Estimation of Parental Effects Using Polygenic Scores

Offspring resemble their parents for both genetic and environmental reasons. Understanding the relative magnitude of these alternatives has long been a core interest in behavioral genetics research, but traditional designs, which compare phenotypic covariances to make inferences about unmeasured genetic and environmental factors, have struggled to disentangle them. Recently, Kong et al. (2018) showed that by correlating offspring phenotypic values with the measured polygenic score of parents’ nontransmitted alleles, one can estimate the effect of “genetic nurture”—a type of passive gene–environment covariation that arises when heritable parental traits directly influence offspring traits. Here, we instantiate this basic idea in a set of causal models that provide novel insights into the estimation of parental influences on offspring. Most importantly, we show how jointly modeling the parental polygenic scores and the offspring phenotypes can provide an unbiased estimate of the variation attributable to the environmental influence of parents on offspring, even when the polygenic score accounts for a small fraction of trait heritability. This model can be further extended to (a) account for the influence of different types of assortative mating, (b) estimate the total variation due to additive genetic effects and their covariance with the familial environment (i.e., the full genetic nurture effect), and (c) model situations where a parental trait influences a different offspring trait. By utilizing structural equation modeling techniques developed for extended twin family designs, our approach provides a general framework for modeling polygenic scores in family studies and allows for various model extensions that can be used to answer old questions about familial influences in new ways.

     

Impact of exposure to parental attention-deficit hyperactivity disorder on clinical features and dysfunction in the offspring

BACKGROUND: Although genes are known to influence the aetiology of ADHD, the impact of exposure to parental ADHD has received limited scientific scrutiny. This study investigated the impact of exposure to parental ADHD on clinical features and dysfunction in offspring. METHODS: We studied 1099 offspring (53% male, mean age 12.4 years) of non-ADHD, remitted ADHD, and persistent ADHD parents, using structured diagnostic interviews and a battery of cognitive and psychosocial measures. Offspring across these three groups were compared on clinical, cognitive and psychosocial outcomes, adjusting for exposure to other parental psychopathology, offspring ADHD status and social class. RESULTS: Parental ADHD was associated with an increased risk for ADHD in offspring relative to no parental ADHD, but no significant differences were found between children of remitted versus persistent ADHD parents. Exposure to parental ADHD predicted higher levels of family conflict and lesser levels of family cohesion relative to families without parental ADHD, independent of other psychopathological conditions in parents or ADHD status. Significant interactions were detected in which parental ADHD had a deleterious impact on measures of school performance in offspring without ADHD but not in those with the disorder. CONCLUSIONS: These results find no support for the hypothesis that exposure to parental ADHD increases the risk for ADHD in children beyond that conveyed by the liability associated with the diagnosis in the parent. However, since exposure to parental ADHD was associated with a disruptive family environment, the identification and treatment of adults with ADHD may be an important component of the treatment plan of youth with ADHD.     

Current parental depression and offspring perceived self-competence: a quasi-experimental examination

A genetically-informed, quasi-experimental design was used to examine the genetic and environmental processes underlying associations between current parental depressive symptoms and offspring perceived self-competence. Participants, drawn from a population-based Swedish sample, were 852 twin pairs and their male (52?%) and female offspring aged 15.7?±?2.4?years. Parental depressive symptoms were measured using the Center for Epidemiological Studies Depression scale. Offspring perceived self-competence was measured using a modified Harter Perceived Competence Scale. Cousin comparisons and Children of Twins designs suggested that associations between maternal depressive symptoms and offspring perceived self-competence were due to shared genetic/environmental liability. The mechanism responsible for father-offspring associations, however, was independent of genetic factors and of extended family environmental factors, supporting a causal inference. Thus, mothers and fathers may impact offspring perceived self-competence via different mechanisms and unmeasured genetic and environmental selection factors must be considered when studying the intergenerational transmission of cognitive vulnerabilities for depression.     

The intergenerational transmission of externalizing behaviors in adult participants: the mediating role of childhood abuse

Childhood abuse was investigated as a potential mediator of the intergenerational transmission of externalizing behaviors (EXT) in adulthood among a large general population sample drawn from the National Comorbidity Survey. Community participants (N = 5,424) underwent diagnostic and psychosocial interviews and reported on their own adult symptoms of antisocial behavior and substance dependence, parental symptoms, and childhood abuse history. Multiple group structural equation modeling revealed that (a) EXT in parents was associated with childhood abuse in offspring, particularly among mother- daughter dyads, (b) abuse had a unique influence on adult EXT in offspring above parental EXT, and (c) abuse accounted for the relationship between parental EXT and offspring EXT in female but not male participants. This article emphasizes the importance of examining different environmental processes which may explain familial transmission of destructive behaviors in men and women and highlights the importance of family interventions that target parental symptoms to ameliorate risk to offspring.     

