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

Externalizing traits and behaviors are broadly defined by impairments in self-regulation and impulse control that typically begin in childhood and adolescence. Externalizing behaviors, traits, and symptoms span a range of traditional psychiatric diagnostic categories. In this study, we sought to generate an algorithm that could reliably identify transdiagnostic childhood-onset externalizing cases and controls within a university hospital electronic health record (EHR) database. Within the Vanderbilt University Medical Center (VUMC) EHR, our algorithm identified cases with a clinician-validated positive predictive value of 90% and controls with a negative predictive value of 88%. In individuals of genetically defined European ancestry (CEU-clustered; N_case = 487, N_control = 5638), case status was significantly associated with psychiatric comorbidity and with elevated externalizing polygenic scores (OR: 1.20; 95% CI: 1.09–1.33; p = 1.14 × 10⁻³; based on published genome-wide association data). To test whether our cohort definitions could be applied to generate novel genetic insights, we examined rare (allele frequency < 0.5%) copy number variation. An association (OR: 9.70; CI: 3.24–29.0) was identified in the CEU-clustered cohort on chromosome 2 (chr2: 45,408,678–45,551,530; duplication), although the statistical strength of this association was modest (p = 0.052). We also examined the role of an externalizing burden score based on the number of externalizing diagnoses present in cases and found similar results to our case–control analysis. This analysis identified several other statistically significant CNV region associations. This study provides a framework for identifying childhood externalizing case–control cohorts within an EHR. Future work should validate this framework within other health systems. A broadly applicable algorithm, like this one, may allow for detection of rare outcomes or outcomes in populations historically excluded from genomic research through meta-analysis of data across health care systems.

Anorexia nervosa (AN) is a psychiatric disorder with an estimated heritability of around 70%. Although the largest meta-analysis of genome-wide association studies on AN identified independent risk-conferring loci for the disorder, the molecular mechanisms underlying the genetic basis of AN remain to be elucidated. To investigate AN, we performed transcriptome profiling in peripheral blood mononuclear cells from 15 AN patients and 15 healthy controls. We validated our mean results in a mouse model of chronic food restriction, which mimics several aspects of AN. In this exploratory study, we identified 673 significantly differentially expressed genes in AN. Among these genes, we identified seven genes previously found to be dysregulated in IPSC-derived neurons from AN individuals and the Vanin-1 (Vnn1) gene, which appears to play an important role in the regulation of several metabolic pathways. We confirmed underexpression of Vnn1, particularly in the liver, in a mouse model of chronic food restriction. These results indicate that quantitative food restriction affects Vnn1 expression, suggesting that this gene may contribute to the anorexic phenotype in the chronic food restriction mouse model as well as in patients with AN. We believe that this report highlights promising candidate genes and gene pathways for AN, and although we did not obtain a significant result in the replication cohort, it identifies Vnn1 as a potential biomarker that may be used as a molecular target to predict and/or to understand AN.

Public stigma and prejudice toward people with psychiatric conditions is highly prevalent and damaging. Explanations for the origins of mental illness can influence attitudes toward people with these conditions. To date, studies exploring the effects of explanations for the origins of mental illness have focused on genetic or environmental explanations, and the impact of evidence-based multifactorial explanations for psychiatric illness on public attitudes remains unknown. Participants were recruited through Amazon Mechanical Turk to watch a 4-min video about the “mental illness jar model”—an evidence-based analogy that explains the complex interactions between genes and environment in the development of mental illness. Participants provided demographic information and completed questions regarding knowledge about the causes of mental illness, and the Prejudice towards People with Mental Illness (PPMI) scale both before and after watching the video. A total of 106 eligible participants completed the study. Watching the video had no significant effect on participants' knowledge about the causes of mental illness (p = 0.06), but there was a significant decrease in prejudicial attitudes toward mental illness (p = 0.0003), the effect size was small (−0.15). The use of this brief video (available at cogastudy.org) is a promising tool to decrease prejudicial attitudes toward mental illness that warrants further study.

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field.

Decisions about when to change antidepressant treatment are complex and benefit from accurate prediction of treatment outcome. Prognostic accuracy can be enhanced by incorporating repeated assessments of symptom severity collected during treatment. Participants (n = 714) from the Genome-Based Therapeutic Drugs for Depression study received escitalopram or nortriptyline over 12 weeks. Remission was defined as scoring ≤ 7 on the Hamilton Rating Scale. Predictors included demographic, clinical, and genetic variables (at 0 weeks) and measures of symptom severity (at 0, 2, 4, and 6 weeks). Longitudinal descriptors extracted with growth curves and topological data analysis were used to inform prediction of remission. Repeated assessments produced gradual and drug-specific improvements in predictive performance. By Week 4, models' discrimination in all samples reached levels that might usefully inform treatment decisions (area under the receiver operating curve (AUC) = 0.777 for nortriptyline; AUC = 0.807 for escitalopram; AUC = 0.794 for combined sample). Decisions around switching or modifying treatments for depression can be informed by repeated symptom assessments collected during treatment, but not until 4 weeks after the start of treatment.

Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus.