Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

The general psychopathology factor from early to middle childhood: Longitudinal genetic and risk analyses.

Accumulating research suggests the structure of psychopathology is best represented by continuous higher-order dimensions, including a general dimension, "p," and more specific dimensions, for example, externalizing and internalizing factors. Here, we aimed to (a) replicate p in early childhood, (b) examine stability and change of genetic and environmental influences on the psychopathology factors from early to midchildhood, (c) externally validate the factors with key constructs of psychological functioning, and (d) test whether the factors can be predicted by early-life measures (e.g., neonatal complications). Data are based on the Longitudinal Israeli Study of Twins. Mothers reported on pregnancy and neonatal conditions and repeatedly filled in questionnaires on each twin's externalizing and internalizing symptoms from ages 3 to 9. Cognitive ability was assessed in the lab at age 6.5, and personality traits, self-esteem, and life satisfaction were self-reported by the twins at ages 11-13. A bifactor model that included p and externalizing and internalizing factors fit the data best, and associations between p, cognitive ability, and personality were replicated. Longitudinal twin analyses indicated that p is highly heritable (64-73%) with a substantial proportion of the genetic influences stable from age 3. The specific internalizing and externalizing factors (net of p) were also highly heritable. Higher p predicted lower self-esteem at age 11. Early-life measures were not strongly associated with psychopathology. Our results show that p is discernible in early childhood, highly heritable, and prospectively associated with negative outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Little evidence for associations between the Big Five personality traits and variability in brain gray or white matter.

Attempts to link the Big Five personality traits of Openness-to-Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism with variability in trait-like features of brain structure have produced inconsistent results. Small sample sizes and heterogeneous methodology have been suspected in driving these inconsistencies. Here, using data collected from 1,107 university students (636 women, mean age 19.69 â€‹± â€‹1.24 years), representing the largest sample to date of unrelated individuals, we tested for associations between the Big Five personality traits and measures of cortical thickness and surface area, subcortical volume, and white matter microstructural integrity. In addition to replication analyses based on a prior study, we conducted exploratory whole-brain analyses. Four supplementary analyses were also conducted to examine 1) possible associations with lower-order facets of personality; 2) modulatory effects of sex; 3) effect of controlling for non-target personality traits; and 4) parcellation scheme effects. Our analyses failed to identify significant associations between the Big Five personality traits and brain morphometry, except for a weak association between greater surface area of the superior temporal gyrus and lower conscientiousness scores. As the latter association is not supported by previous studies, it should be treated with caution. Our supplementary analyses mirrored these predominantly null findings, suggesting they were not substantively biased by our analytic choices. Collectively, these results indicate that if there are associations between the Big Five personality traits and brain structure, they are likely of very small effect size and will require very large samples for reliable detection.

Vitamin D polygenic score is associated with neuroticism and the general psychopathology factor.

Vitamin D, used here to refer to both 25-hydroxyvitamin D, the main circulating form of the vitamin, and 1,25-hydroxyvitamin D, the biologically active form, has been shown to influence brain development and function. Consistent with these findings, low levels of vitamin D have been implicated in various mental disorders, including depression, schizophrenia, and autism. Recently, a shared variance across multiple categories of mental health disorders has been identified and shown to be genetically influenced. This shared variance, thought to represent a general risk for psychopathology, has been termed the p factor. Individuals with high p factor scores are characterized by high neuroticism and low agreeableness and conscientiousness. Here, we investigated the links between vitamin D polygenic scores - derived from the latest genome-wide association study of circulating vitamin D (25-hydroxyvitamin D) levels - the Big Five personality traits (neuroticism, agreeableness, conscientiousness, openness-to-experience, and extraversion), and the p factor, in a sample of 522 (278 women, mean age 20 ± 1 years) non-Hispanic Caucasians. Vitamin D polygenic scores were significantly and negatively associated with neuroticism and the p factor, even after correcting for multiple comparisons, and controlling for sex, age, ancestry, socioeconomic status, and body mass index. Based on previous research implicating neuroticism as a risk factor for psychopathology, mediation was tested. Results showed a significant indirect effect from the vitamin D polygenic score to the p factor via neuroticism. Our findings support a genetic link between vitamin D levels, neuroticism, and the p factor, but due to the cross-sectional nature of our data, future studies are needed to clarify the causal associations between these phenotypes.

The E Is in the G: Gene-Environment-Trait Correlations and Findings From Genome-Wide Association Studies.

