Genetic Risk For Depression and Quality of Life in Patients With Head and Neck Cancer.

Importance: Although patients with head and neck cancer (HNC) have been shown to experience high distress, few longitudinal studies include a comprehensive evaluation of biopsychosocial factors affecting quality of life (QoL), including genetic risk for depression. Objective: To identify factors at the time of cancer diagnosis associated with QoL scores at 3 months after treatment in patients newly diagnosed with a first occurrence of HNC. Design, Setting, and Participants: This prospective longitudinal study of 1464 participants with a 3-month follow-up, including structured clinical interviews and self-administered measures was carried out at the Department of Otolaryngology Head and Neck Surgery at 2 tertiary care McGill University Affiliated Hospitals, McGill University Health Centre, and Jewish General Hospital. Eligible patients were adults newly diagnosed within 2 weeks with a primary first occurrence of HNC, had a Karnofsky Performance Scale score higher than 60, and an expected survival of more than 6 months. Two hundred and twenty-three patients (72%) consented to participate and completed the baseline questionnaire, and 71% completed the 3-month follow-up measures. Exposures: An a priori conceptual model including sociodemographics, medical variables, psychosocial risk factors, and a polygenic risk score for depression (PRS-D) was tested. Main outcomes and measures: The Functional Assessment of Cancer Therapy-Head and Neck measured QoL at baseline and at 3 months. Results: Participants were mostly men (68.7%), with a mean (range) age of 62.9 (31-92) years, 36.6% having a university degree, 35.6% living alone, and 71.4% diagnosed with advanced HNC with mostly cancers being of the oropharynx (42.2%), oral cavity (17%), and larynx (16.3%). QoL at 3 months after HNC diagnosis was associated with higher PRS-D (B = -4.71; 95% CI, -9.18 to -0.23), and a diagnosis of major depressive disorder within 2 weeks of an HNC diagnosis (B = -32.24; 95% CI, -51.47 to 13.02), lifetime suicidal ideation (B = -22.39; 95% CI, -36.14 to -8.65), living with someone (B = 12.48; 95% CI, 3.43-21.52), having smoked cigarettes in the past 30 days pre-HNC diagnosis (B = -15.50; 95% CI, -26.07 to -4.93), chemotherapy type (B = -11.13; 95% CI, -21.23 to -1.02), and total radiotherapy dose (Gy) (B = -0.008; 95% CI, -0.01 to -0.002). Conclusions and relevance: This study identified the predictive value of a genetic predisposition to depression on QoL and function immediately after oncologic treatments. These findings highlight the potential importance of genetic profiling pretreatment to identify those most susceptible to experience QoL and functional compromise. Depression is a clear area of public health concern and should be a central focus in the treatment of patients with HNC.

Independent Prediction of Child Psychiatric Symptoms by Maternal Mental Health and Child Polygenic Risk Scores.

OBJECTIVE: Prenatal maternal symptoms of depression and anxiety are associated with an increased risk for child socioemotional and behavioral difficulties, supporting the fetal origins of mental health hypothesis. However, to date, studies have not considered specific genomic risk as a possible confound. METHOD: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 5,546) was used to test if child polygenic risk score for attention-deficit/hyperactivity disorder (ADHD), schizophrenia, or depression confounds or modifies the impact of prenatal maternal depression and anxiety on child internalizing, externalizing, and total emotional/behavioral symptoms from age 4 to 16 years. Longitudinal child and adolescent symptom data were analyzed in the ALSPAC cohort using generalized estimating equations. Replication analyses were done in an independent cohort (Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] cohort; n = 514) from Finland, which provided complementary measures of maternal mental health and child psychiatric symptoms. RESULTS: Maternal depression and anxiety and child polygenic risk scores independently and additively predicted behavioral and emotional symptoms from childhood through mid-adolescence. There was a robust prediction of child and adolescent symptoms from both prenatal maternal depression (generalized estimating equation estimate = 0.093, 95% CI 0.065-0.121, p = 2.66 × 10-10) and anxiety (generalized estimating equation estimate = 0.065, 95% CI 0.037-0.093, p = 1.62 × 10-5) after adjusting for child genomic risk for mental disorders. There was a similar independent effect of maternal depression (B = 0.156, 95% CI 0.066-0.246, p = .001) on child symptoms in the PREDO cohort. Genetically informed sensitivity analyses suggest that shared genetic risk only partially explains the reported association between prenatal maternal depression and offspring mental health. CONCLUSION: These findings highlight the genomic contribution to the fetal origins of mental health hypothesis and further evidence that prenatal maternal depression and anxiety are robust in utero risks for child and adolescent psychiatric symptoms.

