Evaluating indirect genetic effects of siblings using singletons

Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g. parental educational attainment), but the extent to which siblings affect each other is currently unclear. Here we used data from samples of unrelated individuals, without (singletons) and with biological full-siblings (non-singletons), to investigate and estimate sibling effects. Indirect genetic effects of siblings increase (or decrease) the covariance between genetic variation and a phenotype. It follows that differences in genetic association estimates between singletons and non-singletons could indicate indirect genetic effects of siblings if there is no heterogeneity in other sources of genetic association between singletons and non-singletons. We used UK Biobank data to estimate polygenic score (PGS) associations for height, BMI and educational attainment in self-reported singletons (N = 50,143) and non-singletons (N = 328,549). The educational attainment PGS association estimate was 12% larger (95% C.I. 3%, 21%) in the non-singleton sample than in the singleton sample, but the height and BMI PGS associations were consistent. Birth order data suggested that the difference in educational attainment PGS associations was driven by individuals with older siblings rather than firstborns. The relationship between number of siblings and educational attainment PGS associations was non-linear; PGS associations were 24% smaller in individuals with 6 or more siblings compared to the rest of the sample (95% C.I. 11%, 38%). We estimate that a 1 SD increase in sibling educational attainment PGS corresponds to a 0.025 year increase in the index individual’s years in schooling (95% C.I. 0.013, 0.036). Our results suggest that older siblings may influence the educational attainment of younger siblings, adding to the growing evidence that effects of the environment on phenotypic variation partially reflect social effects of germline genetic variation in relatives.     

Associations between an educational attainment polygenic score with educational attainment in an African American sample

Polygenic propensity for educational attainment has been associated with higher education attendance, academic achievement and criminal offending in predominantly European samples; however, less is known about whether this polygenic propensity is associated with these outcomes among African Americans. Using an educational attainment polygenic score (EA PGS), the present study examined whether this score was associated with post‐secondary education, academic achievement and criminal offending in an urban, African American sample. Three cohorts of participants (N = 1050; 43.9% male) were initially recruited for an elementary school‐based universal prevention trial in a Mid‐Atlantic city and followed into young adulthood. Standardized tests of reading and math achievement were administered in first grade. At age 20, participants reported on their level of education attained, and records of incarceration were obtained from Maryland's Criminal Justice Information System. In young adulthood, DNA was collected and extracted from blood or buccal swabs and genotyped. An EA PGS was created using results from a large‐scale genome‐wide association study on educational attainment. A higher EA PGS was associated with a greater log odds of post‐secondary education. The EA PGS was not associated with reading achievement, although a significant relationship was found with math achievement in the third cohort. These findings contribute to the dearth of molecular genetics work conducted in African American samples and highlight that polygenic propensity for educational attainment is associated with higher education attendance.     

Canalization of the Polygenic Risk for Common Diseases and Traits in the UK Biobank Cohort

Since organisms develop and thrive in the face of constant perturbations due to environmental and genetic variation, species may evolve resilient genetic architectures. We sought evidence for this process, known as canalization, through a comparison of the prevalence of phenotypes as a function of the polygenic score (PGS) across environments in the UK Biobank cohort study. Contrasting seven diseases and three categorical phenotypes with respect to 151 exposures in 408,925 people, the deviation between the prevalence–risk curves was observed to increase monotonically with the PGS percentile in one-fifth of the comparisons, suggesting extensive PGS-by-Environment (PGS×E) interaction. After adjustment for the dependency of allelic effect sizes on increased prevalence in the perturbing environment, cases where polygenic influences are greater or lesser than expected are seen to be particularly pervasive for educational attainment, obesity, and metabolic condition type-2 diabetes. Inflammatory bowel disease analysis shows fewer interactions but confirms that smoking and some aspects of diet influence risk. Notably, body mass index has more evidence for decanalization (increased genetic influence at the extremes of polygenic risk), whereas the waist-to-hip ratio shows canalization, reflecting different evolutionary pressures on the architectures of these weight-related traits. An additional 10 % of comparisons showed evidence for an additive shift of prevalence independent of PGS between exposures. These results provide the first widespread evidence for canalization protecting against disease in humans and have implications for personalized medicine as well as understanding the evolution of complex traits. The findings can be explored through an R shiny app at https://canalization-gibsonlab.shinyapps.io/rshiny/.     

