Gene-environment interactions in disruptive behaviors

Disruptive behavior disorders are relatively common and have a substantial impact on children and their families. For my Ph.D.-research, I investigated the genetics, environmental factors, gene-environment interactions (GxE’s) and neural correlates of disruptive behaviors in children and adolescents. Results of my research show that a variety of environmental factors play a role in relation to disruptive behaviors, including maternal smoking, paracetamol use and stress during pregnancy, and maltreatment and stressful events during childhood. Disruptive behaviors represent complex genetic traits and GxE’s between a multitude of genetic and environmental factors are involved. I investigated and confirmed GxE’s while considering different levels of complexity. In particular, I observed GxE’s involving stressful events during pregnancy and opioid signaling emerged as a potentially underlying pathway. Furthermore, GxE’s were found between genetic variants implicated by genome-wide association studies (GWAS) of disruptive behaviors and smoking during pregnancy and maltreatment during childhood. Polygenic risk scoring analyses pointed to a shared genetic etiology between the disruptive behavior-related traits aggression and callous-unemotional traits. In this respect, shared glutamatergic genetic variation was also observed. Further, I obtained evidence suggesting a relation between polygenic risk scores for aggression and brain structural connectivity in the right hemisphere white-matter. Summarizing, the results of my Ph.D.-research point to a range of genetic and environmental factors, GxE’s and brain regions that may play a role in disruptive behaviors and aid in identifying potentially underlying mechanisms

Disease-Specific Electrocardiographic Lead Positioning for Early Detection of Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by replacement of cardiomyocytes by fibrofatty tissue which can lead to ventricular arrhythmias, heart failure or sudden cardiac death. Genetic defects in desmosomal proteins, as plakophilin-2 (PKP2), are known to contribute to disease development. Current electrocardiographic (ECG) criteria for ARVC diagnosis only focus on right precordial leads, but sensitivity of current depolarization criteria is limited. This study aimed to identify additional depolarization criteria with most optimal lead configurations for early detection of ARVC in PKP2 pathogenic mutation carriers. In PKP2-positive ARVC patients (n=7), PKP2 pathogenic variant carriers (n=16) and control subjects without structural heart disease (n=9), 67-lead body surface potential maps (BSPM) were obtained. Terminal QRS-integrals were determined and quantitatively compared to controls using departure mapping. Significantly different terminal QRS-integrals were identified in lead 34 (conventional V3), 40 and 41 (conventional V4). To conclude, a clear distinction between ARVC patients, asymptomatic mutation carriers and healthy controls was observed

Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort

We investigated gene-environment (G x E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G x E interactions were tested in a sex-stratified way (alpha = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG (P = 0.0015) and rs9471290-AA (P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype (P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype (P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G x E's remained significant, except for rs11215217 x maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G x E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA-G x E's. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification

Prognostic Significance of Negative Lymph Node Long Axis in Esophageal Cancer: Results From the Randomized Controlled UK MRC OE02 Trial

OBJECTIVE: To analyze the relationship between negative lymph node (LNneg) size as a possible surrogate marker of the host antitumor immune response and overall survival (OS) in esophageal cancer (EC) patients. BACKGROUND: Lymph node (LN) status is a well-established prognostic factor in EC patients. An increased number of LNnegs is related to better survival in EC. Follicular hyperplasia in LNneg is associated with better survival in cancer-bearing mice and might explain increased LN size. METHODS: The long axis of 304 LNnegs was measured in hematoxylin-eosin stained sections from resection specimens of 367 OE02 trial patients (188 treated with surgery alone (S), 179 with neoadjuvant chemotherapy plus surgery (C+S)) as a surrogate of LN size. The relationship between LNneg size, LNneg microarchitecture, clinicopathological variables, and OS was analyzed. RESULTS: Large LNneg size was related to lower pN category (P = 0.01) and lower frequency of lymphatic invasion (P = 0.02) in S patients only. Irrespective of treatment, (y)pN0 patients with large LNneg had the best OS. (y)pN1 patients had the poorest OS irrespective of LNneg size (P < 0.001). Large LNneg contained less lymphocytes (P = 0.02) and had a higher germinal centers/lymphocyte ratio (P = 0.05). CONCLUSIONS: This is the first study to investigate LNneg size in EC patients randomized to neoadjuvant chemotherapy followed by surgery or surgery alone. Our pilot study suggests that LNneg size is a surrogate marker of the host antitumor immune response and a potentially clinically useful new prognostic biomarker for (y)pN0 EC patients. Future studies need to confirm our results and explore underlying biological mechanisms

Sensitive liberals and unfeeling conservatives?: Interoceptive sensitivity predicts political liberalism

The stark divide between the political right and left is rooted in conflicting beliefs, values, and personality—and, recent research suggests, perhaps even lower-level physiological differences between individuals. In this registered report, we investigated a novel domain of ideological differences in physiological processes: interoceptive sensitivity—that is, a person’s attunement to their own internal bodily states and signals (e.g., physiological arousal, pain, and respiration). We conducted two studies testing the hypothesis that greater interoceptive sensitivity would be associated with greater conservatism: one laboratory study in the Netherlands using a physiological heartbeat detection task and one large-scale online study in the United States employing an innovative webcam-based measure of interoceptive sensitivity. Contrary to our predictions, we found evidence that interoceptive sensitivity may instead predict greater political liberalism (versus conservatism), although this association was primarily limited to the American sample. We discuss implications for our understanding of the physiological underpinnings of political ideology.Social decision makin

