Introduction Large neutral amino acids (LNAA) tryptophan and phenylalanine have been implicated in the pathogenesis of neurodegenerative diseases. Given limited research on the effects of LNAA on ...brain health across different life stages, vascular risk, and genetic backgrounds, our study aimed to explore the interaction of LNAA levels, metabolic syndrome (MetS), and the presence of the apolipoprotein E ε4 (ApoE ε4) allele brain integrity at midlife. Methods Sixty-eight adults aged 40-61 underwent a health assessment to calculate the number of MetS components, quantify LNAA, measure white matter hyperintensity (WMH) volume, and genotype ApoE ε4. Multivariate linear regression analyses were performed to test the joint effect of LNAA, MetS, and ApoE ε4 on WMH while adjusting for sex, age, and education. Results Significant 3-way interactions were observed between serum tryptophan (β = 0.042, SE = 0.018, p < 0.05) and phenylalanine (β = 0.044, SE = 0.013, p < 0.01) levels, number of MetS components, and ApoE ε4 alleles status on WMH volume. Neither individual LNAA levels nor MetS components alone predicted WMH volume. Conclusions The study highlights significant 3-way interactions between LNAA, MetS, and genetic risk factors in the pathology of WMH, particularly in individuals genetically predisposed to Alzheimer’s disease. These interactions suggest differential impacts of LNAA on WMH volume dependent on both genetic and metabolic factors. Results emphasize the need for personalized metabolic and genetic profile assessments in neurodegenerative disease management.
Cognitive performance is both heritable and sensitive to environmental inputs and sustained practice over time. However, it is currently unclear how genetic effects on cognitive performance change ...over the course of learning. We examine how polygenic scores (PGS) created from genome-wide association studies of educational attainment and cognitive performance are related to improvements in performance across nine cognitive tests (measuring perceptual speed, working memory, and episodic memory) administered to 131 adults (N = 51, ages = 20-31, and N = 80, ages = 65-80 years) repeatedly across 100 days. We observe that PGS associations with performance on a given task can change over the course of learning, with the specific pattern of change in associations differing across tasks. PGS correlations with pre-test to post-test scores may mask variability in how soon learning occurs over the course of practice. The associations between PGS and learning do not appear to simply reconstitute patterns of association between baseline performance and subsequent learning. Associations involving PGSs, however, were small with large confidence intervals. Intensive longitudinal research such as that described here may be of substantial value for clarifying the genetics of learning when implemented as far larger scale.
Dysregulation of biological stress response, as measured by cortisol output, has been a primary candidate mechanism for how social experiences become biologically embedded. Cortisol is the primary ...output of the hypothalamic pituitary adrenal (HPA) axis. Cortisol levels vary systematically across the day and change in response to both sudden, acute stress experiences, as well as prolonged exposure to environmental stress. Using data from 8–15-year-old twins in the Texas Twin Project, we investigate the extent to which genetic influences are shared across different measures of cortisol output: chronic cortisol accumulations in hair (
n
= 1,104), diurnal variation in salivary output (
n
= 488), and salivary response to a standardized, acute in-laboratory stressor (
n
= 537). Multivariate twin models indicate that genetic factors regulating cortisol response to the in-laboratory stressor are separable from those regulating baseline cortisol levels, naturally-occurring diurnal variation in cortisol, and hair cortisol levels. These findings illustrate that novel environments can reveal unique genetic variation, reordering people in terms of their observed phenotype rather than only magnifying or mitigating pre-existing differences.
Dysregulation of biological stress response, as measured by cortisol output, has been a primary candidate mechanism for how social experiences become biologically embedded. Cortisol is the primary ...output of the hypothalamic pituitary adrenal (HPA) axis. Cortisol levels vary systematically across the day and change in response to both sudden, acute stress experiences as well as prolonged exposure to environmental stress. Using data from 8- to 15-year-old twins in the Texas Twin Project, we investigate the extent to which genetic influences are shared across different measures of cortisol output: chronic cortisol accumulations in hair (n = 1,104), diurnal variation in salivary output (n = 488), and salivary response to a standardized, acute in-laboratory stressor (n = 537). Multivariate twin models indicate that genetic factors regulating cortisol response to the in-laboratory stressor are separable from those regulating baseline cortisol levels, naturally occurring diurnal variation in cortisol, and hair cortisol levels. These findings illustrate that novel environments can reveal unique genetic variation, reordering people in terms of their observed phenotype rather than only magnifying or mitigating preexisting differences.
Objective: Examine the moderating effects of response inhibition on the longitudinal association between social preference/relational aggression measured in childhood, and intimate partner violence ...(IPV) measured in young adulthood, among women with (n = 140) and without (n = 88) histories of childhood ADHD. Method: During childhood, social preference was measured through confidential peer sociometric nominations, yielding negative and positive peer regard; relational aggression was assessed via staff behavioral observations; and response inhibition was assessed using commission errors from the continuous performance task. During young adulthood, IPV was ascertained via a clinician-administered, semistructured interview. Results: Social preference and relational aggression independently predicted IPV; this prospective link was moderated by response inhibition. Conclusion: In combination with low social preference or high relational aggression in childhood, poor response inhibition predicted the highest levels of young-adult IPV. Given the developmental significance of peer relationships, additional research on the causes of and treatments for poor social functioning in ADHD is warranted.
High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus ...can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.
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