American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics最新文献

{"title":"Genome-Wide Insights and Polygenic Risk Scores in Common Epilepsies: A Narrative Review.","authors":"Mario Mastrangelo, Simona Petrucci, Giuliana Lentini, Marco Fabiani, Maria Piane, Francesco Pisani","doi":"10.1002/ajmg.b.33040","DOIUrl":"https://doi.org/10.1002/ajmg.b.33040","url":null,"abstract":"<p><p>The research of single gene-related disorders or pathogenic copy-number variations (CNVs) has given a significant impetus to the shift from a diagnostic work-up focused on epileptic syndromes to genomic approaches in individuals with severe pediatric-onset epilepsies and in developmental and epileptic encephalopathies. Genome-wide association studies (GWAS) have identified various loci of susceptibility for common epilepsies and highlighted a strong predisposing role of common variants in several genes involved in well-known monogenic diseases. The largest GWAS identified eight major loci with stronger genome-wide significance for epilepsy, regardless the underlying epileptic syndrome: 2q24.3, 2p16.1, 4p15.1, 7q21.11, 8p23.1, 9q21.13, 10q24.32, 16q12.1, 2p16.1 and 2q24.3 occurred more frequently in patients with genetic generalized epilepsies. Loci 4p12, 8q23.1 and 16p11.2 achieved a high genome-wide significance for Juvenile Myoclonic Epilepsy. Childhood Absence Epilepsy was significantly genome-wide associated with 2p16.1 and 2q22.3. The loci 3q25.31, 6q22.31 and 2q24.3 were significantly associated with non-acquired focal epilepsies. Polygenic risk scores (PRS) are used to quantify the cumulative effects of several common genetic variants in a single score, each of which individually contributes minimally to disease susceptibility. The impact of PRS on clinical practice might be relevant for epilepsy risk prediction in groups of patients at high risk of developing epilepsy in the near future. Elevated PRS values have been observed in genetic generalized epilepsies particularly in familial forms, females, and patients with previous seizure events. Among comorbidities associated with epilepsy, depression, psychosis, and attention-deficit/hyperactivity disorder (ADHD) showed significantly elevated PRS.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"e33040"},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Analysis of Trichotillomania.","authors":"Matthew W Halvorsen, Melanie E Garrett, Michael L Cuccaro, Allison E Ashley-Koch, James J Crowley","doi":"10.1002/ajmg.b.33035","DOIUrl":"10.1002/ajmg.b.33035","url":null,"abstract":"<p><p>Trichotillomania (TTM) is a psychiatric condition in which people feel an overwhelming urge to pull out their hair, resulting in noticeable hair loss and significant distress. Twin and family studies suggest that TTM is at least partly genetic, but no genome-wide analyses have been completed. To fill the gap in this field, we have conducted a case-control study of genotype array data from 101 European ancestry TTM cases and 488 ancestry-matched unaffected controls. TTM cases were ascertained in the United States through web-based recruitment, patient support groups, and conferences organized by the Trichotillomania Learning Center. Following clinical confirmation of a TTM diagnosis, patients completed self-report assessments of frequency and duration of hair pulling, other psychiatric symptoms, and family history. Unaffected controls were also ascertained in the United States and were matched to cases by ancestry. In the first formal genome-wide association study of TTM, we did not identify any common variants with a genome-wide significant (p < 5 × 10^-8) association level with case status. We found that cases carry a higher load of common polygenic risk for psychiatric disorders (p = 0.008). We also detected copy number variants previously associated with neuropsychiatric disorders (specifically, deletions in NRXN1, CSMD1, and 15q11.2). These results further support genetics' role in the etiology of TTM and suggest that larger studies are likely to identify risk variation and, ultimately, specific risk genes associated with the condition.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"e33035"},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apples, Oranges, and Biobanks: Ascertainment Bias in Population-Based Studies of Neurodevelopmental Psychiatric Disorders.","authors":"Brenda M Finucane, Scott M Myers, David H Ledbetter, Christa Lese Martin, Matthew T Oetjens","doi":"10.1002/ajmg.b.33034","DOIUrl":"10.1002/ajmg.b.33034","url":null,"abstract":"","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"e33034"},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children.","authors":"Samira Ismail,&nbsp;Azza Abo Senna,&nbsp;Eman G Behiry,&nbsp;Engy A Ashaat,&nbsp;Maha S Zaki,&nbsp;Neveen A Ashaat,&nbsp;Dina M Salah","doi":"10.1002/ajmg.b.32729","DOIUrl":"https://doi.org/10.1002/ajmg.b.32729","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorders (ASD) is a heterogeneous neurodevelopmental disease, various articles reported that dysfunctional folate-methionine pathway enzymes might assume a paramount part in the pathophysiology of autism. Methylene tetrahydrofolate reductase (MTHFR) is a basic catalyst for this pathway, also MTHFR gene C677T variant accounted as a risk factor of autism.