Genome-wide association studies (GWASs) have shown that pleiotropy is widespread (i.e., the same genetic variants affect multiple traits) and that complex traits are polygenic (i.e., affected by many genetic variants with very small effect sizes). However, despite the growing number of GWASs, the possible contribution of gene-environment correlations (rGEs) to pleiotropy and polygenicity has been mostly ignored. rGEs can lead to environmentally mediated pleiotropy or gene-environment-trait correlations (rGETs), given that an environment that is affected by one genetically influenced phenotype, can in turn affect a different phenotype. By adding correlations with environmentally mediated genetic variants, rGETs can contribute to polygenicity. Socioeconomic status (SES) and the experience of stressful life events may, for example, be involved in rGETs. Both are genetically influenced and have been associated with a myriad of physical and mental disorders. As a result, GWASs of these disorders may find the genetic correlates of SES and stressful life events. Consequently, some of the genetic correlates of physical and mental disorders may be modified by public policy that affects environments such as SES and stressful life events. Thus, identifying rGETs can shed light on findings from GWASs and have important implications for public health.

Divergence of an association between depressive symptoms and a dopamine polygenic score in Caucasians and Asians.

A recent study reported a negative association between a putatively functional dopamine (DA) polygenic score, indexing higher levels of DA signaling, and depressive symptoms. We attempted to replicate this association using data from the Duke Neurogenetics Study. Our replication attempt was made in a subsample of 520 non-Hispanic Caucasian volunteers (277 women, mean age 19.78 ± 1.24 years). The DA polygenic score was based on the following five loci: rs27072 (SLC6A3/DAT1), rs4532 (DRD1), rs1800497 (DRD2/ANKK1), rs6280 (DRD3), and rs4680 (COMT). Because the discovery sample in the original study consisted mostly of Asian participants, we also conducted a post hoc analysis in a smaller subsample of Asian volunteers (N = 316, 179 women, mean age 19.61 ± 1.32 years). In the primary sample of non-Hispanic Caucasians, a linear regression analysis controlling for sex, age, socioeconomic status (SES), body mass index, genetic ancestry, and both early and recent life stress, revealed that higher DA polygenic scores were associated with higher self-reported symptoms of depression. This was in contrast to the original association of higher DA polygenic scores and lower depressive symptoms. However, the direction of the association in our Asian subsample was consistent with this original finding. Our results also suggested that compared to the Asian subsample, the non-Hispanic Caucasian subsample was characterized by higher SES, lower early and recent life stress, and lower depressive symptoms. These differences may have contributed to the observed divergence in associations. Collectively, the current findings add to evidence that specific genetic associations may differ between populations and further encourage explicit modeling of race/ethnicity in examining the polygenic nature of depressive symptoms and depression.

A polygenic score for body mass index is associated with depressive symptoms via early life stress: Evidence for gene-environment correlation.

Increasing childhood obesity rates are associated with not only adverse physical, but also mental health outcomes, including depression. These negative outcomes may be caused and/or exacerbated by the bullying and shaming overweight individuals experience. As body mass index (BMI) can be highly heritable, we hypothesized that a genetic risk for higher BMI, will predict higher early life stress (ELS), which in turn will predict higher depressive symptoms in adulthood. Such a process will reflect an evocative gene-environment correlation (rGE) wherein an individual's genetically influenced phenotype evokes a reaction from the environment that subsequently shapes the individual's health. We modeled genetic risk using a polygenic score of BMI derived from a recent large GWAS meta-analysis. Self-reports were used for the assessment of ELS and depressive symptoms in adulthood. The discovery sample consisted of 524 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (DNS; 278 women, mean age 19.78 ±â€¯1.23 years) and the independent replication sample consisted of 5930 white British individuals from the UK biobank (UKB; 3128 women, mean age 62.66 ±â€¯7.38 years). A significant mediation effect was found in the DNS (indirect effect = 0.207, bootstrapped SE = .10, bootstrapped 95% CI: 0.014 to 0.421), and then replicated in the UKB (indirect effect = 0.04, bootstrapped SE = .01, bootstrapped 95% CI: 0.018 to 0.066). Higher BMI polygenic scores predicted higher ELS, which in turn predicted higher depressive symptoms. Our findings suggest that evocative rGE may contribute to weight-related mental health problems and stress the need for interventions that aim to reduce weight bias, specifically during childhood.