Parental effects on offspring longevity--evidence from 17th to 19th century reproductive histories

BACKGROUND: Family studies provide support for a modest genetic influence on offspring life span, although the magnitude of these correlations is small. AIM: The study aimed to clarify the relative contributions of parental age at birth and overall parental longevity on offspring lifespan, and to identify the biological and cultural mechanisms. SUBJECTS AND METHODS: Information was derived from two village genealogies (1650-1927) encompassing 9979 births (5315 males, 4664 females). Data selection was guided by the inclusion of information about parental age at birth and lifespan, offspring lifespan and cohort-specific life expectancy. RESULTS: Parental age at reproduction displayed a negative association with offspring survivability, which was caused by a host of biological as well as environmental factors. In contrast, parental lifespan was positively associated with offspring age at death. These effects differed by parent's and child's sex. CONCLUSION: The maternal age effect on female progeny is thought to be indicative of a preferential genetic load. From an evolutionary point of view, direct selection for maternal lifespan may be an adaptive strategy to enhance child survival prospects.     

Maternal and paternal effects on offspring internalizing problems: Results from genetic and family‐based analyses

It is unclear to what extent parental influences on the development of internalizing problems in offspring are explained by indirect genetic effects, reflected in the environment provided by the parent, in addition to the genes transmitted from parent to child. In this study, these effects were investigated using two innovative methods in a large birth cohort. Using maternal‐effects genome complex trait analysis (M‐GCTA), the effects of offspring genotype, maternal or paternal genotypes, and their covariance on offspring internalizing problems were estimated in 3,801 mother–father–child genotyped trios. Next, estimated genetic correlations within pedigree data, including 10,688 children, were used to estimate additive genetic effects, maternal and paternal genetic effects, and a shared family effect using linear mixed effects modeling. There were no significant maternal or paternal genetic effects on offspring anxiety or depressive symptoms at age 8, beyond the effects transmitted via the genetic pathway between parents and children. However, indirect maternal genetic effects explained a small, but nonsignificant, proportion of variance in childhood depressive symptoms in both the M‐GCTA (~4%) and pedigree (~8%) analyses. Our results suggest that parental effects on offspring internalizing problems are predominantly due to transmitted genetic variants, rather than the indirect effect of parental genes via the environment.     

3—6岁幼儿感觉统合失调的病例对照研究

目的：探讨家庭生活环境、母孕期和婴幼儿期不良因素以及父母养育方式与幼儿感觉统合失调之间的关系。方法：采用自填问卷在北京市城近郊区15所幼儿园及散居3－6岁幼儿中调查感觉统合失调,家庭生活环境,母孕期和婴幼儿期及父母养育方式诸方面的情况,并进行Logistic回归分析。结果：父母年龄大,母亲受教育程度高可能是感觉统合失调的保护因素;而母孕期与婴幼儿期的不良因素和不良的养育方式可能是感觉统合失调的危险因素。结论：家庭生活环境,母孕期婴幼儿期不良因素和父母养育方式可能对于幼儿感觉统合功能的发育具有一定的影响。     

The Mediating Effect of Parental Neglect on Adolescent and Young Adult Anti-Sociality: A Longitudinal Study of Twins and Their Parents

The causes of correlation between parental treatment and offspring behavior are ambiguous since genetic and social factors are correlated in typical family studies. The problem is complicated by the need to characterize the effects of genes and environment on both juvenile and adult behavioral outcomes. A model is developed for the resemblance between juvenile and adult twins and their parents that allows some of these effects to be resolved. Data on childhood adversity, parental anti-social behavior, and longitudinal adult and juvenile anti-social behavior were obtained from 1,412 families of adolescent and young adult twins. A structural model is fitted that allows for the effects of genetic and social transmission of information from parents to children. Environmental effects of parents may be mediated through measured features of the home environment. Parameters were estimated by diagonal weighted least squares applied to the 33 distinct polychoric correlations between relatives and between variables within and between ages. Sub-hypotheses were tested. Results confirmed that effects of genes and environment were both highly significant. Genetic effects were large in juveniles and largely age and sex-specific. Approximately 30% of the variation due to the shared environment was due to the effect of childhood adversity. The remaining shared environmental effects are unexplained. Adversity is affected significantly by maternal anti-social behavior. The correlation between paternal ASP and adversity may be explained by antisocial fathers selecting (or creating) antisocial mothers. All significant environmental effects of parental ASP are mediated through the measure of adversity. Though transmission of ASP is both genetic and social, passive genotype–environment correlation is very small. Assortative mating for ASP has barely detectable consequence for the genetic correlation between siblings. The longitudinal study of twins and their parents makes it possible to demonstrate there is a direct causal effect of childhood adversity on child conduct disorder over and above any indirect genetic correlation.     

