Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer's disease, which have a strong and ...well-established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample.
Here we examine the association between polygenic scores for Alzheimer's disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score-dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure.
In a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, we found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2).
We recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer's disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer's disease.
Telomere length (TL) is a widely used marker of biological aging and is associated with an increased risk of morbidity and mortality. Recently, there has been evidence for an association between TL ...and socioeconomic status (SES), particularly for measures of education and childhood SES. Individual differences in TL are also influenced by genetic factors, with heritability estimates from twin and sibling studies ranging from 34 to 82 percent. Yet the additive heritability of TL as a result of measured genetic variations and the extent to which heritability is modified by SES is still unknown. Data from the Health and Retirement Study, a nationally representative cohort of older adults (mean age 69 years), were used to provide the first estimates of molecular-based heritability of TL using genome-wide complex trait analysis (GCTA). We found that additive genetic variance contributed 28 percent (p = .012) of total phenotypic variance of TL in the European American sample (n = 3,290). Estimation using the GCTA and KING Robust relationship inference methods did not differ significantly in this sample. None of the variance from the gene-by-SES interactions examined contributed significantly to the total TL variance. Estimation of heritability and genetic interaction with SES in the African American sample (n = 442) was too unstable to provide reliable estimates.
Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study ...was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.
In the US population-based Health and Retirement Study (waves 1995-2014), we evaluated the role of cumulative genetic risk of AD, with and without the
alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.
In the European ancestry sample (n = 8,399), both AD polygenic score excluding the
genetic region (odds ratio OR = 1.10; 95% confidence interval CI: 1.00-1.20) and the presence of any
alleles (OR = 2.42; 95% CI: 1.99-2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any
alleles was associated with 1.77 (95% CI: 1.20-2.61) times higher odds of dementia, whereas the AD polygenic score excluding the
genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97-1.30).
Cumulative genetic risk of AD and
are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.
This dissertation consists of three papers on the interrelatedness of beliefs about family behavior, beliefs about societal development, and variation in family behaviors in a rapidly changing social ...context. The first two essays address the beliefs of ordinary people concerning the relationship between family change and societal modernization. The last essay examines the ways in which individual, parental, and local community beliefs about spouse choice influence later spouse choice participation. My first two essays incorporate two prominent theories of social life—the modernization theory and W.I. Thomas' theorem that people's perceptions have real consequences—into an examination of the belief systems of people living in Nepal's Chitwan Valley. In the first essay I document the extent to which survey respondents expect certain family types (late marriage, polygamy, small families) to be in certain types of societies (developed, poor, educated), and the extent to which they believe family change and societal change are causally connected. Survey results from this rural population in Nepal suggest that the majority of people strongly believe that behaviors related to fertility, marriage, and gender equality are causally related to societal development. Respondents provide similar answers whether a society changes via education, wealth, or development. The second essay extends previous work by examining subgroup variation in belief in developmental models. Results based on the Nepal survey data demonstrate that the most disadvantaged and geographically isolated groups are the most likely to reject aspects of the developmental model. Respondents with higher levels of education and mass media consumption are more supportive of developmental models. In the third essay I create a theoretical framework to explain how the individual, family and local community interrelate to determine spouse choice behavior. This framework pays particular attention to the role of education as an allocator of social status and influence. Analyses on a sample from Nepal show that the attitudes of both young adults and their fathers influence participation in spouse choice, and that young adults with higher levels of education are significantly more likely to get the level of participation they desire than do their counterparts with lower levels of education.
Telomere length (TL) is a widely used marker of biological aging and is associated with an increased risk of morbidity and mortality. Recently, there has been evidence for an association between TL ...and socioeconomic status (SES), particularly for measures of education and childhood SES. Individual differences in TL are also influenced by genetic factors, with heritability estimates from twin and sibling studies ranging from 34 to 82 percent. Yet the additive heritability of TL as a result of measured genetic variations and the extent to which heritability is modified by SES is still unknown. Data from the Health and Retirement Study, a nationally representative cohort of older adults (mean age 69 years), were used to provide the first estimates of molecular-based heritability of TL using genome-wide complex trait analysis (GCTA). We found that additive genetic variance contributed 28 percent (p = .012) of total phenotypic variance of TL in the European American sample (n = 3,290). Estimation using the GCTA and KING Robust relationship inference methods did not differ significantly in this sample. None of the variance from the gene-by-SES interactions examined contributed significantly to the total TL variance. Estimation of heritability and genetic interaction with SES in the African American sample (n = 442) was too unstable to provide reliable estimates.