A longitudinal genetically informed analysis of parental negativity and children's negative emotionality in middle childhood.

Children's negative emotionality (NE) is frequently associated with parental negativity, but causal understanding of this relationship is limited. In addition, little is known about how genetic and environmental factors affect this relationship during middle childhood. We addressed these gaps by applying a quantitative genetic analysis to cross-lagged associations between mothers' and fathers' parental negativity and children's NE during middle childhood. The sample comprised of 456 families when the children were 6.5 years old, and 401 families when the children were 8/9 years old. Mothers' and fathers' negativity and children's NE were assessed using questionnaires. Results showed that variation in parental negativity was mainly accounted for by the environment shared by children, with some indication of an evocative effect of the children's genes on mothers, but not fathers. Children's NE was accounted for by both genetic and shared environmental influences. Parental negativity and children's NE had moderate continuity over the course of two years. Mothers' (but not fathers') negativity when the children were 6.5 years old predicted change in children's NE (rated by the same or the other parent) toward age 8/9 years, but not the other way around. Shared environmental influences were the main contributor to the association between earlier mothers' negativity and later children's NE. Thus, although children's NE was partially heritable, and parenting too was partially accounted for by children's genes, the association between parental negativity and children's NE, at this age, reflects environmental effects and is compatible with mothers' influence on children. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Genetic Risk for Rheumatoid Arthritis is Associated with Increased Striatal Volume in Healthy Young Adults.

Rheumatoid arthritis (RA), an autoimmune disease, has recently been associated with increased striatal volume and decreased intracranial volume (ICV) in longstanding patients. As inflammation has been shown to precede the clinical diagnosis of RA and it is a known moderator of neuro- and gliogenesis, we were interested in testing whether these brain morphological changes appear before the clinical onset of disease in healthy young adult volunteers, as a function of relative genetic risk for RA. Genetic and structural MRI data were available for 516 healthy non-Hispanic Caucasian university students (275 women, mean age 19.78 ± 1.24 years). Polygenic risk scores were computed for each individual based on a genome-wide association study of RA, so that higher scores indicated higher risk. Striatal volume (sum of caudate, putamen, and nucleus accumbens volumes) and ICV were derived for each individual from high-resolution T1-weighted images. After controlling for sex, age, genetic components of ethnicity, socioeconomic status, and depressive symptoms, we found that higher RA polygenic risk scores were associated with increased striatal volume, but not decreased ICV. Our findings suggest that increased striatal volume may be linked to processes that precede disease onset, such as inflammation, while decreased ICV may relate to disease progression.

A genome-wide association study-derived polygenic score for interleukin-1ß is associated with hippocampal volume in two samples.

Accumulating research suggests that the pro-inflammatory cytokine interleukin-1ß (IL-1ß) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL-1ß polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome-wide association study of circulating cytokines that included IL-1ß (N = 3,309). In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL-1ß polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL-1ß and the structure of the hippocampus.

Genetics of nurture: A test of the hypothesis that parents' genetics predict their observed caregiving.

Twin studies have documented that parenting behavior is partly heritable, but it is unclear how parents' genetics shape their caregiving. Using tools of molecular genetics, the present study investigated this process by testing hypotheses about associations between a genome-wide polygenic score for educational attainment and parental caregiving in 702 members of the Dunedin Study, a population-representative birth cohort. Data have been prospectively collected from when Study members were born through to midlife, and include assessments of the caregiving they provided once they became parents. Results showed that parents' polygenic scores predicted warm, sensitive, and stimulating caregiving, both in personal interactions with their young children (as captured on video) and through the home environments they created for their families (as observed by home visitors). The magnitude of this effect was small. Polygenic-score associations were independent of well-established predictors of parenting, such as parents' own childhood experiences of parenting and the age at which they became parents. Polygenic-score associations were mediated by parents' early-emerging cognitive abilities and self-control skills. Findings have implications for theory and research about genetic influences on caregiving and child development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Replication in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity.

BACKGROUND: Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk. METHODS: We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available. RESULTS: Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons. CONCLUSIONS: We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.

Predicting the use of corporal punishment: Child aggression, parent religiosity, and the BDNF gene.

