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Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Background Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. Objectives To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. Design This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. Setting This took place in UK general practice. Participants Participants were pregnant women with depression. Interventions The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. Main outcome measures The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. Data sources UK Clinical Practice Research Datalink. Results Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Limitations Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Conclusions Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Future work Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information. Plain language summary About one in seven women experience depression during pregnancy. Left untreated, this may harm them and their unborn babies. However, the decision to take antidepressants during pregnancy is difficult because women often worry about the risks to their unborn baby. Research findings have been inconsistent, so women often do not have clear information to enable them to make informed decisions. We studied women’s and children’s outcomes after starting (compared with not starting) or continuing (compared with stopping) antidepressants in pregnancy. We used a large UK primary care database and several novel methods of analysis. We tracked 80,103 pregnancies of women with depression for up to 2 years after pregnancy. We also tracked 34,274 children from these pregnancies for at least 4 years to check for developmental outcomes. Women prescribed antidepressants were more likely than women not prescribed antidepressants to use general practice and mental health services during and after pregnancy, and to be prescribed antidepressants 2 years after pregnancy. This suggests that antidepressants were being prescribed to women with greater clinical need. Women who continued antidepressants in pregnancy had no higher likelihood than those who discontinued antidepressants of autism, attention deficit hyperactivity disorder or intellectual disability in their children. This should reassure women making the decision to continue taking their medications in pregnancy. Women who started antidepressants in pregnancy may possibly have had a slightly higher likelihood of autism in their children than those who did not start them. These findings were not seen in all analyses and were based on smaller numbers; therefore, they should be viewed with caution. Importantly, over 98 in every 100 children of women who initiated or continued antidepressants in pregnancy did not receive an autism diagnosis. The findings may help women and clinicians make informed decisions on treatment with antidepressants in pregnancy. Scientific summary Background Depression is common in women of childbearing age and up to one in seven women experience depression during pregnancy. Untreated depression may have serious consequences, such as distress, self-neglect and suicidal behaviour, in affected women and birth complications in their babies. Many women with depression may, therefore, encounter a situation in which they need to decide whether to start or continue an antidepressant during their pregnancy; however, the potential for resulting harm to the neurodevelopment of their offspring is a common concern. In the absence of randomised controlled trials, the information available to guide these decisions is based on observational data, which are subject to confounding. Given that maternal depression may itself lead to adverse outcomes, isolating any effect of antidepressants from the underlying depression is particularly difficult: a problem known as confounding by indication. In the absence of randomised trials, studies designed to emulate such trials and using methods to account for confounding may help triangulate results and strengthen causal inference. Objectives This research aimed to simulate two scenarios that could be tested in pregnant women with depression in a hypothetical target randomised controlled trial asking the following research questions: Does the initiation of antidepressants for depression during pregnancy affect maternal service use outcomes and childhood neurodevelopmental outcomes? Does the continuation of antidepressant use during pregnancy for depression affect maternal service use outcomes and childhood neurodevelopmental outcomes? The data were interrogated using several methods of causal inference, and assessed in relation to dose response, timing of exposure and type of antidepressants according to class and their serotonin-receptor affinity. Methods Design: This was an observational cohort design, with use of multiple methods to strengthen causal inference. Setting and participants: This took place in UK general practice. Participants were UK primary care patients, specifically pregnant women with depression. Data sources: This study used data from the Clinical Practice Research Datalink (CPRD), a large ongoing database of anonymised primary care medical records in the UK. The CPRD’s pregnancy register was used to identify the dates and stages of pregnancy, and the CPRD mother–baby link allowed for the linkage of the records of pregnant women with their live born offspring. For consenting CPRD practices in England, the primary care records were linked to Hospital Episode Statistics, which include registers for inpatient admissions, outpatient care and accident and emergency (A&E) attendance in England, and with mortality data from the Office for National Statistics and Census small-area socioeconomic data. Eligible patients: The data extract covered dates between 1 January 1995 and 31 December 2017. Within this time frame, we identified 344,720 pregnancies in the pregnancy register for which there was evidence of depressive symptoms, or prescription of an antidepressant up to 1 year before or during pregnancy. From this sample, we constructed two cohorts: (1) the pregnant women’s cohort, which contained all pregnancies for which women could be followed up for at least 2 years beyond the pregnancy end date, regardless of the pregnancy outcome or ability to link to the child; (2) the mother and child cohort, which consisted of pregnancies followed up at least until delivery that could be linked with the patient records of the children arising from these pregnancies. The pregnant women’s cohort: The exclusion criteria were (1) records for which the general practice was not yet up to standard, as defined by CPRD (n = 61,704); (2) where the patient had not yet registered with her current general practice 1 year prior to conception (n = 93,638); (3) records suggesting that the woman had transferred out of the general practice while still pregnant (n = 15,627); (4) records with

BackgroundFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.MethodsWe meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.ResultsWe identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.ConclusionsThe meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Children born to parents with fewer years of education are more likely to have depression, anxiety, and attention-deficit hyperactivity disorder (ADHD), but it is unclear to what extent these associations are causal. We estimated the effect of parents' educational attainment on children's depressive, anxiety, and ADHD traits at age 8 years, in a sample of 40,879 Norwegian children born in 1998–2009 and their parents. We used within-family Mendelian randomization, which employs genetic variants as instrumental variables, and controlled for direct genetic effects by adjusting for children's polygenic indexes. We found little evidence that mothers' or fathers' educational attainment independently affected children's depressive, anxiety, or ADHD traits. However, children's own polygenic scores for educational attainment were independently and negatively associated with these traits. Results suggest that differences in these traits according to parents' education may reflect direct genetic effects more than genetic nurture. Consequences of social disadvantage for children's mental health may however be more visible in samples with more socioeconomic variation, or contexts with larger socioeconomic disparities than present-day Norway. Further research is required in populations with more educational and economic inequality and in other age groups. [ABSTRACT FROM AUTHOR]

