Developmental imaging genetics: challenges and promises for translational research

Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology

Personalized Prognosis and Diagnosis of Type 2 Diabetes - Vision or Fiction?

Typical civilization diseases, such as type 2 diabetes, share several features: their worldwide frequency, the complexity of the underlying pathogenic mechanisms, heterogeneity in the phenotypes and their multifactorial nature due to a wide variety of possible combinations of disease susceptibility or protective genes in different tissues and negative or positive environmental factors. This is in sharp contrast to classical inherited diseases, such as Huntington's chorea, which are often caused by complete loss- or gain-of-function mutations in a single gene. The causative polymorphisms of susceptibility genes, however, are characterized by relatively subtle alterations in the function of the corresponding gene products, i.e. low penetrance and effect size, which do not support the pathogenesis per se, and by their high frequency; these two characteristics result in high expenditures for their identification and a rather low predictive value. In the future, the reliable and early diagnosis of common diseases will thus depend on the determination of all (or as many as possible) polymorphisms of each susceptibility gene together with the corresponding gene products and the metabolites emerging thereof for each individual. Great hopes are currently associated with systems biology to cover these demands in time (i.e. along the pathogenesis) and space (i.e. in all relevant tissues). Copyright (C) 2010 S. Karger AG, Base

Variation in the μ-opioid receptor gene (OPRM1) moderates the influence of early maternal care on fearful attachment

There is evidence that both early experience and genetic variation play a role in influencing sensitivity to social rejection. In this study, we aimed at ascertaining if the A118G polymorphism of the k-opioid receptor gene (OPRM1) moderates the impact of early maternal care on fearful attachment, a personality trait strongly related to rejection sensitivity. In 112 psychiatric patients, early maternal care and fearful attachment were measured using the Parental Bonding Inventory and the Relationship Questionnaire (RQ), respectively. The pattern emerging from the RQ data was a crossover interaction between genotype and maternal caregiving. Participants expressing the minor 118 G allele had similar and relatively high scores on fearful attachment regardless of the quality of maternal care. By contrast, early experience made a major difference for participants carrying the A/A genotype. Those who recalled higher levels of maternal care reported the lowest levels of fearful attachment whereas those who recalled lower levels of maternal care scored highest on fearful attachment. Our data fit well with the differential susceptibility model which stipulates that plasticity genes would make some individuals more responsive than others to the negative consequences of adversity and to the benefits of environmental support and enrichment

Recent advances in understanding idiopathic pulmonary fibrosis

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF

An investigation into the link between vitamin D status, erectile dysfunction and cardiovascular risk factors in ageing men in New Zealand : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Palmerston North, New Zealand

Background Cardiovascular disease (CVD) is the leading cause of death worldwide, particularly amongst ageing males. Prevention and/or early identification and effective intervention are essential in the fight against CVD. Erectile dysfunction (ED) is a prevalent and multi-factorial condition that is now accepted to be an early marker of subclinical CVD: the common denominator is endothelial dysfunction. Both the enzymatic capability for bioactivation of vitamin D and the vitamin D receptor (VDR) are expressed in endothelial cells and vitamin D may play a role in endothelial function. Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) concentrations ˂50 nmol/L) is a worldwide pandemic and serum 25(OH)D levels ˂75 nmol/L may result in metabolic and vascular deterioration leading to endothelial dysfunction, ED and CVD. Assessment of erectile function can be used to identify otherwise asymptomatic men at high risk of developing clinical CVD, at a time when effective intervention may prevent, delay or reverse its progression. Vitamin D status may be associated with ED and CVD risk and could help improve erectile function and vascular health. Objectives The aim of this research was to investigate the postulated link between vitamin D status, ED, and CVD risk factors. The objectives were (1) to assess the prevalence of ED (using the 5-item International Index of Erectile Function (IIEF-5)) and its associated sociodemographic, lifestyle, and medical correlates in New Zealand (NZ) men aged 40-70 years; (2) to investigate the relationship between vitamin D status (serum 25(OH)D concentration), ED and other CVD risk factors in men aged 40-70 years living in the Manawatu region of NZ; and (3) to examine the impact of common VDR gene (VDR) polymorphisms on this relationship. Method Two thousand men aged 40-70 years were randomly selected from the NZ Electoral Roll and sent an anonymous postal survey designed to assess the prevalence of ED and its sociodemographic, lifestyle, and medical risk factors. Six hundred men aged 40-70 years living in the Manawatu region were randomly selected from the NZ Electoral Roll and invited to participate in an observational study designed to provide a comprehensive health profile of self-reported healthy men and investigate the relationship between vitamin D status, ED, and a range of CVD risk factors. Eligible participants (n=100) completed a comprehensive health assessment including a medical history, anthropometric and cardiovascular assessment, fasting blood sample, computer-based questionnaire, a submaximal fitness test and a handgrip iv strength test. Blood samples were assessed for four common VDR polymorphisms (rs11568820 (Cdx2), rs10735810 (FokI), rs1544410 (BsmI) and rs731236 (TaqI)) using polymerase chain reaction-high resolution amplicon melt (PCR-HRM) analysis. Results The survey showed 38.4% of respondents presented with ED (IIEF-5 ≤21). Older age, non-European ethnicity and current smoking were significant independent predictors of an increased risk of ED, while a high household income and regular vigorous physical activity (PA) were deemed protective. The observational study showed 30 men presented with ED and a further 37 men had <75 nmol/L 25(OH)D. There was a weak positive correlation between IIEF-5 scores and 25(OH)D levels (rs=0.238, p=0.017). Men with <75 nmol/L had lower IIEF-5 scores compared to men with ≥75 nmol/L 25(OH)D (22(7) vs. 24(3), p=0.001). Men with ED had lower 25(OH)D levels compared to men without ED (74.5(34) vs. 84.5(24), p=0.062). Every 1 nmol/L of 25(OH)D predicted a 2% decrease in the age-adjusted risk of ED (age-adjusted OR=0.98 [0.96-1.00], p=0.046). The PCR-HRM analysis showed that the Cdx2, FokI and BsmI polymorphisms were all significantly associated with an adverse cardiovascular risk profile. The Cdx2 G allele was associated with lower IIEF-5 scores compared to the A allele (23(4) vs. 24(2), p=0.008) and the GA and GG genotypes were predictors of an increased age-adjusted risk of ED (age-adjusted OR=18.78 [1.98-178.60], p=0.011 and 8.53 [1.00-72.73], p=0.050 respectively). However, Cdx2 was not found to modify the age-adjusted association between 25(OH)D levels and ED (multi-adjusted OR=0.97 [0.95-1.00], p=0.032). Conclusions These results suggest that over a third of NZ men aged 40-70 years suffer from ED and it is associated with sociodemographic, lifestyle and medical factors simliar to CVD. Low serum 25(OH)D is associated with the presence and severity of ED in a self-reported healthy population. Common VDR polymorphisms are also associated with ED; however, they do not modify the association between serum 25(OH)D and ED. A randomised placebo-controlled human intervention trial is warranted to investigate whether improving vitamin D status in men with vitamin D deficiency and ED ameliorates symptoms and reduces the risk of CVD

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive syniptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MOD recurrence (P = 0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T + and TCE +); 461 days for T - and TCE + patients; 773 days for T + and TCE - patients and 866 days for T - and TCE - patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P = 0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MOD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MOD recurrence after exposure to childhood trauma