Genetic predisposition to depression and inflammation impacts symptom burden and survival in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: The primary purpose of this study was to investigate the contribution of genetic predispositions to depression and inflammation, as measured through polygenic risk scores, on symptom burden (physical and psychological) in patients with head and neck cancer in the immediate post-treatment period (i.e., at three months post-diagnosis), as well as on 3-, 6-, 12-, 24- and 36-month survival. METHODS: Prospective longitudinal study of 223 adults (72 % participation) newly diagnosed with a first occurrence of primary head and neck cancer, paired with genetic data (Illumina PsychArray), validated psychometric measures, Structured Clinical Interviews for DSM Disorders (SCID-I), and medical chart reviews. RESULTS: Symptom burden at 3 months was predicted by (R2 adj. = 0.38, p < 0.001): a baseline SCID-I Anxiety Disorder (b = 1.69, B = 0.23, 95%CI = 0.43-2.94; p = 0.009), baseline levels of HADS anxiety (b = 0.20, B = 0.29, 95%CI = 0.07-0.34; p = 0.003), the polygenic risk score (PRS) for depression (b = 0.66, B = 0.18, 95%CI = 0.003-1.32; p = 0.049), and cumulated dose of radiotherapy (b = 0.002, B = 0.46, 95%CI = 0.001-0.003; p < 0.001). When controlling for factors known to be associated with cancer survival, patients with a higher PRS associated with depression and inflammation, respectively, presented higher risk of death within 36 months (b = 1.75, Exp(B) = 5.75, 95%CI = 1.55-21.27, p = 0.009 and b = 0.14, Exp(B) = 1.15, 95%CI = 1.01-1.30, p = 0.03). CONCLUSIONS: Our results outline three potential pathways of symptom burden in patients with head and neck cancer: a genetic predisposition towards depression; an initial anxiety disorder upon being diagnosed with cancer or high levels of anxiety upon diagnosis; and a dose-related response to radiotherapy. One may want to investigate early interventions in these areas to alleviate symptom burden in patients faced with a life-threatening disease, as well as consider targeting genetic predisposition towards depression and inflammation implicated in survival. The high prevalence of distress in patients with head and neck cancer is an opportunity to study genetic predispositions, which could potentially be broadly generalized to other cancers and diseases.

Early Life Adversity and Polygenic Risk for High Fasting Insulin Are Associated With Childhood Impulsivity.

While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [N = 467; p t- initial = 0.24 (10,296 SNPs), p t- refined = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [ß = -0.329, p = 0.024], such that higher PRS [ß = -0.551, p = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCoreTM) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity.

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes.

We report that N-acyl-l-homoserine lactones (AHLs), a class of nonionic amphiphiles that common bacteria use as signals to coordinate group behaviors, can promote large-scale remodeling in model lipid membranes. Characterization of supported lipid bilayers (SLBs) of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) by fluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) reveals the well-studied AHL signal 3-oxo-C12-AHL and its anionic head group hydrolysis product (3-oxo-C12-HS) to promote the formation of long microtubules that can retract into hemispherical caps on the surface of the bilayer. These transformations are dynamic, reversible, and dependent upon the head group structure. Additional experiments demonstrate that 3-oxo-C12-AHL can promote remodeling to form microtubules in lipid vesicles and promote molecular transport across bilayers. Molecular dynamics (MD) simulations predict differences in thermodynamic barriers to translocation of these amphiphiles across a bilayer that are reflected in both the type and extent of reformation and associated dynamics. Our experimental observations can thus be interpreted in terms of accumulation and relief of asymmetric stresses in the inner and outer leaflets of a bilayer upon intercalation and translocation of these amphiphiles. Finally, experiments on Pseudomonas aeruginosa, a pathogen that uses 3-oxo-C12-AHL for cell-to-cell signaling, demonstrate that 3-oxo-C12-AHL and 3-oxo-C12-HS can promote membrane remodeling at biologically relevant concentrations and in the absence of other biosurfactants, such as rhamnolipids, that are produced at high population densities. Overall, these results have implications for the roles that 3-oxo-C12-AHL and its hydrolysis product may play in not only mediating intraspecies bacterial communication but also processes such as interspecies signaling and bacterial control of host-cell response. Our findings also provide guidance that could prove useful for the design of synthetic self-assembled materials that respond to bacteria in ways that are useful in the context of sensing, drug delivery, and in other fundamental and applied areas.

Reduced perceptual narrowing in synesthesia.

