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.

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.

Toxoplasma gondii infection enhances testicular steroidogenesis in rats.

The protozoan parasite Toxoplasma gondii enhances the sexual attractiveness of infected male rats and attenuates the innate fear of cat odour in infected individuals. These behavioural changes plausibly lead to greater transmission of parasites through sexual and trophic routes, respectively. Testosterone, a testicular steroid, is known to reduce fear and enhance sexual attractiveness in males. Here, we show that Toxoplasma gondii infection enhances expression of genes involved in facilitating synthesis of testosterone, resulting in greater testicular testosterone production in male rats. In several species, testosterone mediates trade-offs between sexually selected traits and life history decisions. Augmentation of testosterone synthesis by Toxoplasma gondii suggests that parasites may manipulate these trade-offs in rats.

Dissecting maternal care: Patterns of maternal parenting in a prospective cohort study.

Parental care has a strong impact on neurodevelopment and mental health in the offspring. Although numerous animal studies have revealed that the parental brain is a highly complex system involving many brain structures and neuroendocrine systems, human maternal parenting as a multidimensional construct with cognitive, emotional, and behavioural components has not been characterised comprehensively. This unique multi-method analysis aimed to examine patterns of self-reported and observed parenting from 6 to 60 months postpartum in a cohort of 496 mothers (mean maternal age = 32 years). Self-report questionnaires assessed motivational components of mothering, parenting stress, parenting-related mood, maternal investment, maternal parenting style, mother-child relationship satisfaction, and mother-child bonding at multiple time points. Observed parenting variables included the Ainsworth Sensitivity Scales at 6 and 18 months, the Behavioral Evaluation Strategies Taxonomies at 6 months, an Etch-A-Sketch cooperation task at 48 months, and the Parent-Child Early Relationship Assessment at 60 months. To examine whether different latent constructs underlie these measures of maternal parenting, we conducted an exploratory factor analysis. Self-report measures of parenting correlated only weakly with behavioural observations. Factor analysis on a subsample (n = 197) revealed four latent factors that each explained from 7% to 11% of the variance in the data (32% total variance explained). Based on the loadings of the instruments, the factors were interpreted as: Supportive Parenting, Self-Enjoyment Parenting, Overwhelmed Parenting, and Affectionate Parenting. These factor scores showed specific associations with maternal education and depressive symptoms, as well as with child outcomes, including maternally reported internalising and externalising behavioural problems, school readiness, and child-reported symptoms of mental health. These findings parallel the complexity of the parental brain, suggesting that maternal parenting consists of multiple components, each of which is associated with different maternal characteristics and child outcomes.

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.