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1.  Personality, Behavior and Environmental Features Associated with OXTR Genetic Variants in British Mothers 
PLoS ONE  2014;9(3):e90465.
Background
It is assumed that the oxytocin receptor gene (OXTR) is associated with factors that are related to features of reproduction as well as the currently emerging fields of mood and emotional response.
Methods
We analysed data from over 8000 mothers who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). We determined reproductive, emotional and personality differences related to the two SNPs rs53576 and rs2254298 of the oxytocin receptor gene to determine whether there was evidence in this population for: (i) associations with emotional and personality differences, and (ii) behavioural or environmental links with these SNPs using a hypothesis free approach with over 1000 types of exposure.
Results
Our analyses of 7723 women showed that there were no differences in 11 mood, social or relationship characteristics associated with the rs2254298, and just one with rs53576 (with emotional loneliness) – one statistically significant out of 22 tests is no more than would be expected by chance. There were no interactions with childhood abuse. Using a hypothesis-free approach we found few indicators of environmental or behavioural differences associated with rs2254298, but there was an excess of associations with eating habits with rs53576. The findings included an association with dieting to lose weight, and habits typical of bulimia for the women with GG. The nutrition of the women also showed negative associations of the GG genotype with 13 nutrients, including vitamins D, B12 and retinol, and intake of calcium, potassium and iodine.
Conclusions
We conclude that this large database of pregnant women was unable to provide confirmation of the types of personality associated with these two OXTR SNPs, but we have shown some evidence of eating differences in those with GG on rs53576. Confirmation of our hypothesis free associations using other data sets is important.
doi:10.1371/journal.pone.0090465
PMCID: PMC3951216  PMID: 24621820
2.  Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence 
Molecular Autism  2014;5:18.
Background
Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
Methods
Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).
Results
GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007).
Conclusions
Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.
doi:10.1186/2040-2392-5-18
PMCID: PMC3940728  PMID: 24564958
ALSPAC; ASD; Autism; GCTA heritability; GWAS; Social communication
3.  Is the Growth of the Fetus of a Non-Smoking Mother Influenced by the Smoking of Either Grandmother while Pregnant? 
PLoS ONE  2014;9(2):e86781.
Background
There are animal data that indicate that prenatal environmental exposures have sex-specific effects on subsequent generations. In humans, an increase in birthweight has been reported if the maternal grandmother had smoked in the pregnancy giving rise to the mother. Here we assess whether prenatal exposure of either parent to cigarette smoke has a sex-specific effect on the grandchild's birth measurements.
Methods
Information from 12707 maternal and 9677 paternal grandmothers of children in the Avon Longitudinal Study of Parents and Children (ALSPAC) concerned whether they had smoked while expecting the study parent. Study children were weighed and measured at birth. Analyses to test effects of grandmaternal prenatal smoking used multiple regression allowing for several potential confounders; analyses were restricted to births to non-smoking study mothers.
Findings
After adjustment, the average birthweight, birth length and BMI measurements of the grandsons (but not granddaughters) were greater if the maternal grandmother smoked prenatally: birthweight  = +61 [95% CI +30, +92] g; birth length  = +0·19 [95% CI +0·02, +0·35] cm; BMI  = +1·6 [95% CI +0·6, +2·6] g/m2. Similar effects were seen in births to primiparae and multiparae. Additional allowance for maternal birthweight resulted in an average increase in boys to +100 g [95% CI +61, +140] g. There were no fetal growth differences if the paternal grandmother had smoked prenatally.
Conclusions
The evidence from this study suggests that when the mother does not smoke in pregnancy the maternal grandmother's smoking habit in pregnancy has a positive association with her grandson's fetal growth.
doi:10.1371/journal.pone.0086781
PMCID: PMC3913581  PMID: 24504157
4.  Glue Ear, Hearing Loss and IQ: An Association Moderated by the Child’s Home Environment 
PLoS ONE  2014;9(2):e87021.
Background
Glue ear or otitis media with effusion (OME) is common in children and may be associated with hearing loss (HL). For most children it has no long lasting effects on cognitive development but it is unclear whether there are subgroups at higher risk of sequelae.
Objectives
To examine the association between a score comprising the number of times a child had OME and HL (OME/HL score) in the first four/five years of life and IQ at age 4 and 8. To examine whether any association between OME/HL and IQ is moderated by socioeconomic, child or family factors.