Background Body mass index (BMI) and obesity rates have increased sharply since the 1980s. While multiple epidemiologic studies have found that higher adolescent cognitive ability is associated with lower adult BMI, residual and unobserved confounding due to family background may explain these associations. We used a sibling design to test this association accounting for confounding factors shared within households. Methods and findings We used data from four United States general youth population cohort studies: the National Longitudinal Study of Youth 1979 (NLSY-79), the NLSY-79 Children and Young Adult, the NLSY 1997 (NLSY-97), and the Wisconsin Longitudinal Study (WLS); a total of 12,250 siblings from 5,602 households followed from adolescence up to age 62. We used random effects within-between (REWB) and residualized quantile regression (RQR) models to compare between- and within-family estimates of the association between adolescent cognitive ability and adult BMI (20 to 64 years). In REWB models, moving from the 25th to 75th percentile of adolescent cognitive ability was associated with -0.95 kg/m.sup.2 (95% CI = -1.21, -0.69) lower BMI between families. Adjusting for family socioeconomic position reduced the association to -0.61 kg/m.sup.2 (-0.90, -0.33). However, within families, the association was just -0.06 kg/m.sup.2 (-0.35, 0.23). This pattern of results was found across multiple specifications, including analyses conducted in separate cohorts, models examining age-differences in association, and in RQR models examining the association across the distribution of BMI. Limitations include the possibility that within-family estimates are biased due to measurement error of the exposure, confounding via non-shared factors, and carryover effects. Conclusions The association between high adolescent cognitive ability and low adult BMI was substantially smaller in within-family compared with between-family analysis. The well-replicated associations between cognitive ability and subsequent BMI may largely reflect confounding by family background factors., Author(s): Liam Wright 1,*, Neil M. Davies 2,3,4,5, David Bann 1 Introduction Obesity rates have increased dramatically across developed countries since the 1980s [1], with significant consequences for public health [...]

Value-added measures of educational progress have been used by education researchers and policy-makers to assess the performance of teachers and schools, contributing to performance-related pay and position in school league tables. They are designed to control for all underlying differences between pupils and should therefore provide unbiased measures of school and teacher influence on pupil progress, however, their effectiveness has been questioned. We exploit genetic data from a UK birth cohort to investigate how successfully value-added measures control for genetic differences between pupils. We use raw value-added, contextual value-added (which additionally controls for background characteristics) and teacher-reported value-added measures built from data at ages 11, 14 and 16. Sample sizes for analyses range from 4,600 to 6,518. Our findings demonstrate that genetic differences between pupils explain little variation in raw value-added measures but explain up to 20% of the variation in contextual value-added measures (95% CI = 6.06% to 35.71%). Value-added measures built from teacher-rated ability have a greater proportion of variance explained by genetic differences between pupils, with 36.3% of their cross-sectional variation being statistically accounted for by genetics (95% CI = 22.8% to 49.8%). By contrast, a far greater proportion of variance is explained by genetic differences for raw test scores at each age of at least 47.3% (95% CI: 35.9 to 58.7). These findings provide evidence that value-added measures of educational progress can be influenced by genetic differences between pupils, and therefore may provide a biased measure of school and teacher performance. We include a glossary of genetic terms for educational researchers interested in the use of genetic data in educational research.

Research at the intersection of social science and genomics, 'sociogenomics', is transforming our understanding of the interplay between genomics, individual outcomes and society. It has interesting and maybe unexpected implications for education research and policy. Here we review the growing sociogenomics literature and discuss its implications for educational researchers and policymakers. We cover key concepts and methods in genomic research into educational outcomes, how genomic data can be used to investigate social or environmental effects, the methodological strengths and limitations of genomic data relative to other observational social data, the role of intergenerational transmission and potential policy implications. The increasing availability of genomic data in studies can produce a wealth of new evidence for education research. This may provide opportunities for disentangling the environmental and genomic factors that influence educational outcomes and identifying potential mechanisms for intervention. [ABSTRACT FROM AUTHOR]

Objective: To examine antiseizure medication (ASM) prescription during pregnancy. Design: Population‐based drug utilisation study. Setting: UK primary and secondary care data, 1995–2018, from the Clinical Practice Research Datalink GOLD version. Population or Sample: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. Methods: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. Main Outcome Measures: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. Results: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non‐epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. Conclusions: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics. [ABSTRACT FROM AUTHOR]

We estimated the effects of an intervention which provided information about graduate wages to 5593 students in England, using a blinded cluster randomised controlled trial in 50 schools (registration: AEARCTR-0000468). Our primary outcome was students' choice of A-level subjects at age 16. We also recorded the students' expectations of future wages and the A-level subjects they intended to take before and after the intervention, and linked their data into national administrative school examination records. We found that an hour-long lesson on information about graduate wages affected students' beliefs about and choice of subject. They were more likely to take mathematics and less likely to take biology and computing. We found strong evidence that mediating factors such as their beliefs about average graduate salaries and their own likely salary in each subject were affected by the intervention. This suggests that providing accessible and credible information on labour market consequences of school choices may influence students' decisions. In the light of concerns about the quality of careers guidance for school students and expectations that educational choices should be well-informed, the study has clear implications for policy and practice.