Analysing the contributions of genes and parent-child interaction to childhood behavioural and emotional problems: a model for the children of twins

BACKGROUND: Despite the demonstrable influence of both genes and the family environment on children's behavioural and emotional development, the mechanisms by which these factors are transmitted from parents to their children are not known. Numerous aspects of the family have long been associated with behavioural and emotional problems in children; it is not clear, however, whether these family variables represent genuine environmental risks or secondary consequences of the underlying genetic liability shared between parents and their children. METHOD: In this study we present a model for analysing the non-genetic contributions of family background to risk for childhood and adolescent depression and conduct disturbance using simulated data on adult MZ and DZ twins, their spouses and children. RESULTS: The twin offspring design provides substantial power to detect remarkably small non-genetic effects on parent-offspring resemblance against the background of genetic transmission. As presented, the model is able to resolve the direction of transmission from both parent to child (passive genotype environment correlation) and child to parent (evocative genotype environment correlation). CONCLUSIONS: Unlike many other genetic studies, a study of twins and their children can sort out which putative family environmental risk factors do actually have a significant environmental impact on the child and which ones only appear to do so because they are associated with genetic mediation.     

Offspring psychological and biological correlates of parental posttraumatic stress: Review of the literature and research agenda

Millions of individuals with posttraumatic stress disorder (PTSD) are parents. A burgeoning literature suggests that offspring of parents with this condition may be at increased risk for psychological problems. The current paper provides an integrative and comprehensive review of the diverse research literature examining the sequelae of parental posttraumatic stress among offspring. Over 100 studies that evaluated psychological and/or biological variables among children of parents with PTSD are reviewed. Findings suggest parental symptoms of posttraumatic stress are uniquely related to an array of offspring outcomes, including internalizing-type problems, general behavioral problems, and altered hypothalamic-pituitary-adrenal axis functioning. Although very little work has directly evaluated mechanisms of transmission, there is increasing support for genetic and epigenetic effects as well as parenting behaviors. These and other mechanisms are discussed; drawing upon findings from other literatures to consider how parental PTSD may impart psychobiological vulnerability upon offspring. We conclude with a detailed discussion of the methodological strengths and challenges of the extant research, along with a recommended agenda for future research in this important area of study.     

Interaction of genes and nutritional factors in the etiology of autism and attention deficit/hyperactivity disorders: A case control study

ObjectiveTo compare risk factors of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) to age/sex-matched controls with particular attention to family history, parental age and nutrition.Method31 ASD and 81 ADHD patients were compared to 612 age/sex-matched controls by reviewing charts for parental age, sibling order, gestational age, and early feeding, and by parental interview for early feeding and family history of psychopathology on affected patients and 139 of those controls.FindingsParental age affected ASD and ADHD females but not males. First-born males were at increased risk for both disorders even though their siblings had older parents and their parents were not more likely to stop having children. Breastfeeding in the absence of parental psychopathology reduced ADHD risk, but breastfeeding of first-born males by older mothers with psychopathology was a risk for ASD. Breastfeeding was only a risk for ADHD if the mother had psychopathology. Parent emigration from a place of high fish consumption was a significant ASD risk factor.Resulting hypothesesADHD and ASD share risk factors due to shared genetic and nutritional interactions, likely revolving around deficiencies of omega-3 fatty acids (n3FAs) during brain development. Fatty acid metabolism genes are important in that process. The 4:1 male to female ratio for both disorders results from hormonally driven fat metabolism differences. Risk factors for both disorders including maternal smoking, prematurity, and gestational diabetes may also be attributed to their effect on n3FA supplies. Breastfeeding can be a risk factor when the mother’s genes and/or age affect her milk quality. Parental age and gene defects may affect female more than male offspring. Childbirth with adequate spacing and breastfeeding can override maternal age and protect subsequent offspring. Genetic variations in fat metabolism can be influenced by cultural/geographic diet, causing deficiencies in offspring with migration-influenced diet changes. Interaction of n3FA deficient diets, delayed child-bearing, and breastfeeding by mothers with psychopathology may be important factors in the rising incidence of ASD and ADHD in recent decades. Partial prevention through diet and supplements may be possible.     