Methods
Prospective, longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). 1155 children tested using tympanometry on up to nine occasions and hearing for speech (word recognition) on up to three occasions between age 8 months and 5 years. An OME/HL score was created and associations with IQ at ages 4 and 8 were examined. Potential moderators included a measure of the child’s cognitive stimulation at home (HOME score).
Results
For the whole sample at age 4 the group with the highest 10% OME/HL scores had performance IQ 5 points lower [95% CI −9, −1] and verbal IQ 6 points lower [95% CI −10, −3] than the unaffected group. By age 8 the evidence for group differences was weak. There were significant interactions between OME/HL and the HOME score: those with high OME/HL scores and low 18 month HOME scores had lower IQ at age 4 and 8 than those with high OME/HL scores and high HOME scores. Adjusted mean differences ranged from 5 to 8 IQ points at age 4 and 8.
Conclusions
The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss.
doi:10.1371/journal.pone.0087021
PMCID: PMC3911938  PMID: 24498289
6.  Effect of Prenatal Alcohol Exposure on Childhood Academic Outcomes: Contrasting Maternal and Paternal Associations in the ALSPAC Study 
PLoS ONE  2013;8(10):e74844.
Background
The impact of low-to-moderate levels of alcohol consumption during pregnancy on child cognitive outcomes has been of recent concern. This study has tested the hypothesis that low-to-moderate maternal alcohol use in pregnancy is associated with lower school test scores at age 11 in the offspring via intrauterine mechanisms.
Methods
We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort study based in the South West of England. Analyses were conducted on 7062 participants who had complete data on: maternal and paternal patterns of alcohol use in the first trimester and at 18 weeks' gestation, child's academic outcomes measured at age 11, gender, maternal age, parity, marital status, ethnicity, household crowding, home ownership status and parental education. We contrasted the association of mother's alcohol consumption during pregnancy with child's National Curriculum Key Stage 2 (KS2) test scores with the association for father's alcohol consumption (during the time the mother was pregnant) with child's National Curriculum Key Stage 2 (KS2) test scores. We used multivariate linear regression to estimate mean differences and 95% confidence intervals [CI] in KS2 scores across the exposure categories and computed f statistics to compare maternal and paternal associations.
Findings and conclusions
Drinking up to 1 unit of alcohol a day during pregnancy was not associated with lower test scores. However, frequent prenatal consumption of 4 units (equivalent to 32 grams of alcohol) on each single drinking occasion was associated with reduced educational attainment [Mean change in offspring KS2 score was −0.68 (−1.03, −0.33) for maternal alcohol categories compared to 0.27 (0.07, 0.46) for paternal alcohol categories]. Frequent consumption of 4 units of alcohol during pregnancy may adversely affect childhood academic outcomes via intrauterine mechanisms.
doi:10.1371/journal.pone.0074844
PMCID: PMC3794033  PMID: 24130672
7.  Dietary Predictors of Maternal Prenatal Blood Mercury Levels in the ALSPAC Birth Cohort Study 
Environmental Health Perspectives  2013;121(10):1214-1218.
Background: Very high levels of prenatal maternal mercury have adverse effects on the developing fetal brain. It has been suggested that all possible sources of mercury should be avoided. However, although seafood is a known source of mercury, little is known about other dietary components that contribute to the overall levels of blood mercury.
Objective: Our goal was to quantify the contribution of components of maternal diet to prenatal blood mercury level.
Methods: Whole blood samples and information on diet and sociodemographic factors were collected from pregnant women (n = 4,484) enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). The blood samples were assayed for total mercury using inductively coupled plasma dynamic reaction cell mass spectrometry. Linear regression was used to estimate the relative contributions of 103 dietary variables and 6 sociodemographic characteristics to whole blood total mercury levels (TBM; untransformed and log-transformed) based on R2 values.
Results: We estimated that maternal diet accounted for 19.8% of the total variation in ln-TBM, with 44% of diet-associated variability (8.75% of the total variation) associated with seafood consumption (white fish, oily fish, and shellfish). Other dietary components positively associated with TBM included wine and herbal teas, and components with significant negative associations included white bread, meat pies or pasties, and french fries.
Conclusions: Although seafood is a source of dietary mercury, seafood appeared to explain a relatively small proportion of the variation in TBM in our UK study population. Our findings require confirmation, but suggest that limiting seafood intake during pregnancy may have a limited impact on prenatal blood mercury levels.
