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

{"title":"Psychiatric polygenic risk scores: Child and adolescent psychiatrists' knowledge, attitudes, and experiences","authors":"Stacey Pereira,&nbsp;Katrina A. Muñoz,&nbsp;Brent J. Small,&nbsp;Takahiro Soda,&nbsp;Laura N. Torgerson,&nbsp;Clarissa E. Sanchez,&nbsp;Jehannine Austin,&nbsp;Eric A. Storch,&nbsp;Gabriel Lázaro-Muñoz","doi":"10.1002/ajmg.b.32912","DOIUrl":"10.1002/ajmg.b.32912","url":null,"abstract":"<p>Psychiatric polygenic risk scores (PRS) have potential utility in psychiatric care and prevention, but there are concerns about their implementation. We surveyed 960 US-based practicing child and adolescent psychiatrists' (CAP) about their experiences, perspectives, and potential uses of psychiatric PRS. While 23% of CAP reported that they had never heard of PRS, 10 % of respondents have had a patient/family bring PRS to them and 4% have generated PRS for patients. Though 25% stated they would request PRS if a patient/caregiver asked, 35% indicated that nothing would prompt them to request PRS. Most respondents (54%) believed psychiatric PRS are currently at least slightly useful and 87% believed they will be so in 5 years. More than 70% indicated they would take action in response to a child with a top fifth percentile psychiatric PRS but no diagnosis: 48% would increase monitoring of symptoms, 42% would evaluate for current symptoms, and 4% would prescribe medications. Yet, most respondents were concerned that high-PRS results could lead to overtreatment and negatively impact patients' emotional well-being. Findings indicate emerging use of psychiatric PRS within child and adolescent psychiatry in the US. It is critical to examine the ethical and clinical challenges that PRS may generate and begin efforts to promote their informed and responsible use.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 7-8","pages":"293-302"},"PeriodicalIF":2.8,"publicationDate":"2022-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10689807","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":"Recommendations to encourage participation of individuals from diverse backgrounds in psychiatric genetic studies","authors":"Casey MacDermod,&nbsp;Michaela A. Pettie,&nbsp;Emily A. Carrino,&nbsp;Susana Cruz Garcia,&nbsp;Sophie Padalecki,&nbsp;Jody E. Finch,&nbsp;Christina Sanzari,&nbsp;Hannah L. Kennedy,&nbsp;Pratiksha S. Pawar,&nbsp;Makenna M. Mcgough,&nbsp;Ava Iwashita,&nbsp;Mary Takgbajouah,&nbsp;Danielle Coan,&nbsp;Lindsey Szakasits,&nbsp;Rachel W. Goode,&nbsp;Ya-Ke Wu,&nbsp;Mae Lynn Reyes-Rodríguez,&nbsp;Eva María Trujillo Chi Vacuán,&nbsp;Martin A. Kennedy,&nbsp;Lana Cleland,&nbsp;Jennifer Jordan,&nbsp;Sarah Maguire,&nbsp;Jerry D. Guintivano,&nbsp;Paola Giusti-Rodríguez,&nbsp;Jessica H. Baker,&nbsp;Laura M. Thornton,&nbsp;Cynthia M. Bulik","doi":"10.1002/ajmg.b.32906","DOIUrl":"10.1002/ajmg.b.32906","url":null,"abstract":"<p>We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for various psychiatric disorders across all demographic groups. We present approaches developed as part of the Eating Disorders Genetics Initiative (EDGI), a study that required tailored approaches to recruit diverse populations across many countries. Considerations include research priorities and design, recruitment and study branding, transparency, and community investment and ownership. Ensuring representation in participants is costly and funders need to provide adequate support to achieve diversity in recruitment in prime awards, not just as supplemental afterthoughts. The need for diverse samples in genetic studies is critical to minimize the risk of perpetuating health disparities in psychiatry and other health research. Although the EDGI strategies were designed specifically to attract and enroll individuals with eating disorders, our approach is broadly applicable across psychiatry and other fields.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 5","pages":"163-173"},"PeriodicalIF":2.8,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a4/87/AJMG-189-163.PMC9542122.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9453554","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 actions and interactions of family genetic risk scores for alcohol use disorder and major depression on the risk for these two disorders","authors":"Kenneth S. Kendler,&nbsp;Sara L. Lönn,&nbsp;Jan Sundquist,&nbsp;Kristina Sundquist","doi":"10.1002/ajmg.b.32909","DOIUrl":"10.1002/ajmg.b.32909","url":null,"abstract":"<p>We know little about how genetic risk factors for two disorders jointly act and interact in predisposing to illness. Therefore, in the Swedish population, born 1970–1990 (<i>n</i> = 2,116,082) and followed through 2015, we examine, using additive Cox models, the impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and major depression (MD), their interaction with each other and with the relevant comorbid disorder on risk for AUD and MD. FGRS scores are constructed using rates of illness in first-fourth degree relatives. FGRS for AUD and MD interacted in predicting of both disorders and one FRGS (e.g., for AUD) interacted with the phenotype of MD to predict that disorder (e.g., AUD). These FGRS interactions were not substantially attenuated by adding interactions with the disorders. These results replicated across sexes. In predicting risk for a given disorder, we rarely consider genetic liabilities for other disorders. But such effects were here significant and interactive. Furthermore, the primary disorder genetic risk interacts with comorbid disorders. The pathways to risk for disorders from their and other disorders' genetic liability may be more complex than commonly considered.