Contracting COVID-19: a longitudinal investigation of the impact of beliefs and knowledge

Recent work has found that an individual’s beliefs and personal characteristics can impact perceptionsof and responses to the COVID-19 pandemic. Certain individuals—such as those who are politicallyconservative or who endorse conspiracy theories—are less likely to engage in preventative behaviorslike social distancing. The current research aims to address whether these individual differencesnot only affect people’s reactions to the pandemic, but also their actual likelihood of contractingCOVID-19. In the early months of the pandemic, U.S. participants responded to a variety of individualdifference measures as well as questions specific to the pandemic itself. Four months later, 2120 ofthese participants responded with whether they had contracted COVID-19. Nearly all of our includedindividual difference measures significantly predicted whether a person reported testing positive forthe virus in this four-month period. Additional analyses revealed that all of these relationships wereprimarily mediated by whether participants held accurate knowledge about COVID-19. These findingsoffer useful insights for developing more effective interventions aimed at slowing the spread of bothCOVID-19 and future diseases. Moreover, some findings offer critical tests of the validity of suchtheoretical frameworks as those concerning conspiratorial ideation and disgust sensitivity within areal-world context.Social decision makin

Polygenic risk scores for antisocial behavior in relation to amygdala morphology across an attention deficit hyperactivity disorder case-control sample with and without disruptive behavior

Antisocial and aggressive behaviors show considerable heritability and are central to disruptive behavior disorders (DBDs), but are also frequently observed in attention deficit hyperactivity disorder (ADHD). While the amygdala is implicated as a key neural structure, it remains unclear whether common genetic variants underlie this brain-behavior association. We hypothesized that polygenic (risk) scores for antisocial and aggressive behaviors (ASB-PRS) would be related to amygdala morphology. Using the Broad Antisocial Behavior Consortium genome-wide association study (GWAS; mostly population based cohorts), we calculated ASB-PRS in the NeuroIMAGE I ADHD case-control sample with varying levels of DBD symptomatology (n=679 from 379 families, aged 7 - 29). We first investigated associations of several ASB-PRS p value thresholds with the presence of DBD symptoms and self-reported antisocial behavior (ASB) to determine the threshold for further analyses. This PRS was then related to amygdala volume and shape using regression and vertex-wise analyses. Our results showed associations of ASB-PRS with the presence of DBD symptoms, self-reported ASB, and left basolateral amygdala shape, independent of ADHD symptom severity and ADHD-PRS, with a relative outward displacement of the vertices. No associations of ASB-PRS, DBD symptoms or self-reported ASB with amygdala volume were found. Our results indicate that genetic risk for antisocial and aggressive behaviors is related to amygdala shape alterations, and point to genetic sharing across different DBD and ASB and aggression-related phenotypes as a spectrum of genetically related quantitative traits. Additionally, our findings support the utility of vertex-based shape analyses in genetic studies of ASB, aggression, and DBDs

Lymph node response to chemoradiotherapy in oesophageal cancer patients: relationship with radiotherapy fields

Background The presence of lymph node metastasis (LNmets) is a poor prognostic factor in oesophageal cancer (OeC) patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Tumour regression grade (TRG) in LNmets has been suggested as a predictor for survival. The aim of this study was to investigate whether TRG in LNmets is related to their location within the radiotherapy (RT) field. Methods Histopathological TRG was retrospectively classified in 2565 lymph nodes (LNs) from 117 OeC patients treated with nCRT and surgery as: (A) no tumour, no signs of regression; (B) tumour without regression; (C) viable tumour and regression; and (D) complete response. Multivariate survival analysis was used to investigate the relationship between LN location within the RT field, pathological TRG of the LN and TRG of the primary tumour. Results In 63 (54%) patients, viable tumour cells or signs of regression were seen in 264 (10.2%) LNs which were classified as TRG-B (n = 56), C (n = 104) or D (n = 104) LNs. 73% of B, C and D LNs were located within the RT field. There was a trend towards a relationship between LN response and anatomical LN location with respect to the RT field (p = 0.052). Multivariate analysis showed that only the presence of LNmets within the RT field with TRG-B is related to poor overall survival. Conclusion Patients have the best survival if all LNmets show tumour regression, even if LNmets are located outside the RT field. Response in LNmets to nCRT is heterogeneous which warrants further studies to better understand underlying mechanisms

Sensitive liberals and unfeeling conservatives? Interoceptive sensitivity predicts political liberalism

The stark divide between the political right and left is rooted in conflicting beliefs, values, and personality - and, recent research suggests, perhaps even lower-level physiological differences between individuals. In this registered report, we investigated a novel domain of ideological differences in physiological processes: interoceptive sensitivity - that is, a person's attunement to their own internal bodily states and signals (e.g., physiological arousal, pain, and respiration). We conducted two studies testing the hypothesis that greater interoceptive sensitivity would be associated with greater conservatism: one laboratory study in the Netherlands using a physiological heartbeat detection task and one large-scale online study in the United States employing an innovative webcam-based measure of interoceptive sensitivity. Contrary to our predictions, we found evidence that interoceptive sensitivity may instead predict greater political liberalism (versus conservatism), although this association was primarily limited to the American sample. We discuss implications for our understanding of the physiological underpinnings of political ideology