Ethnicity,sibling, and family correlates of young adults’ status attainment: A follow‐up study

Abstract

Longitudinal data were used to examine relationships among sibling variables, perceptions of family environments, and measures of educational attainment, occupational status, and occupational aspirations. The analyses involved 21‐year‐old Australians from Anglo‐Australian, Greek, and Southern Italian families. Regression surfaces were plotted from models that included terms to test for possible linear, interaction, and curvilinear associations among the variables. The study indicated that sibsize and birth order continued to have many significant associations with young adults’ status attainment even after taking into account the mediating influence of perceived family environments. Also, the investigation suggested that there are ethnic‐group differences in relations among sibling variables, perceived parents’ support for learning, and young adults’ status attainment.     

Educational attainment polygenic score predicts inhibitory control and academic skills in early and middle childhood

Inhibitory control skills are important for academic outcomes across childhood, but it is unknown whether inhibitory control is implicated in the association between genetic variation and academic performance. This study examined the relationship between a GWAS-based (EduYears) polygenic score indexing educational attainment (EA PGS) and inhibitory control in early (M_age = 3.80 years) and middle childhood (M_age = 9.18 years), and whether inhibitory control in early childhood mediated the relation between EA PGS and academic skills. The sample comprised 731 low-income and racially/ethnically diverse children and their families from the longitudinal early steps multisite study. EA PGS predicted middle childhood inhibitory control (estimate = 0.09, SE = 0.05, p < 0.05) and academic skills (estimate = 0.18, SE = 0.05, p < 0.01) but did not predict early childhood inhibitory control (estimate = 0.08, SE = 0.05, p = 0.11); thus, mediation was not tested. Sensitivity analyses showed that effect sizes were similar across European and African American groups. This study suggests that inhibitory control could serve as a potential mechanism linking genetic differences to educational outcomes.     

Decoupling genetics from attainments: The role of social environments

This paper examines the extent to which growing up in a socially mobile environment might decouple genetic endowments related to educational attainment with actual attainments. Many models of intergenerational transmission of advantage contain both a transmission channel through endowments (i.e. genetics) from parents to children as well as from parental investments and “luck”. Indeed, many scholars consider the intergenerational links due to the transmission of genetically-based advantage to place a lower bound on plausible levels of social mobility—genetics may be able to “lock in” advantage across generations. This paper explores this idea by using genetic measurements in the Health and Retirement Study to examine potential interactions between social environments and genetics related to attainments. The results suggest evidence of gene environment interactions: children born in high mobility states have lower genetic penetrance—the interaction between state-level mobility and the polygenic score for education is negative. These results suggest a need to incorporate gene-environment interactions in models of attainment and mobility and to pursue the mechanisms behind the interactions.     

The impact of early adversity and education on genetic and brain morphological predictors of cognitive ability

Cognitive ability is a strong predictor of occupational achievement, quality of life and physical health. While variation in cognition is strongly heritable and has been robustly associated with early environment and brain morphology, little is known about how these factors combine and interact to explain this variation in cognition. To address this, we modelled the relationship between common genetic variation, grey matter volume, early life adversity and education and cognitive ability in a UK Biobank sample of N = 5237 individuals using structural equation modelling. We tested the hypotheses that total grey matter volume would mediate the association between genetic variation and cognitive ability, and that early life adversity and educational attainment would moderate this relationship. Common genetic variation, grey matter volume and early life adversity were each significant predictors in the model, explaining ~15% of variation in cognitive ability. Contrary to our hypothesis, grey matter volume did not mediate the relation between genetic variation and cognition performance. Neither did early life adversity or educational attainment moderate this relation, although educational attainment was observed to moderate the relationship between grey matter volume and cognitive performance. We interpret these findings in terms of the modest explanatory value of currently estimated polygenic scores accounting for variation in cognitive performance (~5%), making potential mediating and moderating variables difficult to confirm.     