</p><p><strong>Objective: </strong>The present study aimed to investigate the association of MTHFR gene rs1801133(C677T) variant among Egyptian autistic children.</p><p><strong>Methods: </strong>The study included 78 autistic children, and 80 matched healthy control children. Full clinical and radiological examinations were conducted. MTHFR genetic variant, rs1801133(C677T) was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods followed by direct sequencing technique.</p><p><strong>Results: </strong>MTHFR (C677T) allele frequency was found to be higher significantly in ASD cases compared with nonautistic children. Also, we had a higher distribution of combined CT + TT genotypes among autistic patients with consanguinity and family history of psychological disease. In Gastrointestinal tract (GIT) and sleep disorders showed a higher distribution of hetero CT genotype as well as combined CT + TT genotypes.</p><p><strong>Conclusion: </strong>This study demonstrated a role of MTHFR gene (C667T) variant with the increased risk for ASD.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"305-309"},"PeriodicalIF":2.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32729","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37356500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between newborn screening analytes and childhood autism in a Texas Medicaid population, 2010-2012.","authors":"Mark A Canfield,&nbsp;Peter H Langlois,&nbsp;Gary W Rutenberg,&nbsp;Dorothy J Mandell,&nbsp;Fei Hua,&nbsp;Brendan Reilly,&nbsp;Duke J Ruktanonchai,&nbsp;Janice F Jackson,&nbsp;Patricia Hunt,&nbsp;Debra Freedenberg,&nbsp;Rachel Lee,&nbsp;John F Villanacci","doi":"10.1002/ajmg.b.32728","DOIUrl":"https://doi.org/10.1002/ajmg.b.32728","url":null,"abstract":"<p><p>Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. It is commonly diagnosed at 3 or 4 years of age. We explored whether there was an association of any analytes measured by newborn screening tests with a later diagnosis of ASD. A database was compiled of 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Two controls (without any ASD diagnosis) were matched to each case by infant sex and birth year/month. All study subjects were linked to their 2007-2009 birth and newborn screening laboratory records, including values for 36 analytes or analyte ratios. We examined the association of analytes/ratios with a later diagnosis of ASD. Among 3,258 cases and 6,838 controls, seven analytes (e.g., 17-hydroxyprogesterone, acylcarnitines) were associated with a later ASD diagnosis. In this exploratory study, an ASD diagnosis was associated with 7 of 36 newborn screening analytes/ratios. These findings should be replicated in other population-based datasets.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"291-304"},"PeriodicalIF":2.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32728","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37179379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies.","authors":"Thelma B González-Castro,&nbsp;Carlos A Tovilla-Zárate,&nbsp;Alma D Genis-Mendoza,&nbsp;Isela E Juárez-Rojop,&nbsp;Humberto Nicolini,&nbsp;María L López-Narváez,&nbsp;José J Martínez-Magaña","doi":"10.1002/ajmg.b.32731","DOIUrl":"https://doi.org/10.1002/ajmg.b.32731","url":null,"abstract":"<p><p>Multiple large-scale studies such as genome-wide association studies (GWAS) have been performed to identify genetic contributors to suicidal behaviors (SB). We aimed to summarize and analyze the information obtained in SB GWAS, to explore the biological process gene ontology (GO) of genes associated with SB from GWAS, and to determine the possible implications of the genes associated with SB in Kyoto encyclopedias of genes and genomes (KEGG) biological pathways. The articles included in the analysis were obtained from PubMed and Scopus databases. Enrichment analyses were performed in Enrichr to evaluate the KEGG pathways and GO of the genes associated with SB of GWAS. The findings of biological process GO analysis showed 924 GO involved in genes related with SB; of those, the regulation of glucose import in response to insulin stimulus, regulation of protein localization to plasma membrane, positive regulation of endopeptidase activity, heterotypic cell-cell adhesion, regulation of cardiac muscle cell contraction, positive regulation of protein localization to plasma membrane, and positive regulation of protein localization to cell periphery biological process GO showed significant statistical association. Furthermore, we obtained 130 KEGG pathways involved in genes related with SB, which Aldosterone synthesis and secretion, Rap1 signaling pathway and arrhythmogenic right ventricular cardiomyopathy pathways showed a significant statistical association. These findings give a better perspective of the biological participation of genes associated with SB, which will be important to perform adequate strategies to prevent and treat SB.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"320-329"},"PeriodicalIF":2.