Showing papers by "Debbie A Lawlor published in 2018"

Exploring the association of genetic factors with participation in the Avon Longitudinal Study of Parents and Children

Abstract: Background It is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation. Methods Using data on mothers (N = 7486) and children (N = 7508) from the Avon Longitudinal Study of Parents and Children, we: (i) examined the association of polygenic risk scores for a range of sociodemographic and lifestyle characteristics and health conditions related to continued participation; (ii) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a subsample who participated in a recent follow-up; and (iii) determined the proportion of variation in participation explained by common genetic variants, using genome-wide data. Results We found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation; and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, attention-deficit hyperactivity disorder (ADHD) and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data [odds ratio (OR) for ever smoking per standard deviation (SD) increase in polygenic score: 0.85, 95% confidence interval (CI): 0.81, 0.89} and subsample (OR: 0.96, 95% CI: 0.89, 1.03). In genome-wide analysis, single nucleotide polymorphism based heritability explained 18–32% of variability in participation. Conclusions Genetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract: Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Improving the accuracy of two-sample summary data Mendelian randomization: moving beyond the NOME assumption

Abstract: Two-sample summary data Mendelian randomization (MR) incorporating multiple genetic variants in a meta-analysis framework is a popular technique for assessing causality in epidemiology. If all genetic variants satisfy the instrumental variable (IV) assumptions, then their individual causal ratio estimates should be homogeneous. Observed heterogeneity, therefore, supports the notion that a portion of variants violate the IV assumptions due to pleiotropy. Model fitting and heterogeneity assessment in MR requires an approximation for the variance of each ratio estimate. We show that the most popular approximation can lead to an inflation in the chances of detecting heterogeneity when in fact it is not present. Conversely, an ostensibly more accurate approximation can dramatically increase the chances of failing to detect heterogeneity, when it is truly present. Here we derive a ‘modified 2nd order’ approximation to the variance that makes use of the derived causal estimate to mitigate both of these adverse effects. Using Monte Carlo simulations, we show that the modified 2nd order approximation outperforms both its 1st and 2nd order counterparts in the presence of weak instruments or a large causal effect. We illustrate the utility of the new method using data from a recent two-sample summary data MR analysis to assess the causal role of systolic blood pressure on coronary heart disease risk. Modified 2nd order weighting should be used as standard within two-sample summary data MR studies for model fitting, the quantification of heterogeneity and the detection of outliers. R code is provided to apply these weights in practice.

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Metabolic characterization of menopause: cross-sectional and longitudinal evidence

Abstract: Women who experience menopause are at higher cardiometabolic risk and often display adverse changes in metabolic biomarkers compared with pre-menopausal women It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging Well-conducted longitudinal studies are required to determine this The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status, defined according to the 2012 Stages of Reproductive Aging Workshop criteria, with 74 metabolic biomarkers, and establish whether any associations are independent of age-related changes We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women In a subgroup of 1,492 women who had repeat assessments after 25 years, we assessed how the change in reproductive status was associated with the changes in metabolic biomarkers Metabolic profiles were measured by high-throughput quantitative nuclear magnetic resonance metabolomics In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive-status category change to that of the reference of being pre-menopausal at both time points As all women aged by a similar amount during follow-up, these analyses contribute to distinguishing age-related changes from those related to change in reproductive status Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting the transition to menopause induces multiple metabolic changes independent of chronological aging The metabolic changes included increased concentrations of very small very low-density lipoproteins, intermediate-density lipoproteins, low-density lipoproteins (LDLs), remnant, and LDL cholesterol, and reduced LDL particle size, all toward an atherogenic lipoprotein profile Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein Also, levels of glutamine and albumin increased during the transition Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years The transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory The adverse changes in multiple apolipoprotein-B-containing lipoprotein subclasses and increased inflammation may underlie women’s increased cardiometabolic risk in their post-menopausal years

Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania

Abstract: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4–17.4) for underweight women, 14.5 kg (11.5–17.7) for normal weight women, 13.9 kg (10.1–17.9) for overweight women, and 11.2 kg (7.0–15.7), 8.7 kg (4.3–13.4) and 6.3 kg (1.9–11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment

Abstract: Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To asse...

Prevalence of Prenatal Depression Symptoms Among 2 Generations of Pregnant Mothers: The Avon Longitudinal Study of Parents and Children.