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 5","pages":"128-138"},"PeriodicalIF":2.8,"publicationDate":"2022-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9469448","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":"Medical genetics in the 19th century as background to the development of psychiatric genetics","authors":"Kenneth S. Kendler","doi":"10.1002/ajmg.b.32910","DOIUrl":"10.1002/ajmg.b.32910","url":null,"abstract":"<p>This article examines the relationship between the early efforts of alienists to understand the role of heredity in the etiology of insanity in the 19th century and the parallel efforts of the nascent discipline of medical genetics. I review three monographs on general medical genetics: Adams in 1814, Steinau in 1843, and Lithgow in 1889. Numerous parallels were seen between their writings and those of their contemporary alienists working on mental disorders including (i) an emphasis on the transmission of the liability to illness rather than the illness itself, (ii) discussions of the homogeneous versus heterogeneous nature of familial transmission of disease, (iii) the relative value of direct versus indirect hereditary effects, (iv) the role of mothers versus fathers in transmitting liability, (v) possible environmental sources of familial clustering, and (vi) the transmission of age at onset of illness. All three medical genetic authors noted that insanity was among the more heritable of human disorders. Furthermore, Lithgow noted the importance of heritable influences on the non-psychotic forms of psychiatric illness rarely seen in asylums. This survey demonstrates substantial consilience in the topics of interest and conclusions of the nascent general medical and psychiatric genetics' communities in the 19th century.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 5","pages":"119-127"},"PeriodicalIF":2.8,"publicationDate":"2022-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40464503","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":"Cover Image, Volume 189B, Number 5, July 2022","authors":"","doi":"10.1002/ajmg.b.32854","DOIUrl":"https://doi.org/10.1002/ajmg.b.32854","url":null,"abstract":"","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"1 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44228269","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":"Network-based meta-analysis and the candidate gene association studies reveal novel ethnicity-specific variants in MFSD3 and MRPL43 associated with dementia with Lewy bodies","authors":"Daichi Shigemizu,&nbsp;Yuya Asanomi,&nbsp;Shintaro Akiyama,&nbsp;Sayuri Higaki,&nbsp;Takashi Sakurai,&nbsp;Kengo Ito,&nbsp;Shumpei Niida,&nbsp;Kouichi Ozaki","doi":"10.1002/ajmg.b.32908","DOIUrl":"10.1002/ajmg.b.32908","url":null,"abstract":"<p>Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia in elderly people, following Alzheimer's disease. Only three genes, <i>SNCA</i> (α-synuclein), <i>APOE</i> (apolipoprotein E), and <i>GBA</i> (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Here, we applied whole-genome sequencing to blood samples from 61 DLB patients and 45 cognitively normal controls. We used accumulation of candidate mutations to detect novel DLB-associated genes. Subsequent single nucleotide polymorphism (SNP) genotyping and association studies in a large number of samples from Japanese individuals revealed novel heterozygous variants in <i>MFSD3</i> (rs143475431, c.888T&gt;A:p.C296*; <i>n</i> = 5,421, <i>p</i> = 0.00063) and <i>MRPL43</i> (chr10:102746730, c.241A&gt;C:p.N81H; <i>n</i> = 4,782, <i>p</i> = 0.0029). We further found that the <i>MFSD3</i> variant increased plasma levels of butyrylcholinesterase (<i>n</i> = 1,206, <i>p</i> = 0.029). We believe that our findings will contribute to the understanding of DLB and provide insight into its pathogenic mechanism for future studies.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 5","pages":"139-150"},"PeriodicalIF":2.8,"publicationDate":"2022-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/28/AJMG-189-139.PMC9543256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965323","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":"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":"189 5","pages":"151-162"},"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":"65 1","pages":""},"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":"189 3-4","pages":"51-59"},"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":"189 3-4","pages":"86-99"},"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}