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37205536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder.","authors":"Özgür Albayrak,&nbsp;Carolin Pütter,&nbsp;Anna-Lena Volckmar,&nbsp;Sven Cichon,&nbsp;Per Hoffmann,&nbsp;Markus M Nöthen,&nbsp;Karl-Heinz Jöckel,&nbsp;Stefan Schreiber,&nbsp;H-Erich Wichmann,&nbsp;Stephen V Faraone,&nbsp;Benjamin M Neale,&nbsp;Beate Herpertz-Dahlmann,&nbsp;Gerd Lehmkuhl,&nbsp;Judith Sinzig,&nbsp;Tobias J Renner,&nbsp;Marcel Romanos,&nbsp;Andreas Warnke,&nbsp;Klaus-Peter Lesch,&nbsp;Andreas Reif,&nbsp;Benno G Schimmelmann,&nbsp;André Scherag,&nbsp;Johannes Hebebrand,&nbsp;Anke Hinney","doi":"10.1002/ajmg.b.32144","DOIUrl":"https://doi.org/10.1002/ajmg.b.32144","url":null,"abstract":"<p><p>Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr  = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr  = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"295-305"},"PeriodicalIF":2.8,"publicationDate":"2013-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40229430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overlap and specificity of genetic and environmental influences on excessive acquisition and difficulties discarding possessions: Implications for hoarding disorder.","authors":"Ashley E Nordsletten,&nbsp;Benedetta Monzani,&nbsp;Lorena Fernández de la Cruz,&nbsp;Alessandra C Iervolino,&nbsp;Miquel A Fullana,&nbsp;Juliette Harris,&nbsp;Fruhling Rijsdijk,&nbsp;David Mataix-Cols","doi":"10.1002/ajmg.b.32149","DOIUrl":"https://doi.org/10.1002/ajmg.b.32149","url":null,"abstract":"<p><p>A reluctance to discard items, leading to severely cluttered living spaces, is the landmark feature of hoarding disorder (HD). Many, but not all, individuals with HD also excessively acquire, buy or even steal items that they do not need and for which no space is available. In DSM-5, \"excessive acquisition\" can be coded as a specifier of HD. Despite their consistent co-occurrence, the question of whether excessive acquisition and difficulties discarding possessions share a common etiology remains unanswered. The current study sought to flesh out this relationship by examining the extent of shared genetic and environmental influences on the association between excessive acquisition and difficulties discarding in a community sample of adult, female twins. A total of 5,022 female twins (2,529 pairs; mean age = 55.5 years) completed a self-report measure of hoarding symptoms, including items assessing excessive acquisition and difficulties discarding. The data were analyzed using bivariate twin modeling methods in the statistical program Mx. As expected, we found a strong phenotypic correlation (0.63) between excessive acquisition and difficulty discarding items. Both traits were moderately heritable. The genetic correlation between the traits was estimated to be 0.77 (95% CI: 0.69-0.85), indicating a substantial but imperfect genetic overlap. The non-shared environmental correlation (0.50 [95% CI: 0.42-0.57]), though lower, was also significant. The findings demonstrate a substantial genetic, and more modest environmental, etiological overlap between the excessive acquisition of possessions and difficulties discarding them, providing a possible explanation for their frequent co-occurrence in HD. However, given that the etiological overlap is not perfect, unique etiological influences, particularly environmental, on each phenotype seem plausible.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"380-7"},"PeriodicalIF":2.8,"publicationDate":"2013-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40228508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.","authors":"Frédérique Béna,&nbsp;Damien L Bruno,&nbsp;Mats Eriksson,&nbsp;Conny van Ravenswaaij-Arts,&nbsp;Zornitza Stark,&nbsp;Trijnie Dijkhuizen,&nbsp;Erica Gerkes,&nbsp;Stefania Gimelli,&nbsp;Devika Ganesamoorthy,&nbsp;Ann Charlotte Thuresson,&nbsp;Audrey Labalme,&nbsp;Marianne Till,&nbsp;Frédéric Bilan,&nbsp;Laurent Pasquier,&nbsp;Alain Kitzis,&nbsp;Christele Dubourgm,&nbsp;Massimiliano Rossi,&nbsp;Armand Bottani,&nbsp;Maryline Gagnebin,&nbsp;Damien Sanlaville,&nbsp;Brigitte Gilbert-Dussardier,&nbsp;Michel Guipponi,&nbsp;Arie van Haeringen,&nbsp;Marjolein Kriek,&nbsp;Claudia Ruivenkamp,&nbsp;Stylianos E Antonarakis,&nbsp;Britt Marie Anderlid,&nbsp;Howard R Slater,&nbsp;Jacqueline Schoumans","doi":"10.1002/ajmg.b.32148","DOIUrl":"https://doi.org/10.1002/ajmg.b.32148","url":null,"abstract":"<p><p>This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the β-isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"388-403"},"PeriodicalIF":2.8,"publicationDate":"2013-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40229223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the Reelin signaling cascade (ligands-receptors-adaptor complex) on cognition in schizophrenia.","authors":"Phebe Verbrugghe,&nbsp;Sonja Bouwer,&nbsp;Steven Wiltshire,&nbsp;Kim Carter,&nbsp;David Chandler,&nbsp;Matthew Cooper,&nbsp;Bharti Morar,&nbsp;Muhammad F M Razif,&nbsp;Anjali Henders,&nbsp;Johanna C Badcock,&nbsp;Milan Dragovic,&nbsp;Vaughan Carr,&nbsp;Osvaldo P Almeida,&nbsp;Leon Flicker,&nbsp;Grant Montgomery,&nbsp;Assen Jablensky,&nbsp;Luba Kalaydjieva","doi":"10.1002/ajmg.b.32042","DOIUrl":"https://doi.org/10.1002/ajmg.b.32042","url":null,"abstract":"<p><p>Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia.</p>","PeriodicalId":520553,"journal":{"name":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","volume":" ","pages":"392-404"},"PeriodicalIF":2.8,"publicationDate":"2012-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/ajmg.b.32042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40166029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}