Abstract: Importance Depression during pregnancy (prenatal depression) is common and has important consequences for mother and child. Evidence suggests an increasing prevalence of depression, especially in young women. It is unknown whether this is reflected in an increasing prevalence of prenatal depression. Objective To compare the prevalence of depression during pregnancy in today’s young mothers with their mothers’ generation. Design, Setting, and Participants In a longitudinal cohort study, we compared prenatal depressive symptoms in 2 generations of women who participated in the Avon Longitudinal Study of Parents and Children. Participants were the original mothers (recruited when they were pregnant) and their female offspring, or female partners of male offspring, who became pregnant. Both groups were limited to the same age range (19-24 years). The first generation of pregnancies occurred in 1990 to 1992 (n = 2390) and the second in 2012 to 2016 (n = 180). In both generations, women were born in the same geographical area (southwest England). Main Outcomes and Measures Depressed mood measured prenatally using the Edinburgh Postnatal Depression Scale in self-reported surveys in both generations. A score of 13 or greater on a scale of 0 to 30 indicated depressed mood. Results Of 2390 pregnant women in the first generation who were included in analysis (mean [SD] age, 22.1 [2.5] years), 408 (17%) had high depressive symptom scores (≥13). Of 180 pregnant women in the second generation who were included in the analysis (mean [SD] age, 22.8 [1.3] years), 45 (25%) had high depressive symptom scores. Having high depressive symptom scores was more common in the second generation of young pregnant women than in their mothers’ generation (relative risk, 1.51; 95% CI, 1.15-1.97), with imputation for missing confounding variable data and adjustment for age, parity, education, smoking, and body mass index not substantially changing this difference. Results were essentially the same when analyses were restricted to the 66 mother-offspring pairs. Maternal prenatal depression was associated with daughters’ prenatal depression (relative risk, 3.33; 95% CI, 1.65-6.67). Conclusions and Relevance In this unique study of 2 generations of women who answered identical questionnaires in pregnancy, evidence was found that depressed mood may be higher in young pregnant women today than in their mothers’ generation. Because of the multiple and diverse consequences of prenatal depression, an increase in prevalence has important implications for families, health care professionals, and society.

Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses

Abstract: Background: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages—nor with deta...

Roles of mothers and fathers in supporting child physical activity: a cross-sectional mixed-methods study.

Abstract: Objectives Examine the extent that parent gender is associated with supporting children’s physical activity. Design Cross-sectional mixed-methods study. Setting 47 primary schools located in Bristol (UK). Participants 944 children aged 8–9 years and one of their parents provided quantitative data; 51 parents (20 fathers) were interviewed. Methods Children wore an accelerometer, and mean minutes of moderate-to-vigorous physical activity (MVPA) per day, counts per minute (CPM) and achievement of national MVPA guidelines were derived. Parents reported who leads in supporting child activity during the week and weekend. Linear and logistic regression examined the association between gender of parent who supports child activity and child physical activity. For the semistructured telephone interviews, inductive and deductive content analyses were used to explore the role of gender in how parents support child activity. Results Parents appeared to have a stronger role in supporting boys to be more active, than girls, and the strongest associations were when they reported that both parents had equal roles in supporting their child. For example, compared with the reference of female/mother support, equal contribution from both parents during the week was associated with boys doing 5.9 (95% CI 1.2 to 10.6) more minutes of MVPA per day and more CPM when both parents support on weekday and weekends (55.1 (14.3 to 95.9) and 52.8 (1.8 to 103.7), respectively). Associations in girls were weaker and sometimes in the opposite direction, but there was no strong statistical evidence for gender interactions. Themes emerged from the qualitative data, specifically; parents proactively supporting physical activity equally, mothers supporting during the week, families getting together at weekends, families doing activities separately due to preferences and parents using activities to bond one-to-one with children. Conclusions Mothers primarily support child activity during the week. Children, possibly more so boys, are more active if both parents share the supporting role.

