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

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial–lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

Medical professionals frequently underestimate stress level of parents/caregivers of patients with rare disorders as RASopathies, the latter might experience elevated stress levels, with their own health frequently overlooked despite significant responsibilities and hurdles encountered. The aim of this study is to assess the stress experienced by parents of individuals with Noonan syndrome and related conditions. Forty-eight parents (20 fathers; 28 mothers), among the 31 recruited families, completed the Italian version of the Parenting Stress Index–Short Form. Our study shows abnormally elevated scores (≥ 85° percentile) in 35.4% of parents. Data retrieved from subscales reveal a perception of a difficult child in 25% of cases, a dysfunctional parental-child interaction in 20.8%, a general parental distress in 10.4% of cases, and an elevated overall stress in 18.8% of parents. Questionnaires as the Parenting Stress Index–Short Form are valuable tools to evaluate stress in parents/caregivers of children with RASopathies. Evaluation by professionals is fundamental to support parents and caregivers in managing stressors and to enhance their quality of life and relationships. To prevent stress escalation and parents' burnout, an early assessment to tailor a timely treatment should be introduced as soon as possible as good clinical practice.

Although Beckwith–Wiedemann syndrome spectrum (BWSp) is not usually associated with intellectual disability, recent evidences calls for further investigation of cognitive development and academic skills in children with BWSp. Moreover, research has documented social difficulties and emotional-behavioral problems associated with BWSp. Nevertheless, a full characterization of socio-emotional development in BWSp is still lacking. In the current study, cognitive and socio-emotional development was assessed in 29 children with BWSp aged 5–18 years, using a test of nonverbal intelligence, a neuropsychological battery covering multiple domains, academic skills tests, and questionnaires evaluating autistic traits and emotional-behavioral problems. As expected, most participants showed adequate performance in cognitive tests. However, the findings also highlighted greater difficulties in language than visuospatial processing, strengths in social perception, as well as slowness in reading and mental calculation. The assessment of emotional-behavioral difficulties indicated a prevalent phenotype characterized by increased anxiety, low self-esteem, social withdrawal and a tendency to control externalizing reactions, but no associations with autistic traits, cognitive outcomes, and the clinical score proposed by the recent Consensus statement. Increased social perception and internalization problems likely result from coping strategies with social and care-related stress. Overall, the findings of this study inform clinical management and genetic counseling for children and adolescents with BWSp.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (r_g = 0.57–0.85), although two were small (r_g = 0.35–0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are frequently applied to human and animal gene-expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. As such, they have the potential to elucidate the mechanisms by which molecular genomic variation contributes to individual differences in complex traits. Although increasingly used to test for associations between modules and complex traits, the genetic and environmental etiology of MEs has not been empirically established. It is unclear if, and to what degree, individual differences in blood-derived MEs reflect random variation versus familial aggregation arising from heritable or shared environmental influences. We used biometrical genetic analyses to estimate the contribution of genetic and environmental influences on MEs derived from blood lymphocytes collected on a sample of N = 661 older male twins from the Vietnam Era Twin Study of Aging (VETSA) whose mean age at assessment was 67.7 years (SD = 2.6 years, range = 62–74 years). Of the 26 detected MEs, 14 (56%) had statistically significant additive genetic variation with an average heritability of 44% (SD = 0.08, range = 35%–64%). Despite the relatively small sample size, this demonstration of significant family aggregation including estimates of heritability in 14 of the 26 MEs suggests that blood-based MEs are reliable and merit further exploration in terms of their associations with complex traits and diseases.

Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of neuropsychiatric disorders and highlighted their complexity. Careful consideration of the polygenicity and complex genetic architecture could aid in the understanding of the underlying brain mechanisms. We introduce an innovative approach to polygenic scoring, utilizing imaging-derived phenotypes (IDPs) to predict a clinical phenotype. We leveraged IDP GWAS data from the UK Biobank, to create polygenic imaging-derived scores (PIDSs). As a proof-of-concept, we assessed genetic variations in brain structure between individuals with ADHD and unaffected controls across three NeuroIMAGE waves (n = 954). Out of the 94 PIDS, 72 exhibited significant associations with their corresponding IDPs in an independent sample. Notably, several global measures, including cerebellum white matter, cerebellum cortex, and cerebral white matter, displayed substantial variance explained for their respective IDPs, ranging from 3% to 5.7%. Conversely, the associations between each IDP and the clinical ADHD phenotype were relatively weak. These findings highlight the growing power of GWAS in structural neuroimaging traits, enabling the construction of polygenic scores that accurately reflect the underlying polygenic architecture. However, to establish robust connections between PIDS and behavioral or clinical traits such as ADHD, larger samples are needed. Our novel approach to polygenic risk scoring offers a valuable tool for researchers in the field of psychiatric genetics.