American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

{"title":"Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development","authors":"Sam J. Washer,&nbsp;Robert Flynn,&nbsp;Asami Oguro-Ando,&nbsp;Eilis Hannon,&nbsp;Joe Burrage,&nbsp;Aaron Jeffries,&nbsp;Jonathan Mill,&nbsp;Emma L. Dempster","doi":"10.1002/ajmg.b.32905","DOIUrl":"10.1002/ajmg.b.32905","url":null,"abstract":"<p>Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the <i>AS3MT</i> gene. Although <i>AS3MT</i> is hypothesized to play a role in neuronal development and differentiation, work to fully understand the function of this gene has been limited. In this study we explored the function of <i>AS3MT</i> using a neuronal cell line (SH-SY5Y). We confirm previous findings of isoform specific expression of <i>AS3MT</i> during SH-SY5Y differentiation toward neuronal fates. Using CRISPR-Cas9 gene editing we generated <i>AS3MT</i> knockout SH-SY5Y cell lines and used RNA-seq to identify significant changes in gene expression in pathways associated with neuronal development, inflammation, extracellular matrix formation, and RNA processing, including dysregulation of other genes strongly implicated in schizophrenia. We did not observe any morphological changes in cell size and neurite length following neuronal differentiation and MAP2 immunocytochemistry. These results provide novel insights into the potential role of <i>AS3MT</i> in brain development and identify pathways through which genetic variation in this region may confer risk for schizophrenia.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39999884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-polygenic scores in psychiatry: from disorder-specific to transdiagnostic perspectives","authors":"Yingjie Shi, E. Sprooten, P. Mulders, J. Vrijsen, J. Bralten, D. Demontis, A. Børglum, G. Walters, K. Stefánsson, P. V. van Eijndhoven, I. Tendolkar, B. Franke, N. R. Mota","doi":"10.1101/2022.05.30.22275563","DOIUrl":"https://doi.org/10.1101/2022.05.30.22275563","url":null,"abstract":"The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. In a deeply-phenotyped sample (n=513) consisting of 452 patients from tertiary care with mood disorders, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and/or substance use disorders (SUD) and 61 unaffected comparison individuals, we derived subject-specific multi-base polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions. High PRS for depression was unselectively associated with the diagnosis of SUD, ADHD, anxiety disorders, mood disorders, and the comorbidities among them. In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems but not others. This study highlights a misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology, and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87015850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Henri Legrand du Saulle's 1873 book: “La Folie Héréditaire” (hereditary madness)","authors":"Kenneth S. Kendler","doi":"10.1002/ajmg.b.32902","DOIUrl":"10.1002/ajmg.b.32902","url":null,"abstract":"<p>In his 1873 monograph “La Folie Héréditaire,” the French Alienist Legrand du Saulle (LdS) first outlined his understanding of hereditary factors in insanity and then described in detail the theory of Hereditary Madness (HM) that emerged from the writings of his mentor Bénédict Morel. This form of insanity was thought to arise only in families with neuropathic traits. Degeneration theory, proposed by Morel, postulated a within-family “evolution” of increasingly severe psychopathology, typically beginning with mild neuropathic traits and associated idiosyncrasies, and progressing over generations to hereditary madness, mental retardation, epilepsy, and eventual sterility. LdS took strong positions in favor of (i) the heterogeneous transmission of mental illness within families, (ii) consideration of both direct and collateral relatives, and (iii) the inheritance of a predisposition to illness, not the illness itself. He carefully examined the wide range of psychopathology and physical stigmata that occurred in what he called “inheritors” of the neuropathic trait. A unique feature of his work was the use of familial patterns of psychopathology to define a psychiatric disorder. While the theory of HM did not gain wide popularity outside of 19th century France, the concept of neuropathic traits was used extensively in early 20th century psychiatric genetics.