Revealing the genetic structure of a trait by sequencing a population under selection

One approach to understanding the genetic basis of traits is to study their pattern of inheritance among offspring of phenotypically different parents. Previously, such analysis has been limited by low mapping resolution, high labor costs, and large sample size requirements for detecting modest effects. Here, we present a novel approach to map trait loci using artificial selection. First, we generated populations of 10-100 million haploid and diploid segregants by crossing two budding yeast strains of different heat tolerance for up to 12 generations. We then subjected these large segregant pools to heat stress for up to 12 d, enriching for beneficial alleles. Finally, we sequenced total DNA from the pools before and during selection to measure the changes in parental allele frequency. We mapped 21 intervals with significant changes in genetic background in response to selection, which is several times more than found with traditional linkage methods. Nine of these regions contained two or fewer genes, yielding much higher resolution than previous genomic linkage studies. Multiple members of the RAS/cAMP signaling pathway were implicated, along with genes previously not annotated with heat stress response function. Surprisingly, at most selected loci, allele frequencies stopped changing before the end of the selection experiment, but alleles did not become fixed. Furthermore, we were able to detect the same set of trait loci in a population of diploid individuals with similar power and resolution, and observed primarily additive effects, similar to what is seen for complex trait genetics in other diploid organisms such as humans.     

Retroposed new genes out of the X in Drosophila

New genes that originated by various molecular mechanisms are an essential component in understanding the evolution of genetic systems. We investigated the pattern of origin of the genes created by retroposition in Drosophila. We surveyed the whole Drosophila melanogaster genome for such new retrogenes and experimentally analyzed their functionality and evolutionary process. These retrogenes, functional as revealed by the analysis of expression, substitution, and population genetics, show a surprisingly asymmetric pattern in their origin. There is a significant excess of retrogenes that originate from the X chromosome and retropose to autosomes; new genes retroposed from autosomes are scarce. Further, we found that most of these X-derived autosomal retrogenes had evolved a testis expression pattern. These observations may be explained by natural selection favoring those new retrogenes that moved to autosomes and avoided the spermatogenesis X inactivation, and suggest the important role of genome position for the origin of new genes.     

The genetic epidemiology of parental discipline

BACKGROUND: Previous studies of parental discipline have identified little influence of heritability on parental control, and some influence of gene-environment correlations, shared environment and child temperament. METHOD: Using interview data from 2003 female twins from a population-based twin registry and 1472 of their parents, we examined reports of parental discipline from four perspectives: (1) father and mother reporting separately on the type of discipline they provided for their offspring; (2) each twin reporting on the type of discipline they received from their parents; (3) each parent reporting on the discipline provided by their spouse; and, (4) each twin reporting on the discipline they provided for their own offspring. Using factor analysis and univariate structural equation modelling, we examined the structure of parental discipline, and the genetic and environmental influences thereon. RESULTS: The seven discipline items yielded two factors, physical discipline and limit setting, which were moderately positively correlated. Parents perceived discipline as largely a common environmental experience for the twins, whereas the twins indicated that discipline was influenced by unique environmental factors and the genotype of the child. Twins as parents indicated no influence of shared environment on discipline, with the majority of influence accounted for by non-shared environment and parental genotype. CONCLUSIONS: Parents recall providing similar discipline to their children, whereas children emphasize the differences in parental discipline. Sources of individual variation in parental discipline vary according to which family member report is examined. In total, parental discipline is partially influenced by the genotype of both the parent and child, and by environmental factors shared by the twins and unique to the individual.     

An epigenetic,transgenerational model of increased mental health disorders in children,adolescents and young adults

Prevalence rates of mental health disorders in children and adolescents have increased two to threefold from the 1990s to 2016. Some increase in prevalence may stem from changing environmental conditions in the current generation which interact with genes and inherited genetic variants. Current measured genetic variant effects do not explain fully the familial clustering and high heritability estimates in the population. Another model considers environmental conditions shifting in the previous generation, which altered brain circuits epigenetically and were transmitted to offspring via non-DNA-based mechanisms (intergenerational and transgenerational effects). Parental substance use, poor diet and obesity are environmental factors with known epigenetic intergenerational and transgenerational effects, that regulate set points in brain pathways integrating sensory-motor, reward and feeding behaviors. Using summary statistics for eleven neuropsychiatric and three metabolic disorders from 128,989 families, an epigenetic effect explains more of the estimated heritability when a portion of parental environmental effects are transmitted to offspring alongside additive genetic variance.Subject terms: Genetic variation, ADHD, Addiction, Autism spectrum disorders, Genetic variation     

Familial aggregation for conduct disorder symptomatology: the role of genes, marital discord and family adaptability