Background
To examine the potential mediating role of parenting behaviors in the longitudinal, bidirectional relationships between maternal depression and child internalizing symptoms (i.e. ...depression and anxiety).
Methods
We analyzed data from 4,581 mother–child dyads from the Fragile Families and Child Wellbeing Study, assessed when the child was 3, 5, and 9 years old. Data included maternal depression diagnosis, child internalizing symptoms, and parenting behaviors (i.e. psychological aggression, nonviolent discipline, and physical assault). Data were analyzed using cross‐lagged panel models.
Results
Results indicated bidirectional relationships between maternal depression and child internalizing symptoms over childhood. Mediation analyses suggested that maternal depression led to subsequent increased psychological aggression toward their child, which in turn led to increased child internalizing symptoms. Nonviolent discipline and physical assault did not mediate this relationship. However, greater use of nonviolent discipline at age 5 among all parents predicted higher child internalizing symptoms at age 9. No parenting behaviors were both predicted by earlier child internalizing symptoms and predictive of subsequent maternal depression.
Conclusions
Our results suggest a bidirectional relationship between child and maternal internalizing psychopathology that is partially explained by depressed mothers’ greater use of psychological aggression toward their children. It is important to note that the size of these effects were small, suggesting that the relationship between parent and child psychopathology is likely additionally explained by factors not assessed in the current study. Nonetheless, these results have implications for prevention and intervention strategies targeting child anxiety and depression.
Irritability is a dimensional trait in typical development and a common presenting symptom in many psychiatric disorders, including depression. However, little is known about the developmental ...trajectory of irritability or how child irritability interacts with maternal depression. The present study identifies classes of irritability trajectories from toddlerhood to middle childhood; characterizes maternal depression and other family, social environment, and child variables within each irritability trajectory class; and, as a more exploratory analysis, examines bidirectional associations between maternal depression and child irritability.
A total of 4,898 families from the Fragile Families and Child Wellbeing Study reported on irritability symptoms at ages 3, 5, and 9 years, assessed with items from the Child Behavior Checklist. Parental major depressive episode was assessed using the Composite International Diagnostic Interview-Short Form at child ages 1, 3, 5, and 9 years.
A latent class growth analysis identified 5 irritability classes: low decreasing; moderate decreasing; high steady; initially very high, then decreasing; and high increasing. Children with more severe irritability trajectories are more likely to have mothers with recurrent depression, and, with the exception of the most severe (high increasing irritability) class, were more likely to have mothers who were exposed to violence. Moreover, paternal depression and alcohol abuse, as well as maternal drug and alcohol abuse, were also risk factors for membership in the more severe irritability classes. A latent auto-regressive cross-lag model showed that child irritability at ages 3 and 5 years is associated with increased mother depression at ages 5 and 9, respectively. Conversely, mother depression at child ages 1 and 3 years is associated with increased child irritability at 3 and 5.
Irritability development across toddlerhood and middle childhood has 5 main trajectory types, which differ on maternal depression recurrence and exposure to violence. Maternal depression and child irritability influence each other bidirectionally, particularly early in development. Understanding irritability development and its bidirectional relationship with maternal depression and association with violence exposure may help identify intervention targets.
Epigenetics, and especially DNA methylation, have recently become provocative biological explanations for early-life environmental effects on later health. Despite the large increase in papers on the ...topic over the last few years, many questions remain with regards to the biological feasibility of this mechanism and the strength of the evidence to date. In this review, we examine the literature on early-life effects on epigenetic patterns, with special emphasis on social environmental influences. First, we review the basic biology of epigenetic modification of DNA and debate the role of early-life stressful, protective, and positive environments on gene-specific, system-specific, and whole-genome epigenetic patterns later in life. Second, we compare the epigenetic literatures of both humans and other animals and review the research linking epigenetic patterns to health in order to complete the mechanistic pathway. Third, we discuss physical environmental and social environmental effects, which have to date, generally not been jointly considered. Finally, we close with a discussion of the current state of the area's research, its future direction, and its potential use in pediatric health.
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