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48837819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of METTL3-mediated m6A modification in depression-induced cognitive deficits","authors":"Juan Niu,&nbsp;Bailing Wang,&nbsp;Tian Wang,&nbsp;Tiantian Zhou","doi":"10.1002/ajmg.b.32892","DOIUrl":"10.1002/ajmg.b.32892","url":null,"abstract":"<p>Depressive disorder (DD) is associated with N6-methyladenosine (m6A) hypermethylation. This study sought to explore the molecular mechanism of Methyltransferase-like 3 (METTL3) in cognitive deficits of chronic unpredictable mild stress (CUMS)-treated rats and provide novel targets for DD treatment. A DD rat model was established via CUMS treatment. Cognitive deficits were assessed via body weighing and behavioral tests. METTL3, microRNA (miR)-221-3p, pri-miR-221, GRB2-associated binding protein 1 (Gab1) expressions in hippocampal tissues were detected via RT-qPCR and Western blotting. m6A, DiGeorge syndrome critical region gene 8 (DGCR8)-bound pri-miR-221 and pri-miR-221 m6A levels were measured. The binding relationship between miR-221-3p and Gab1 was testified by dual-luciferase and RNA pull-down assays. Rescue experiments were designed to confirm the role of miR-221-3p and Gab1. METTL3 was highly expressed in CUMS rats, and silencing METTL3 attenuated cognitive deficits of CUMS rats. METTL3-mediated m6A modification facilitated processing and maturation of pri-miR-221 via DGCR8 to upregulate miR-221-3p. miR-221-3p targeted Gab1. miR-221-3p overexpression or Gab1 downregulation reversed the role of silencing METTL3 in CUMS rats. Overall, METTL3-mediated m6A modification facilitated processing and maturation of pri-miR-221 to upregulate miR-221-3p and then inhibit Gab1, thereby aggravating cognitive deficits of CUMS rats.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46020572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population features of alleles and genotypes frequency distribution of polymorphic genetic markers of antipsychotic medications pharmacokinetics in the Kazakh population","authors":"Korlan Z. Saduakassova,&nbsp;Gulnara S. Svyatova","doi":"10.1002/ajmg.b.32893","DOIUrl":"10.1002/ajmg.b.32893","url":null,"abstract":"<p>The presented article is relevant, as the main goals of schizophrenia treatment are to achieve a response to psychopharmacotherapy, reduction and stabilization of psychopathological symptoms, qualitative remission, which in general implies the creation of a stable quality of life for the patient. The purpose of the study was to evaluate the population features of the frequency distribution of alleles and genotypes of polymorphic genetic variants of according to genome-wide association studies analysis of pharmacokinetics-associated antipsychotic medications, in an ethnically homogeneous Kazakh population. The research material was deoxyribonucleic acid (DNA) isolated from the peripheral blood of 1,800 conditionally healthy persons of Kazakh nationality. DNA isolation was carried out by the magnetic polyvinyl alcohol magnetic particle separation method. The analysis of the frequency distribution of the studied genotypes in the Kazakh population showed their compliance with the Hardy–Weinberg equilibrium for all studied polymorphisms (<i>p</i> &gt; .05). The obtained results showed that CYP2C19 (rs4244285, rs4986893) polymorphisms occurs in Kazakhs significantly more often than European and a number of Asian populations, which significantly affects the decrease in effectiveness and increases the risk of side complications during therapy with antipsychotic medications in the Kazakh population.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51503298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information ‐ TOC","authors":"","doi":"10.1002/ajmg.b.32903","DOIUrl":"https://doi.org/10.1002/ajmg.b.32903","url":null,"abstract":"","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43152618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended familial risk of suicide death is associated with younger age at death and elevated polygenic risk of suicide","authors":"Hilary Coon,&nbsp;Andrey Shabalin,&nbsp;Amanda V. Bakian,&nbsp;Emily DiBlasi,&nbsp;Eric T. Monson,&nbsp;Anne Kirby,&nbsp;Danli Chen,&nbsp;Alison Fraser,&nbsp;Zhe Yu,&nbsp;Michael Staley,&nbsp;William Brandon Callor,&nbsp;Erik D. Christensen,&nbsp;Sheila E. Crowell,&nbsp;Douglas Gray,&nbsp;David K. Crockett,&nbsp;Qingqin S. Li,&nbsp;Brooks Keeshin,&nbsp;Anna R. Docherty","doi":"10.1002/ajmg.b.32890","DOIUrl":"10.1002/ajmg.b.32890","url":null,"abstract":"<p>Suicide accounts for &gt;800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), <i>n</i> = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), <i>n</i> = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, <i>n</i> = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with &gt;90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fb/08/AJMG-189-60.PMC9149029.