Gestational diabetes and ultrasound-assessed fetal growth in South Asian and White European women: findings from a prospective pregnancy cohort

Abstract: Maternal gestational diabetes (GDM) is an established risk factor for large size at birth, but its influence on intrauterine fetal growth in different ethnic populations is less well understood. Here, we examine the joint associations of GDM and ethnicity with longitudinal fetal growth in South Asian and White European origin women. This study included 10,705 singletons (4747 White European and 5958 South Asian) from a prospective cohort of women attending an antenatal clinic in Bradford, in the North of England. All women completed a 75-g oral glucose tolerance test at 26–28 weeks’ gestation. Ultrasound measurements of fetal head circumference (HC), femur length (FL) abdominal circumference (AC), and estimated fetal weight (EFW), and corresponding anthropometric measurements at birth were used to derive fetal growth trajectories. Associations of GDM and ethnicity with these trajectories were assessed using multilevel fractional polynomial models. Eight hundred thirty-two pregnancies (7.8%) were affected by GDM: 10.4% of South Asians and 4.4% of White Europeans. GDM was associated with a smaller fetal size in early pregnancy [differences (95% CI) in mean HC at 12 weeks and mean AC and EFW at 16 weeks comparing fetuses exposed to GDM to fetuses unexposed (reference) = − 1.8 mm (− 2.6; − 1.0), − 1.7 mm (− 2.5; − 0.9), and − 6 g (− 10; − 2)] and a greater fetal size from 24 weeks’ gestation through to term [differences (95% CI) in mean HC, AC, and EFW comparing fetuses exposed to GDM to those unexposed = 0.9 mm (0.3; 1.4), 0.9 mm (0.2; 1.7), and 7 g (0; 13) at 24 weeks]. Associations of GDM with fetal growth were of similar magnitude in both ethnic groups. Growth trajectories, however, differed by ethnicity with South Asians being smaller than White Europeans irrespective of GDM status. Consequently, South Asian fetuses exposed to GDM were smaller across gestation than fetuses of White Europeans without GDM. In both ethnic groups, GDM is associated with early fetal size deviations prior to GDM diagnosis, highlighting the need for novel strategies to diagnose pregnancy hyperglycemia earlier than current methods. Our findings also suggest that ethnic-specific fetal growth criteria are important in identifying hyperglycemia-associated pathological effects.

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.

Abstract: OBJECTIVE: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's Disease (PD), but these studies were not designed to test causality If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk METHODS: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study dataset which included 13,708 PD cases and 95,282 controls Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method Two additional methods, MR-Egger and a penalized weighted median based (PWM) approach, were used to assess potential bias due to pleiotropy or invalid instruments RESULTS: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of OR 103 (95% CI 088-120) per 1 SD increase in plasma urate levels MR Egger and PWM analyses yielded similar estimates (OR 099 [95% CI 083-117] and 099 [95% CI 086-114], respectively) INTERPRETATION: We do not find evidence for a linear causal protective effect by urate on PD risk The associations observed in previous observational studies may be in part due to confounding or reverse causality In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk

Maternal thyroid function and child educational attainment: Prospective cohort study

Abstract: Objective To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design Prospective cohort study. Setting Avon Longitudinal Study of Parents and Children cohort in the UK. Participants 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement.

Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization

Abstract: Consumption of coffee, tea and alcohol might be shaped by individual differences in bitter taste perception but inconsistent observational findings provide little insight regarding causality. We conducted Mendelian randomization analyses using genetic variants associated with the perception of bitter substances (rs1726866 for propylthiouracil [PROP], rs10772420 for quinine and rs2597979 for caffeine) to evaluate the intake of coffee, tea and alcohol among up to 438,870 UK Biobank participants. A standard deviation (SD) higher in genetically predicted bitterness of caffeine was associated with increased coffee intake (0.146 [95%CI: 0.103, 0.189] cups/day), whereas a SD higher in those of PROP and quinine was associated with decreased coffee intake (-0.021 [-0.031, -0.011] and -0.081 [-0.108, -0.054] cups/day respectively). Higher caffeine perception was also associated with increased risk of being a heavy (>4 cups/day) coffee drinker (OR 1.207 [1.126, 1.294]). Opposite pattern of associations was observed for tea possibly due to the inverse relationship between both beverages. Alcohol intake was only negatively associated with PROP perception (-0.141 [-1.88, -0.94] times/month per SD increase in PROP bitterness). Our results reveal that bitter perception is causally associated with intake of coffee, tea and alcohol, suggesting a role of bitter taste in the development of bitter beverage consumption.