Corporal punishment (CP) has been associated with deleterious child outcomes, highlighting the importance of understanding its underpinnings. Although several factors have been linked with parents' CP use, genetic influences on CP have rarely been studied, and an integrative view examining the interplay between different predictors of CP is missing. We focused on the separate and joint effects of religiosity, child aggression, parent's gender, and a valine (Val) to methionine (Met) substitution in the brain-derived neurotrophic factor (BDNF) gene. Data came from a twin sample (51% male, aged 6.5 years). We used mothers' and fathers' self-reports of CP and religiosity, and the other parent's report on child aggression. Complete data were available for 244 mothers and their 466 children, and for 217 fathers and their 409 children. The random split method was employed to examine replicability. For mothers, only the effect of religiosity appeared to replicate. For fathers, several effects predicting CP use replicated in both samples: child aggression, child sex, religiosity, and a three-way (GxExE) interaction implicating fathers' BDNF genotype, child aggression and religiosity. Religious fathers who carried the Met allele and had an aggressive child used CP more frequently; in contrast, secular fathers' CP use was not affected by their BDNF genotype or child aggression. Results were also repeated longitudinally in a subsample with age 8-9 data. Findings highlight the utility of a bio-ecological approach for studying CP use by shedding light on pertinent gene-environment interaction processes. Possible implications for intervention and public policy are discussed.

Reward-Related Ventral Striatum Activity Buffers against the Experience of Depressive Symptoms Associated with Sleep Disturbances.

Sleep disturbances represent one risk factor for depression. Reward-related brain function, particularly the activity of the ventral striatum (VS), has been identified as a potential buffer against stress-related depression. We were therefore interested in testing whether reward-related VS activity would moderate the effect of sleep disturbances on depression in a large cohort of young adults. Data were available from 1129 university students (mean age 19.71 ± 1.25 years; 637 women) who completed a reward-related functional MRI task to assay VS activity and provided self-reports of sleep using the Pittsburgh Sleep Quality Index and symptoms of depression using a summation of the General Distress/Depression and Anhedonic Depression subscales of the Mood and Anxiety Symptoms Questionnaire-short form. Analyses revealed that as VS activity increased the association between sleep disturbances and depressive symptoms decreased. The interaction between sleep disturbances and VS activity was robust to the inclusion of sex, age, race/ethnicity, past or present clinical disorder, early and recent life stress, and anxiety symptoms, as well as the interactions between VS activity and early or recent life stress as covariates. We provide initial evidence that high reward-related VS activity may buffer against depressive symptoms associated with poor sleep. Our analyses help advance an emerging literature supporting the importance of individual differences in reward-related brain function as a potential biomarker of relative risk for depression.SIGNIFICANCE STATEMENT Sleep disturbances are a common risk factor for depression. An emerging literature suggests that reward-related activity of the ventral striatum (VS), a brain region critical for motivation and goal-directed behavior, may buffer against the effect of negative experiences on the development of depression. Using data from a large sample of 1129 university students we demonstrate that as reward-related VS activity increases, the link between sleep disturbances and depression decreases. This finding contributes to accumulating research demonstrating that reward-related brain function may be a useful biomarker of relative risk for depression in the context of negative experiences.

Neurogenetic plasticity and sex influence the link between corticolimbic structural connectivity and trait anxiety.

Corticolimbic pathways connecting the amygdala and ventral prefrontal cortex (vPFC) are linked with trait anxiety, but it remains unclear what potential genetic moderators contribute to this association. We sought to address this by examining the inter-individual variability in neuroplasticity as modeled by a functional polymorphism (rs6265) in the human gene for brain derived neurotrophic factor (BDNF). Amygdala-vPFC pathway fractional anisotropy (FA) from 669 diffusion magnetic resonance images was used to examine associations with trait anxiety as a function of rs6265 genotype. We first replicated the inverse correlation between trait anxiety and amygdala-vPFC pathway FA in women. Furthermore, we found a moderating influence of rs6265 genotype such that the association between trait anxiety and right amygdala-vPFC pathway FA was strongest in women carrying the Met allele, which is linked with decreased activity-dependent neuroplasticity. Results indicate that the microstructural integrity of pathways supporting communication between the amygdala and vPFC help shape the expression of trait anxiety in women, and that this association is further modulated by genetically driven variability in neuroplasticity.

Parental brain-derived neurotrophic factor genotype, child prosociality, and their interaction as predictors of parents' warmth.