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39960171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic risk scores for neuropsychiatric, inflammatory, and cardio-metabolic traits highlight possible genetic overlap with suicide attempt and treatment-emergent suicidal ideation","authors":"Giuseppe Fanelli,&nbsp;Marcus Sokolowski,&nbsp;Danuta Wasserman,&nbsp;European College of Neuropsychopharmacology (ECNP) Network on Suicide Research and Prevention,&nbsp;Siegfried Kasper,&nbsp;Joseph Zohar,&nbsp;Daniel Souery,&nbsp;Stuart Montgomery,&nbsp;Diego Albani,&nbsp;Gianluigi Forloni,&nbsp;Panagiotis Ferentinos,&nbsp;Dan Rujescu,&nbsp;Julien Mendlewicz,&nbsp;Diana De Ronchi,&nbsp;Alessandro Serretti,&nbsp;Chiara Fabbri","doi":"10.1002/ajmg.b.32891","DOIUrl":"10.1002/ajmg.b.32891","url":null,"abstract":"<p>Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (<i>N</i>_eff = 2,258) and 214 with TWESI (<i>N</i>_eff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11–1.38; <i>p</i> = 1.73 × 10⁻⁴). Nominal associations were shown between PRSs for coronary artery disease (CAD) (<i>p</i> = 4.6 × 10⁻³), loneliness (<i>p</i> = .009), or chronic pain (<i>p</i> = .016) and SA, PRSs for MDD or CAD and TWESI (<i>p</i> = .043 and <i>p</i> = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39943392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of a “Psychiatric Genetics for Genetic Counselors” workshop on genetic counselor attendees: An exploratory study","authors":"Amy Dillon,&nbsp;Jehannine Austin,&nbsp;Kevin McGhee,&nbsp;Melanie Watson","doi":"10.1002/ajmg.b.32889","DOIUrl":"10.1002/ajmg.b.32889","url":null,"abstract":"<p>Genetic counseling is the process of supporting patients’ and families’ adaptation to genetic information. Psychiatric genetic counseling has been proven to be effective in improving empowerment, self-efficacy, and knowledge even in the absence of genetic testing. Despite this, only one specialist psychiatric genetic counseling clinic currently exists. In order to engage genetic counselors in providing psychiatric genetic counseling, a 2-day workshop: “Psychiatric Genetic Counseling for Genetic Counselors”, was developed and implemented aimed at empowering genetic counselors to feel confident and competent in this practice domain. The aim of the study was to qualitatively explore the impact of the workshop. Semistructured interviews were carried out with 12 genetic counselors who attended the workshop between 2015 and 2018. Thematic analysis revealed that the workshop empowered all participants to feel comfortable and confident offering psychiatric genetic counseling to patients. Participants also reflected how the workshop highlighted the stigma associated with mental illnesses and offered support in normalizing these conditions. Overall, this study presents that the “Psychiatric Genetic Counseling for Genetic Counselors” workshop fulfilled its proposed aims and outcomes.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39936551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The place of Franz Kallmann's 1938 “the genetics of schizophrenia” in the history of psychiatric genetics","authors":"Kenneth S. Kendler,&nbsp;Astrid Klee","doi":"10.1002/ajmg.b.32886","DOIUrl":"10.1002/ajmg.b.32886","url":null,"abstract":"<p>This essay provides the historical context and key findings of one of the largest fieldwork-based family studies ever done in the history of psychiatric genetics conducted in Berlin by Franz Kallmann from 1929 to 1933. It included over 1,000 schizophrenic probands and 12,500 of their relatives including siblings, offspring, nieces/nephews and grandchildren. The work was analyzed in close collaboration with Rüdin, Schulz, and Luxenburger in Munich. Born of Jewish parents, Kallmann had to leave Germany in 1936, completing and publishing the monograph in the United States in 1938. This study included a number of methodologic advances over the classic 1916 sibling study of Rüdin: (a) joint analysis of multiple classes of relatives; (b) subdivision of schizophrenia into four subtypes; (c) a focus on schizoid personality [schizoidia]; (d) examination of the familial aggregation of schizophrenia; and (e) a more complex genetic model—with schizophrenia arising from a single-recessive gene with 70% penetrance and background polygenic influences, and schizoidia from heterozygotes. Kallmann found important differences in risk of relatives in nuclear versus peripheral subtypes and concluded that schizoidia was a part of schizophrenia disease complex while other psychopathies, feeblemindedness, and organic brain disorders were not. Kallmann was strongly invested in the eugenic implications of his results.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32886","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39905677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}