nbsp;Danielle Posthuma ,&nbsp;Antonio Pardiñas ,&nbsp;Stephan Ripke","doi":"10.1016/j.euroneuro.2024.08.036","DOIUrl":"10.1016/j.euroneuro.2024.08.036","url":null,"abstract":"<div><div>The latest schizophrenia GWAS meta-analysis found 287 loci that reached genome-wide statistical significance (67,390 cases and 94,015 controls). In these loci, 120 genes were prioritized using fine-mapping, summary-based Mendelian Randomization (SMR), and enhancer-promoter interaction (via Hi-C). However, these methods only use information within a given locus, ignoring information from the rest of the genome. Combining locus-based approaches with tools that incorporate genome-wide information such as the Polygenic Priority Score (PoPS) have been shown to improve gene prioritization precision. To more accurately characterize genes that play a role in schizophrenia etiology, we prioritized 62 genes based on their distance to GWAS signals, PoPS, fine-mapped coding variants, and ultra-rare coding variant burden tests. We prioritized DRD2, the target of most approved antipsychotics, which was not highlighted by previous efforts. In addition, we prioritized 9 genes that are targeted by approved or investigational drugs and may therefore present drug repurposing opportunities. These included drugs targeting calcium channels (CACNA1C and CACNB2), glutamatergic receptors (GRIN2A and GRM3), and GABAB receptor (GABBR2). We highlighted 3 additional genes (PDE4B, VRK2, and PLCL2) in loci that are shared with a recent addiction GWAS. While it is challenging to assess psychotic symptoms in rodents, high-quality rodent addiction models exist for a wide range of substances. Modulation of these genes could be tested in rodent addiction models and, if successful, may warrant further testing in human clinical trials of addiction and/or schizophrenia. Adding to previous gene prioritization efforts, we hope that our list of prioritized genes will ultimately facilitate the development of new medicines for people living with schizophrenia.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 12"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442132","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":"GENOME-WIDE ASSOCIATION STUDIES OF SUICIDAL THOUGHTS AND BEHAVIORS: AN UPDATE FROM THE PSYCHIATRIC GENOMICS CONSORTIUM SUICIDE WORKING GROUP","authors":"Sarah Colbert ,&nbsp;The Suicide Working Group of the Psychiatric Genomics Consortium ,&nbsp;Douglas Ruderfer ,&nbsp;Anna Docherty ,&nbsp;Niamh Mullins","doi":"10.1016/j.euroneuro.2024.08.049","DOIUrl":"10.1016/j.euroneuro.2024.08.049","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Suicidal thoughts and behaviors, specifically suicidal ideation (SI), suicide attempt (SA) and suicide death (SD), are substantially heritable, with twin and family studies estimating heritabilities in the range of 30-55%. Recently, genome-wide association studies (GWAS) have reached sufficient sample sizes to conduct well-powered analyses, leading to the identification of 4, 12 and 2 loci associated with SI, SA, and SD, respectively. Importantly, these phenotypes show strong, yet incomplete, genetic correlations with each other, motivating genetic studies of each phenotype separately to understand their underlying biology and the progression from one to the next. Here, we present an update on the progress of the latest and most extensive GWAS of SI, SA, and SD, conducted by the Psychiatric Genomics Consortium Suicide Working Group (PGC SUI).&lt;/div&gt;&lt;div&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Data comprise 30 cohorts contributing to the SI GWAS (N cases=256,257, N controls=1,298,106), 42 cohorts contributing to the SA GWAS (N cases=73,087, N controls=1,327,350), and 6 cohorts contributing to the SD GWAS (N cases=6,775, N controls=841,216). Notably, these cohorts comprise individuals from four diverse genetic ancestry groups: admixed European ancestries (EUR), admixed African ancestries (AA), East Asian ancestries (EA) and admixed Latino ancestries (LAT). New phenotyping and analytic protocols have been developed by PGC SUI to ensure exceptional rigor and comparability across cohorts. GWAS meta-analyses will be conducted via inverse variance-weighted fixed effects models to identify novel genetic risk loci. Post-GWAS analyses include pathway, tissue and drug target enrichment, and examination of the SNP-heritabilities (h2SNP), and genetic relationships between SI, SA, and SD.&lt;/div&gt;&lt;div&gt;Preliminary analysis using the currently available SA data (SA cases = 47,174, controls = 941,010 from 26 cohorts) yielded a h2SNP of 5.6% (se = 0.003, p = 1.2e-68) and ten replicated and three novel genome-wide significant (GWS) loci, containing FYN, AIG1, and DCC. Eight GWS loci were identified in the EUR meta-analysis (h2SNP = 7%, se = 0.004) which replicated previous findings. No GWS loci were identified in the AA (h2SNP = 9.8%, se = 0.02), EA (h2SNP 5.1%, se = 0.04) or LAT (h2SNP = 10%, se =0.07) GWAS meta-analyses. We also identified significant enrichment in genes expressed in several brain tissues from GTEx and summary data-based Mendelian Randomization revealed two novel genes (GMPPB, FURIN) significantly associated with SA. This SA GWAS showed significant genetic correlations with published GWAS of SI (rg = 0.80, se = 0.04), SD (rg = 0.77, se = 0.05), and several psychiatric disorders (rgs = 0.26-0.70).&lt;/div&gt;&lt;div&gt;Additional data intake is almost complete within PGC SUI, and this presentation will share the final GWAS results and novel biological insights. Increased sample sizes in combination with streamlined protocols for phenotyping and analyzing suicidal tho","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"87 ","pages":"Page 18"},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442217","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}