Citation: Golding J, Steer CD, Hibbeln JR, Emmett PM, Lowery T, Jones R. 2013. Dietary predictors of maternal prenatal blood mercury levels in the ALSPAC birth cohort study. Environ Health Perspect 121:1214–1218; http://dx.doi.org/10.1289/ehp.1206115
doi:10.1289/ehp.1206115
PMCID: PMC3801454  PMID: 23811414
8.  Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment 
Background There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance.
Methods We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring’s IQ score had been assessed in clinic (N = 4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N = 6268), contributed to the analyses.
Results Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers’ genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification.
Conclusions Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
doi:10.1093/ije/dyt172
PMCID: PMC3807618  PMID: 24065783
Alcohol dehydrogenase; causality; cognition; confounding factors; educational measurement; ethanol; Mendelian randomization analysis; pregnancy
9.  Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case–control study 
BMC Pediatrics  2013;13:147.
Background
To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months.
Method
Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty-three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old.
Results
None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case–control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041).
Conclusions
JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention.
doi:10.1186/1471-2431-13-147
PMCID: PMC3848970  PMID: 24063312
Avon longitudinal study of parents and children (ALSPAC), Autism, Attention deficit hyperactivity disorder (ADHD), Disruptive behaviour disorders, Joint attention behaviours
10.  Common variation contributes to the genetic architecture of social communication traits 
Molecular Autism  2013;4:34.
Background
Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype.
Methods
We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364).
Results
Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009
Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027).
Conclusion
Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
doi:10.1186/2040-2392-4-34
PMCID: PMC3853437  PMID: 24047820
ALSPAC; RAINE; Autistic trait; GWAS; Social communication; Association
PLoS ONE  2013;8(9):e72371.
Background
Lead is a widespread environmental toxin. The behaviour and academic performance of children can be adversely affected even at low blood lead levels (BLL) of 5–10 µg/dl. An important contribution to the infant's lead load is provided by maternal transfer during pregnancy.
Objectives
Our aim was to determine BLL in a large cohort of pregnant women in the UK and to identify the factors that contribute to BLL in pregnant women.
Methods
Pregnant women resident in the Avon area of the UK were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) in 1991–1992. Whole blood samples were collected at median gestational age of 11 weeks and analysed by inductively coupled plasma dynamic reaction cell mass spectrometry (n = 4285). Self-completion postal questionnaires were used to collect data during pregnancy on lifestyle, diet and other environmental exposures. Statistical analysis was carried out with SPSS v19.
Results
The mean±SD BLL was 3.67±1.47 (median 3.41, range 0.41–19.14) µg/dl. Higher educational qualification was found to be one of the strongest independent predictor of BLL in an adjusted backwards stepwise logistic regression to predict maternal BLL <5 or ≥5 µg/dl (odds ratio 1.26, 95% confidence interval 1.12–1.42; p<0.001). Other predictive factors included cigarette smoking, alcohol and coffee drinking, and heating the home with a coal fire, with some evidence for iron and calcium intake having protective effects.
Conclusion
The mean BLL in this group of pregnant women is higher than has been found in similar populations in developed countries. The finding that high education attainment was independently associated with higher BLL was unexpected and currently unexplained. Reduction in maternal lead levels can best be undertaken by reducing intake of the social drugs cigarettes, alcohol and caffeine, although further investigation of the effect of calcium on lead levels is needed.
doi:10.1371/journal.pone.0072371
PMCID: PMC3764234  PMID: 24039753
PLoS ONE  2013;8(7):e67671.
Background
Little is known about relationships between dietary patterns, n-3 polyunsaturated fatty acids (PUFA) intake and excessive anxiety during pregnancy.
Objective
To examine whether dietary patterns and n-3 PUFA intake from seafood are associated with high levels of anxiety during pregnancy.
Design
Pregnant women enrolled from 1991–1992 in ALSPAC (n 9,530). Dietary patterns were established from a food frequency questionnaire using principal component analysis. Total intake of n-3 PUFA (grams/week) from seafood was also examined. Symptoms of anxiety were measured at 32 weeks of gestation with the Crown-Crisp Experiential Index; scores ≥9 corresponding to the 85th percentile was defined as high anxiety symptoms. Multivariate logistic regression models were used to estimate the OR and 95% CI, adjusted by socioeconomic and lifestyle variables.