BACKGROUND: Parental warmth has been associated with various child behaviors, from effortful control to callous-unemotional traits. Factors that have been shown to affect parental warmth include heritability and child behavior. However, there is limited knowledge about which specific genes are involved, how they interact with child behavior, how they affect differential parenting, and how they affect fathers. We examined what affects paternal and maternal warmth by focusing on the child's prosocial behavior and parents' genotype, specifically a Valine to Methionine substitution at codon 66 in the brain-derived neurotrophic factor (BDNF) gene. METHODS: Data was available from a sample of 6.5 year-old twins, consisting of 369 mothers and 663 children and 255 fathers and 458 children. Self-reports were used to assess mothers' and fathers' warmth. Child prosociality was assessed with the other-parent report and experimental assessments. RESULTS: Mothers' warmth was not affected by their BDNF genotype, neither as a main effect nor in an interaction with child prosociality. Fathers with the Met allele scored higher on warmth. Additionally, there was a significant interaction between fathers' BDNF genotype and child prosociality. For fathers with the Met allele there was a positive association between warmth and child prosociality. Conversely, for fathers with the Val/Val genotype there was no association between warmth and child prosociality. Results were repeated longitudinally in a subsample with data on age 8-9 years. A direct within family analysis showed that fathers with the Met allele were more likely than Val/Val carriers to exhibit differential parenting toward twins who differed in their prosocial behavior. The same pattern of findings was found with mother-rated and experimentally assessed prosociality. CONCLUSIONS: These results shed light on the genetic and environmental underpinnings of paternal behavior and differential parenting.

Parenting as a reaction evoked by children's genotype: a meta-analysis of children-as-twins studies.

Parenting has been extensively studied but mostly as a causal factor influencing child outcomes. The aim of the current article is to examine the child's side of the relationship by meta-analyzing studies which used quantitative genetic methods that provide leverage in understanding causality. A meta-analysis of 32 children-as-twins studies of parenting revealed a heritability estimate of 23%, thus indicating that genetically influenced behaviors of the child affect and shape parental behavior. The shared- and nonshared-environmental estimates, which amounted to 43% and 34%, respectively, indicate not only substantial consistency in parental behavior but also differential treatment within the family. Assessment method, age, and parenting dimension were found to be significant moderators of these influences. Our findings stress the importance of accounting for genotype-environment correlations in child-development studies and call into question previous research that interpreted correlational results in unidirectional terms with parenting as the sole causal factor.

The Longitudinal Israeli Study of Twins (LIST)-an integrative view of social development.

The Longitudinal Israeli Study of Twins (LIST) is a social developmental study, which implements social-developmental, molecular genetic, epigenetic, and behavioral genetic methods to advance knowledge on the development of individual differences in social behavior. Twins are followed from the age of three and both observational and parental-questionnaire data are collected on their empathy, temperament, and pro-social behavior. The parenting styles of parents are also evaluated using self-reports and observations and DNA samples are collected from parents and twins. In the current paper, we provide a review of our recent work and discuss the future aims of the LIST.

Boys' serotonin transporter genotype affects maternal behavior through self-control: a case of evocative gene-environment correlation.

Self-control, involving processes such as delaying gratification, concentrating, planning, following instructions, and adapting emotions and behavior to situational requirements and social norms, may have a profound impact on children's adjustment. The importance of self-control suggests that parents are likely to modify their parenting based on children's ability for self-control. We study the effect of children's self-control, a trait partially molded by genetics, on their mothers' parenting, a process of evocative gene-environment correlation. Israeli 3.5-year-old twins (N = 320) participated in a lab session in which their mothers' parenting was observed. DNA was available from most children (N = 228). Mothers described children's self-control in a questionnaire. Boys were lower in self-control and received less positive parenting from their mothers, in comparison with girls. For boys, and not for girls, the serotonin transporter linked polymorphic region gene predicted mothers' levels of positive parenting, an effect mediated by boys' self-control. The implications of this evocative gene-environment correlation and the observed sex differences are discussed.

Human maternal behaviour is associated with arginine vasopressin receptor 1A gene.

Parenting is one of the main influences on children's early development, and yet its underlying genetic mechanisms have only recently begun to be explored, with many studies neglecting to control for possible child effects. This study focuses on maternal behaviour and on an allele at the RS3 promoter region of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with autism and with higher amygdala activation in a face-matching task. Mothers were observed during a free-play session with each of their 3.5-year-old twins. Multilevel regression analyses revealed that mothers who are carriers of the AVPR1A RS3 allele tend to show less structuring and support throughout the interaction independent of the child's sex and RS3 genotype. This finding advances our understanding of the genetic influences on human maternal behaviour.