Differential reproduction: Its relation to IQ test score,education, and occupation

Abstract

The correlations among IQ test score, educational attainment rating, socioeconomic status, total number of children in the family of origin, total number of offspring in completed families, and mean age at birth of live‐born children are examined for a representative sample of the Minnesota white population. Natural selection appears to be favoring an increase in the mean IQ score in the sample, or at least there is no evidence for a decrease. The data show positive marital assortment for IQ score and for educational attainment. Four estimates of the heritability of the phenotype “IQ test score” coincide well with each other. The value of h² estimated from parent‐children regression is 0.631; from a weighted regression of children's scores on the score of the father alone, it is 0.668 and on the score of the mother alone, it is 0.654. The estimate from the intra‐class correlation of full siblings is 0.666.     

Ethnicity, sibling, and family correlates of young adults' status attainment: a follow-up study

Longitudinal data were used to examine relationships among sibling variables, perceptions of family environments, and measures of educational attainment, occupational status, and occupational aspirations. The analyses involved 21-year-old Australians from Anglo-Australian, Greek, and Southern Italian families. Regression surfaces were plotted from models that included terms to test for possible linear, interaction, and curvilinear associations among the variables. The study indicated that sibsize and birth order continued to have many significant associations with young adults' status attainment even after taking into account the mediating influence of perceived family environments. Also, the investigation suggested that there are ethnic-group differences in relations among sibling variables, perceived parents' support for learning, and young adults' status attainment.     

Gender,family configuration,and the effect of family background on educational attainment

Abstract

A comprehensive model of family influences on educational resemblance of siblings expands the traditional sibling pair model to a full sibship model in order to investigate how gender, gender composition of sibships, and a measure of ordinal position moderate the effect of social origins on educational attainments of siblings. One common family factor is sufficient to explain the variation of educational attainment among brothers and sisters. Although effects of social origin variables on brothers are larger than on sisters, the relative effects of measured social origins are virtually the same among sisters and brothers. The disparity between educational attainments of brothers and sisters persists across sex composition and family size. Ordinal position does not alter the effects of social origins on educational attainment nor does it directly affect educational attainment. Father's and mother's education are equally important for all siblings regardless of birth order, gender composition, and family size.     

Polygenic score for neuroticism is related to sleep difficulties

Neuroticism, a broad trait measure of the tendency to experience negative emotions and vulnerability to stress, is consistently related to poor sleep quality. Less is known about potential pleiotropy in the genetic risk for high neuroticism and poor sleep. Therefore, the present study examined whether polygenic score (PGS) for neuroticism is related to sleep quality in two large samples of adults. In addition, depressive symptoms, anxiety and phenotypical neuroticism were tested as mediators in both samples. Participants were 8316 individuals aged from 50 to 101 years (mean age = 68.29, SD = 9.83) from the Health and Retirement Study, and 4973 individuals aged from 63 to 67 years (mean age = 64.30, SD = 0.68) from the Wisconsin Longitudinal Study. Participants from both samples were genotyped and answered questions on sleep quality. A higher PGS for neuroticism was related to lower sleep quality concurrently and over time in both samples. Anxiety, depressive symptoms and neuroticism mediated these relationships in the two samples. Although effect sizes were small, the present study provides replicable evidence that individuals with a higher genetic predisposition to experience negative emotions and distress are at risk of sleep difficulties.     