Results
Multivariate results showed that women in the highest tertile of the health-conscious (OR 0.77; 0.65–0.93) and the traditional (OR 0.84; 0.73–0.97) pattern scores were less likely to report high levels of anxiety symptoms. Women in the highest tertile of the vegetarian pattern score (OR 1.25; 1.08–1.44) were more likely to have high levels of anxiety, as well as those with no n-3 PUFA intake from seafood (OR 1.53; 1.25–1.87) when compared with those with intake of >1.5 grams/week.
Conclusions
The present study provides evidence of a relationship between dietary patterns, fish intake or n-3 PUFA intake from seafood and symptoms of anxiety in pregnancy, and suggests that dietary interventions could be used to reduce high anxiety symptoms during pregnancy.
doi:10.1371/journal.pone.0067671
PMCID: PMC3710017  PMID: 23874437
Ear wax type and axillary odor are genetically determined by rs17822931, a Single Nucleotide Polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in East Asians. Influence on deodorant usage has not been investigated. In this work we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N~17,000 individuals) population cohort (The Avon Longitudinal Study of Parents and Children, ALSPAC). We found strong evidence (P=3.7×10−20) indicating differential deodorant usage according to rs17822931 genotype. AA homozygotes were almost 5-fold over-represented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically non-odorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence previously unreported of a behavioural effect associated with rs17822931. This effect has a biological basis which can result in a change in the family’s environment if an aerosol deodorant is used. It also indicates potential cost saving to the non-odorous and scope for personalised genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.
doi:10.1038/jid.2012.480
PMCID: PMC3674910  PMID: 23325016
ABCC11 gene; deodorant usage; axillary odor; personalised genetics
Human Molecular Genetics  2011;21(7):1504-1512.
Minor alleles of polymorphisms in the fatty acid desaturase (FADS) gene cluster have been associated with reduced desaturation of the precursor polyunsaturated fatty acids (FAs) in small studies. The effects of these polymorphisms during progressive developmental stages have not previously been reported. Data from blood samples for 4342 pregnant women, 3343 umbilical cords reflecting the newborn's blood supply and 5240 children aged 7 years were analysed to investigate the associations of polyunsaturated FAs with rs1535 and rs174575—two polymorphisms in the FADS2 gene. Strong positive associations were observed between the minor G allele for these two markers, especially rs1535, and the substrates linoleic (18:2n-6) and α-linolenic (18:3n-3) acid. Negative associations were observed for the more highly unsaturated FAs such as arachidonic acid (20:4n-6), timnodonic acid (EPA, 20:5n-3) and cervonic acid (DHA, 22:6n-3). Bivariable genetic associations using the mother and child genotypes suggested that the newborn metabolism had a greater capacity to synthesize the more highly unsaturated omega-6 FAs than the more highly unsaturated omega-3 FAs. Nevertheless, despite the immaturity of the neonate, there was evidence that synthesis of DHA was occurring. However, by 7 years, no associations were observed with the maternal genotype. This suggested that the children's FA levels were related only to their own metabolism with no apparent lasting influences of the in utero environment.
doi:10.1093/hmg/ddr588
PMCID: PMC3465695  PMID: 22194195
PLoS ONE  2012;7(11):e49407.
Background
Observational studies have generated conflicting evidence on the effects of moderate maternal alcohol consumption during pregnancy on offspring cognition mainly reflecting problems of confounding. Among mothers who drink during pregnancy fetal alcohol exposure is influenced not only by mother’s intake but also by genetic variants carried by both the mother and the fetus. Associations between children’s cognitive function and both maternal and child genotype at these loci can shed light on the effects of maternal alcohol consumption on offspring cognitive development.
Methods
We used a large population based study of women recruited during pregnancy to determine whether genetic variants in alcohol metabolising genes in this cohort of women and their children were related to the child’s cognitive score (measured by the Weschler Intelligence Scale) at age 8.
Findings
We found that four genetic variants in alcohol metabolising genes in 4167 children were strongly related to lower IQ at age 8, as was a risk allele score based on these 4 variants. This effect was only seen amongst the offspring of mothers who were moderate drinkers (1–6 units alcohol per week during pregnancy (per allele effect estimates were −1.80 (95% CI = −2.63 to −0.97) p = 0.00002, with no effect among children whose mothers abstained during pregnancy (0.16 (95%CI = −1.05 to 1.36) p = 0.80), p-value for interaction  = 0.009). A further genetic variant associated with alcohol metabolism in mothers was associated with their child’s IQ, but again only among mothers who drank during pregnancy.
doi:10.1371/journal.pone.0049407
PMCID: PMC3498109  PMID: 23166662
BMJ Open  2012;2(4):e001370.