Synesthesia is a neurologic trait in which specific inducers, such as sounds, automatically elicit additional idiosyncratic percepts, such as color (thus "colored hearing"). One explanation for this trait-and the one tested here-is that synesthesia results from unusually weak pruning of cortical synaptic hyperconnectivity during early perceptual development. We tested the prediction from this hypothesis that synesthetes would be superior at making discriminations from nonnative categories that are normally weakened by experience-dependent pruning during a critical period early in development-namely, discrimination among nonnative phonemes (Hindi retroflex /d̪a/ and dental /ɖa/), among chimpanzee faces, and among inverted human faces. Like the superiority of 6-mo-old infants over older infants, the synesthetic groups were significantly better than control groups at making all the nonnative discriminations across five samples and three testing sites. The consistent superiority of the synesthetic groups in making discriminations that are normally eliminated during infancy suggests that residual cortical connectivity in synesthesia supports changes in perception that extend beyond the specific synesthetic percepts, consistent with the incomplete pruning hypothesis.

Maternal antenatal depression and child mental health: Moderation by genomic risk for attention-deficit/hyperactivity disorder.

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.

A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions.

BACKGROUND: Activation of brain insulin receptors modulates reward sensitivity, inhibitory control and memory. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related mental disorders (attention deficit hyperactivity disorder or ADHD, addiction, dementia), in agreement with the high co-morbidity between insulin resistance and psychopathology. These neurobiological mechanisms can be explored using genetic studies. We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic and hippocampal insulin receptor-related gene networks, and investigate if it predicts endophenotypes (impulsivity, cognitive ability) in community samples of children, and psychopathology (addiction, dementia) in adults. METHODS: Lists of genes co-expressed with the insulin receptor in the mesocorticolimbic system or hippocampus were created. SNPs from these genes (post-clumping) were compiled in a polygenic score using the association betas described in a conventional GWAS (ADHD in the mesocorticolimbic score and Alzheimer in the hippocampal score). Across multiple samples (n = 4502), the biologically informed, mesocorticolimbic or hippocampal specific insulin receptor polygenic scores were calculated, and their ability to predict impulsivity, risk for addiction, cognitive performance and presence of Alzheimer's disease was investigated. FINDINGS: The biologically-informed ePRS-IR score showed better prediction of child impulsivity and cognitive performance, as well as risk for addiction and Alzheimer's disease in comparison to conventional polygenic scores for ADHD, addiction and dementia. INTERPRETATION: This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders. FUND: Toxic Stress Research network of the JPB Foundation, Jacobs Foundation (Switzerland), Sackler Foundation.

PRS-on-Spark (PRSoS): a novel, efficient and flexible approach for generating polygenic risk scores.

BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach. RESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%). CONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.

The early care environment and DNA methylome variation in childhood.

Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.

Estimating epidemic arrival times using linear spreading theory.

We study the dynamics of a spatially structured model of worldwide epidemics and formulate predictions for arrival times of the disease at any city in the network. The model is composed of a system of ordinary differential equations describing a meta-population susceptible-infected-recovered compartmental model defined on a network where each node represents a city and the edges represent the flight paths connecting cities. Making use of the linear determinacy of the system, we consider spreading speeds and arrival times in the system linearized about the unstable disease free state and compare these to arrival times in the nonlinear system. Two predictions are presented. The first is based upon expansion of the heat kernel for the linearized system. The second assumes that the dominant transmission pathway between any two cities can be approximated by a one dimensional lattice or a homogeneous tree and gives a uniform prediction for arrival times independent of the specific network features. We test these predictions on a real network describing worldwide airline traffic.

Referential labeling can facilitate phonetic learning in infancy.

All languages employ certain phonetic contrasts when distinguishing words. Infant speech perception is rapidly attuned to these contrasts before many words are learned, thus phonetic attunement is thought to proceed independently of lexical and referential knowledge. Here, evidence to the contrary is provided. Ninety-eight 9-month-old English-learning infants were trained to perceive a non-native Cantonese tone contrast.Two object­tone audiovisual pairings were consistently presented, which highlighted the target contrast (Object A with Tone X; Object B with Tone Y). Tone discrimination was then assessed. Results showed improved tone discrimination if object­tone pairings were perceived as being referential word labels, although this effect was modulated by vocabulary size. Results suggest how lexical and referential knowledge could play a role in phonetic attunement.

Valproate reopens critical-period learning of absolute pitch.

Absolute pitch, the ability to identify or produce the pitch of a sound without a reference point, has a critical period, i.e., it can only be acquired early in life. However, research has shown that histone-deacetylase inhibitors (HDAC inhibitors) enable adult mice to establish perceptual preferences that are otherwise impossible to acquire after youth. In humans, we found that adult men who took valproate (VPA) (a HDAC inhibitor) learned to identify pitch significantly better than those taking placebo-evidence that VPA facilitated critical-period learning in the adult human brain. Importantly, this result was not due to a general change in cognitive function, but rather a specific effect on a sensory task associated with a critical-period.