BACKGROUND: There is extensive evidence of statistical associations between family discord/ maladaptation and antisocial behaviour in the children, but questions remain on the extent to which the psychopathological risks are genetically or environmentally mediated. METHODS: Twin pairs (N = 1,350), aged 8 to 16 years, in the general population-based Virginia Twin Study of Adolescent Behavioral Development were assessed using the Child and Adolescent Psychiatric Assessment interview administered separately to both twins and both parents. Structured interviews for parental lifetime psychiatric disorders were also administered to the mothers and fathers. Maternal reports on Olsson's Family Adaptability and Cohesiveness questionnaire and the Dyadic Adjustment Scale were used as indices of the family environment. A path analytical model based on an extended twin-family design was used to test hypotheses about parent offspring similarity for conduct disorder symptomatology. RESULTS: Family discord and maladaptation, which intercorrelated at 0.63, were associated with a roughly two-fold increase in risk for conduct disorder symptomatology. When parental conduct disorder was included in the model the environmental mediation effect for family maladaptation remained, but that for family discord was lost. CONCLUSION: It is concluded that there is true environmental mediation from family maladaptation, operating as a shared effect, which accounts for 3.5 % of the phenotypic variance. The assumptions underlying this genetic research strategy are made explicit, together with its strengths and limitations.     

Family interaction and the development of borderline personality disorder: a transactional model

Although no prospective epidemiological studies have evaluated the relationship between family interactions and the development of borderline personality disorder (BPD), there is considerable evidence for the central role of family interactions in the development of BPD. This paper describes the role of family interactions or processes, especially those that might be regarded as invalidating or conflictual, negative or critical, and the absence of more validating, positive, supportive, empathic interactions, in the development of BPD. Perhaps more importantly, the proposed model considers how these parental and family behaviors transact with the child's own behaviors and emotional vulnerabilities, resulting in a developmental model of BPD that is neither blaming of the family member with BPD nor of her or his parents and caregivers, and has important and specific implications for both prevention and intervention.     

Transmission of symptoms of anxiety and depression in nuclear families

Anxiety and depression symptom scores from the SCL-90 questionnaire were observed in a large sample of nuclear families, and the effects of genes or family environment were estimated. Assuming no environmental transmission from parents to offspring, heritability was estimated at 0.43 for both anxiety and depression scores, and common sibling environment or reciprocal sibling influence explained 19% of the variances for both scores. Most of the (genetic or environmental) family effect seemed to be common for the two scores. There was no evidence of common determinants in the family for the symptom scores and alcohol consumption, not even of any substantial relationship within persons between symptoms and consumption. The spouse correlations were 0.25 for anxiety and 0.38 for depression. Similar values for the correlations between anxiety in one person and depression in his/her spouse implies a mate selection based on a single latent variable to which the two observed traits contribute.     

The changing impact of genes and environment on brain development during childhood and adolescence: initial findings from a neuroimaging study of pediatric twins

Human brain development is created through continuing complex interactions of genetic and environmental influences. The challenge of linking specific genetic or environmental risk factors to typical or atypical behaviors has led to interest in using brain structural features as an intermediate phenotype. Twin studies in adults have found that many aspects of brain anatomy are highly heritable, demonstrating that genetic factors provide a significant contribution to variation in brain structures. Less is known about the relative impact of genes and environment while the brain is actively developing. We summarize results from the ongoing National Institute of Mental Health child and adolescent twin study that suggest that heritability of different brain areas changes over the course of development in a regionally specific fashion. Areas associated with more complex reasoning abilities become increasingly heritable with maturation. The potential mechanisms by which gene-environment interactions may affect heritability values during development is discussed.     

Social class and parenting children with mild and moderate mental retardation.

Based on Kohn's (1977) and Gecas' (1979) theories of social class and parenting values, the role of socioeconomic status (SES) as a determinant of parenting attitudes and behaviors and as a moderator of problems associated with raising children with handicaps was evaluated among 171 families raising a child with mild or moderate mental retardation. Self-report measures assessed mothers' and fathers' attitudes regarding control, independence, and closeness within the family, and parental and family problems. Supportive, aversive, and controlling parent-child interactions were observed in the home. As expected, higher SES was associated with parental attitudes and behaviors related to fostering independent initiative in the family, and lower SES parents exhibited relatively more controlling and negative behaviors. However, regardless of SES, controlling parental behaviors also were responsive to the level of functioning of the child with mental retardation. Consistent with an hypothesis about violations of SES-related values, negative and controlling interactions with the child were more highly correlated with the parents' reports of parental and family problems for upper SES as opposed to lower SES parents. Several models of SES and family adaptation are discussed.