Objectives
To assess whether the prevalence of growing pains varies with indicators of fatty acid exposure. Growing pains (limb pains of no obvious explanation) have been shown to be strongly linked to a family history of arthritis, and are thought to predict an increased risk of the development of arthritis in adulthood. Much has been made of the possibility of fatty acids, particularly the ω-3 fatty acids, playing a preventive role in the development of arthritis, but little research has been undertaken to determine whether such fatty acids might reduce the risk of growing pains. We aimed to assess whether the prevalence of growing pains varies with indicators of fatty acid exposures.
Design
Case–control study nested within a prospective longitudinal cohort comparing prenatal and postnatal diet, blood measures and variants in fatty acid desaturase (FADS) genes that influence the metabolism of fatty acids. Statistical analysis took account of factors such as gender, smoke exposure, maternal age and education, social class and parity.
Setting
Avon Longitudinal Study of Parents & Children.
Participants
All children born between 1 April 1991 and 31 December 1992 (approximately14 000) within the Avon area (only that part of Avon under the South-West Regional Health Authority). This project compared 1676 children who reported ‘growing pains’ at age 8 with 6155 with no such pain.
Primary outcome
Reported limb pains of no apparent origin.
Results
There was no indication that the affected children had diets that differed with regard to ω-3, plasma levels of fatty acids, or the FADS genetic variants. We also assessed fetal and infant exposure but neither maternal prenatal blood levels nor maternal dietary intake, or duration of breast feeding showed any significant relationships even after adjustment for confounders.
Conclusions
Thus, there is no evidence that ω-3 fatty acid status protects against the development of growing pains in childhood.
doi:10.1136/bmjopen-2012-001370
PMCID: PMC3432839  PMID: 22923631
Epidemiology; Genetics; Paediatric clinical genetics & dysmorphology; Nutrition & Dietetics; Orthopaedic & Trauma Surgery; Musculoskeletal disorders; Pain Management
PLoS ONE  2012;7(6):e38893.
Background and Aim
Exposure to stressful life events during pregnancy has been suggested as a potential risk factor for offspring Autism Spectrum Disorders (ASD), but the literature is limited and inconsistent. We tested the hypothesis that maternal exposure to stressful life events would be associated with increased risks of offspring ASD, and that these risks would be highest for exposures during the prenatal period.
Methods and Results
We used prospectively collected data from two large population based studies in Sweden and England. In the Swedish study of 4429 ASD cases and 43277 controls, our exposure comprised the occurrence of any severe life event before and during pregnancy and the child's early life. In the English study (maximum n = 11554, ASD n = 72), we studied the risk of offspring ASD in relation to a combined maternal exposure to multiple (up to 42) common and rare life events, as well as their perceived impact upon the mother during pregnancy and early life. In crude and adjusted regression analyses in both studies, we found no evidence of an association between prenatal life events, or their number and perceived impact and the risk of offspring ASD. Sub-group analysis of ASD with and without intellectual disability in the Swedish study yielded similar results.
Conclusion
We found no evidence to support the hypotheses that exposure to stressful life events during the prenatal period is associated with an increased risk of offspring ASD.
doi:10.1371/journal.pone.0038893
PMCID: PMC3374800  PMID: 22719977
Background
Prenatal loss, the death of a fetus/child through miscarriage or stillbirth, is associated with significant depression and anxiety, particularly in a subsequent pregnancy.
Aims
This study examined the degree to which symptoms of depression and anxiety associated with a previous loss persisted following a subsequent successful pregnancy.
Method
Data were derived from the Avon Longitudinal Study of Parents and Children cohort, a longitudinal cohort study in the west of England that has followed mothers from pregnancy into the postnatal period. A total of 13133 mothers reported on the number and conditions of previous perinatal losses and provided self-report measures of depression and anxiety at 18 and 32 weeks’ gestation and at 8 weeks and 8, 21 and 33 months postnatally. Controls for pregnancy outcome and obstetric and psychosocial factors were included.
Results
Generalised estimating equations indicated that the number of previous miscarriages/stillbirths significantly predicted symptoms of depression (β = 0.18, s.e. = 0.07, P < 0.01) and anxiety (β = 0.14, s.e. = 0.05, P < 0.01) in a subsequent pregnancy, independent of key psychosocial and obstetric factors. This association remained constant across the pre- and postnatal period, indicating that the impact of a previous prenatal loss did not diminish significantly following the birth of a healthy child.