Profiles of children’s physical activity and sedentary behaviour between age 6 and 9: a latent profile and transition analysis

Abstract: Physical activity is associated with improved physical and mental health among children. However, physical activity declines and sedentary time increases with age, and large proportions of older children do not meet the recommended hour per day of moderate-to-vigorous-intensity physical activity (MVPA). The aim of this paper is to identify profiles of children based on the complex relationship between physical activity and sedentary time at ages 6 and 9 and explore how those profiles are associated with other covariates and how they change over time. Valid accelerometer data were collected for 1132 children aged 6 and 1121 at age 9, with 565 children with data at both ages. We calculated the proportions of total wear time spent in sedentary, light and MVPA activity on both weekdays and weekends. Latent profile (class) analysis was applied separately to the two age groups to identify activity profiles. We then used latent transition analysis to explore transitions between profiles at the two time points. We identified five profiles of activity at age 6 and six profiles at age 9. Although profiles were not directly equivalent, five classes captured similar patterns at both ages and ranged from very active to inactive. At both ages, active profiles, where the majority achieved the recommended MVPA guidelines, were more likely to be active at weekends than on weekdays. There was substantial movement between classes, with strongest patterns of movement to classes with no change or a decrease in MVPA. Transition between classes was associated with sex, BMI z-score, screen-viewing and participation in out-of-school activities. This paper is the first to apply latent profile analysis to the physical activity of UK children as they move through primary school. Profiles were identified at ages 6 and 9, reflecting different weekday and weekend patterns of physical activity and sedentary time. There was substantial movement between profiles between ages 6 and 9, mostly to no change or less active profiles. Weekend differences suggest that greater focus on how weekend activity contributes to an average of 60 min per day of MVPA across the week may be warranted.

Maternal and fetal genetic contribution to gestational weight gain

Abstract: Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10 â '8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Experiencing menopause in the UK: The interrelated narratives of normality, distress, and transformation

Abstract: We investigated the experience and perspectives of menopause among 48 UK mothers through qualitative in-depth interviews. Interviews were analyzed thematically then explored using social science theories. Three interdependent narratives emerged: menopause as a normal, biological process, distinct from self and social transitions; menopause as struggle, an “idiom of distress” expressing upset, identity loss, shame, and social upheaval; and menopause as transformative and liberating, arising from biopsychic and relational changes. Some women followed a predictable “rite of passage” trajectory with transformation emerging from distress, but not all: Menopause arises from a complex interplay of personal predicament, somatic change, and sociocultural context.

Associations Between Maternal Prepregnancy Body Mass Index and Gestational Weight Gain and Daughter's Age at Menarche: The Avon Longitudinal Study of Parents and Children

Abstract: Earlier puberty and menarche are associated with adverse health outcomes. Reported associations of maternal adiposity with daughter's age at menarche are inconsistent. We examined associations between maternal prepregnancy body mass index (BMI; weight (kg)/height (m)2) and gestational weight gain (GWG) and daughter's ages at menarche (n = 3,935 mother-offspring pairs), pubarche (Tanner stage 2 for pubic hair) (n = 2,942 pairs), and thelarche (Tanner stage 2 for breast development) (n = 2,942 pairs) in the Avon Longitudinal Study of Parents and Children, a prospective United Kingdom pregnancy cohort study (baseline 1991-1992). During a follow-up period of up to 17 years (1991-2008), mean menarcheal age was 12.6 (standard deviation, 1.2) years. Both maternal prepregnancy BMI and GWG were inversely associated with daughter's age at menarche after adjustment for maternal age, parity, socioeconomic status, smoking, maternal menarcheal age, and ethnicity (mean differences were -0.34 months (95% confidence interval: -0.45, -0.22) per BMI unit and -0.17 months (95% confidence interval: -0.26, -0.07) per kg, respectively). Associations remained unchanged after adjustment for birth weight and gestational age but were attenuated to the null when results were adjusted for daughter's prepubertal BMI. Similar results were found for ages at pubarche and thelarche. These findings indicate that greater prepregnancy BMI and GWG are associated with earlier puberty in daughters and that these associations are mediated by daughters' prepubertal BMIs.

Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study

Abstract: Objective To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia. Design One and two sample mendelian randomisation analyses. Setting Two European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study). Participants 7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis. Exposures Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables. Main outcome measures Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy. Results In the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels Conclusions No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X-Ray Absorptiometry-Derived Hip Shape in a Population-Based Cohort of Perimenopausal Women.

Abstract: Objective To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population-based cohort of perimenopausal women in order to investigate whether hip shape contributes to OA development. Methods Hip shape was measured, using statistical shape modeling, on dual x-ray absorptiometry scans of the hip from mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC). The proximal femur and superior acetabulum were outlined, and independent hip shape modes were generated. In a subregional model, points were restricted to the acetabulum and superior femoral head. Associations between 11 OA-related single-nucleotide polymorphisms, identified by literature search, and shape modes were analyzed in a multivariate canonical correlation analysis. Results A total of 3,111 women (mean age 48 years) had genetic and hip shape data. The KLHDC5/PTHLH rs10492367 OA risk allele was associated with a wider upper femur in the whole shape model (P = 1 × 10-5 ). The DOT1L rs12982744 OA risk allele was associated with reduced superior joint space in the subregional shape model (P = 2 × 10-3 ). The COL11A1 rs4907986 OA risk allele was associated with lateral displacement of the femoral head relative to the acetabulum in the subregional shape model (P = 5 × 10-4 ). Regional association plots identified an additional COL11A1 locus in moderate linkage disequilibrium with rs4907986, which was more strongly associated with hip shape (rs10047217; P = 3 × 10-6 ). Colocalization analysis indicated sharing of genetic signals for hip shape and hip OA for the KLHDC5/PTHLH and COL11A1 loci. Conclusion Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet-to-be-identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.

GWAS in 446,118 European adults identifies 78 genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

Abstract: Sleep is an essential homeostatically-regulated state of decreased activity and alertness conserved across animal species, and both short and long sleep duration associate with chronic disease and all-cause mortality. Defining genetic contributions to sleep duration could point to regulatory mechanisms and clarify causal disease relationships. Through genome-wide association analyses in 446,118 participants of European ancestry from the UK Biobank, we discover 78 loci for self-reported sleep duration that further impact accelerometer-derived measures of sleep duration, daytime inactivity duration, sleep efficiency and number of sleep bouts in a subgroup (n=85,499) with up to 7-day accelerometry. Associations are enriched for genes expressed in several brain regions, and for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission, catecholamine production, synaptic plasticity, and unsaturated fatty acid metabolism. Genetic correlation analysis indicates shared biological links between sleep duration and psychiatric, cognitive, anthropometric and metabolic traits and Mendelian randomization highlights a causal link of longer sleep with schizophrenia.

Association of Genetic Instrumental Variables for Lung Function on Coronary Artery Disease Risk: A 2-Sample Mendelian Randomization Study.

Abstract: Background: Lung function, assessed by forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC), is inversely associated with coronary artery disease (CAD), but these associations could be because of confounding or reversed causality. We conducted a 2-sample Mendelian randomization study, using publicly available data from relevant genome-wide association studies, to examine the role of FEV 1 or FVC on CAD. Methods: We used the most recent genome-wide association studies on lung function to extract genetic instruments related to FEV 1 and FVC (n=92 749). Data on the association between genetic instruments and CAD were obtained from Coronary Artery Disease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics 1000 Genomes-based genome-wide association studies (60 801 CAD cases and 123 504 controls). We used inverse-variance weighting with a multiplicative random effect to estimate the genetic instrumented association of FEV 1 and FVC on CAD. Sensitivity analyses included weighted median and MR-Egger methods. Results: Each SD greater FEV 1 was associated with a lower risk of CAD (odds ratio, 0.78 per SD; 95% confidence interval, 0.62–0.98) with a similar magnitude for FVC on CAD risk (odds ratio, 0.82 per SD; 95% confidence interval, 0.64–1.06). Estimates for FEV 1 were similar when using MR-Egger method (odds ratio, 0.80 per SD; 95% confidence interval, 0.33–1.94) although the magnitude was smaller for weighted median method (odds ratio, 0.93 per SD; 95% confidence interval, 0.75–1.17). Estimates for FVC in the sensitivity analyses were attenuated (median) or changed direction (MR-Egger). Conclusions: Our study suggested an inverse relation between FEV 1 and CAD, but for FVC, evidence is less clear.