Trends in educational attainment by race/ethnicity,nativity, and sex in the United States, 1989–2005

Despite the importance of education for shaping individuals’ life chances, little research has examined trends and differences in educational attainment for detailed demographic subpopulations in the United States. We use labour market segmentation and cohort replacement theories, linear regression methods, and data from the National Health Interview Survey to understand educational attainment by race/ethnicity, nativity, birth cohort, and sex between 1989 and 2005 in the United States. There have been significant changes in educational attainment over time. In support of the cohort replacement theory, we find that across cohorts, females have enjoyed greater gains in education than men, and for some race/ethnic groups, recent cohorts of women average more years of education than comparable men. And in support of labour market segmentation theories, foreign-born Mexican Americans continue to possess relatively low levels of educational attainment. Our results can aid policymakers in identifying vulnerable populations, and form the base from which to better understand changing disparities in education.     

Genetic Variation Associated with Differential Educational Attainment in Adults Has Anticipated Associations with School Performance in Children

Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10⁻¹⁰) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10⁻⁰⁴ and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.     

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in “complement” function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.     

Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.     

How family,immigrant group,and school contexts shape ethnic educational disparities

Scholars have long questioned why average educational attainments among children of immigrants vary greatly by country of origin. Immigrants’ children from the same country share similar contexts of exit and reception and often similar school and family contexts. What is the relative importance of these factors in explaining ethnic differences in educational attainment? Using cross-classified multi-level models, this study shows that family contexts and immigrant group educational selectivity, but not school contexts, help explain ethnic differences. Immigrant selectivity is more decisive in shaping the second-generation’s educational attainment than other group characteristics related to immigrants’ contexts of exit and reception. While school socioeconomic status (SES) only influences the attainment of immigrants’ children from high-SES families, immigrant group selectivity matters regardless of the SES of the family or school, thus shedding light on why members of some national-origin groups tend to complete more education than others despite similar family and school contexts.     

Performance of Polygenic Scores for Predicting Phobic Anxiety

Context

Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits.

Objective

To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes.

Design

Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort.

Setting and Participants

Study participants (n = 11,127) were individuals from the Nurses'' Health Study and Health Professionals Follow-up Study.

Main Outcome Measure

Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived.

Results

We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety.

Conclusion

There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.     

Trends in Educational Attainment by Race/Ethnicity, Nativity, and Sex in the United States, 1989-2005

Despite the importance of education for shaping individuals' life chances, little research has examined trends and differences in educational attainment for detailed demographic subpopulations in the United States. We use labor market segmentation and cohort replacement theories, linear regression methods, and data from the National Health Interview Survey to understand educational attainment by race/ethnicity, nativity, birth cohort, and sex between 1989 and 2005 in the United States. There have been significant changes in educational attainment over time. In support of the cohort replacement theory, we find that across cohorts, females have enjoyed greater gains in education than men, and for some race/ethnic groups, recent cohorts of women average more years of education than comparable men. And in support of labor market segmentation theories, foreign-born Mexican Americans continue to possess relatively low levels of educational attainment. Our results can aid policymakers in identifying vulnerable populations, and form the base from which to better understand changing disparities in education.     

Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis

BackgroundChronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.ConclusionsGenetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.     

城-镇-乡人口教育差距的演变及影响机制

在城乡一体化的过程中,以平均受教育水平测量的城乡人口教育差距,并没有出现库兹涅茨倒U型发展,乡村、县镇与城市之间的差距都在不断扩大。对近20年间差距演变的过程进行分析表明,乡村和县镇人口平均受教育水平的增长速度始终低于城市,尤其是县镇区域几乎没有增长。通过对主要影响因素及作用机制的理论分析和实证检验,研究发现,经济发展水平的提高并没有促使已经存在的差距自然消弥,城乡两个被分割的群体通过显性渠道与隐性渠道不断地文化教育再生产是差距存在和扩大的社会基础;高中阶段教育投入的增加更多是促进了城镇人口受教育水平的提高,初中阶段教育投入城乡差距的扩大直接导致人口受教育程度差距的扩大,而小学阶段教育投入城乡差距没有显示出统计上显著的影响;非户籍人口流动造成城乡人口结构的异质化,并进而扩大城乡常住人口受教育程度的差距;户籍人口迁入对城市和县镇人口受教育程度都有提升作用,迁出在抵消迁入的提升作用后,仍然导致城市与县镇之间教育差距的扩大。