Conclusions
Depression and anxiety associated with a previous prenatal loss shows a persisting pattern that continues after the birth of a subsequent (healthy) child. Interventions targeting women with previous prenatal loss may improve the health outcomes of women and their children.
doi:10.1192/bjp.bp.110.083105
PMCID: PMC3084335  PMID: 21372060
The British Journal of Psychiatry  2011;198(5):373-378.
Background
Prenatal loss, the death of a fetus/child through miscarriage or stillbirth, is associated with significant depression and anxiety, particularly in a subsequent pregnancy.
Aims
This study examined the degree to which symptoms of depression and anxiety associated with a previous loss persisted following a subsequent successful pregnancy.
Method
Data were derived from the Avon Longitudinal Study of Parents and Children cohort, a longitudinal cohort study in the west of England that has followed mothers from pregnancy into the postnatal period. A total of 13 133 mothers reported on the number and conditions of previous perinatal losses and provided self-report measures of depression and anxiety at 18 and 32 weeks’ gestation and at 8 weeks and 8, 21 and 33 months postnatally. Controls for pregnancy outcome and obstetric and psychosocial factors were included.
Results
Generalised estimating equations indicated that the number of previous miscarriages/stillbirths significantly predicted symptoms of depression (β = 0.18, s.e. = 0.07, P<0.01) and anxiety (β = 0.14, s.e. = 0.05, P<0.01) in a subsequent pregnancy, independent of key psychosocial and obstetric factors. This association remained constant across the pre- and postnatal period, indicating that the impact of a previous prenatal loss did not diminish significantly following the birth of a healthy child.
Conclusions
Depression and anxiety associated with a previous prenatal loss shows a persisting pattern that continues after the birth of a subsequent (healthy) child. Interventions targeting women with previous prenatal loss may improve the health outcomes of women and their children.
doi:10.1192/bjp.bp.110.083105
PMCID: PMC3084335  PMID: 21372060
The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enrol pregnant women in the Bristol area of the UK during 1990–92; this was extended to include additional children eligible using the original enrolment definition up to the age of 18 years. The children from 14 541 pregnancies were recruited in 1990–92, increasing to 15 247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks–18 years of age) and 9 clinical assessment visits (7–17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11 343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data.
doi:10.1093/ije/dys064
PMCID: PMC3600618  PMID: 22507743
Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.
doi:10.1093/ije/dys066
PMCID: PMC3600619  PMID: 22507742
Objective
There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors.
Method
Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors.
Results
LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy.
Conclusions
Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5.
doi:10.1016/j.jaac.2011.05.015
PMCID: PMC3163265  PMID: 21871371
social-communication trait; hyperactive-inattentive trait; maternal smoking; teenage pregnancy; ALSPAC
Biological Psychiatry  2011;70(2):152-158.
Background
Apolipoprotein E (APOE) genotype (ε2/ε3/ε4: rs429358 ε4 allele; rs7412 ε2 allele) is strongly associated with both lipid levels and Alzheimer's disease. Although there is also evidence of milder cognitive impairment in later life in carriers of the APOE ε4 allele, there have been few studies investigating the impact of APOE genotype on cognitive function in children.
Methods
We determined APOE genotype in 5995 children from the Avon Longitudinal Study of Parents and Children and investigated associations between APOE genotype and plasma lipids (at age 9), IQ (at age 8), memory (at ages 8 and 10), and performance in school attainment tests (at ages 7, 11, and 14).
Results
Observed genotype group counts were consistent with Hardy–Weinberg equilibrium (χ2p value = .84). There were strong relationships between APOE genotype and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, which follow the same patterns as in adults. There was no strong evidence to suggest that APOE genotype was associated with IQ (all p values ≥ .46), memory function (p ≥ .35), or school attainment test results (p ≥ .28).
Conclusion
Although APOE genotype does have strong associations with lipid levels in childhood, there does not seem to be meaningful effects on cognitive performance, suggesting that any detrimental effects of the ε4 allele on cognitive function are not important until later life.
doi:10.1016/j.biopsych.2010.10.033
PMCID: PMC3130925  PMID: 21215387
APOE; children; cognitive function; IQ; lipids; memory
European Heart Journal  2010;31(12):1502-1510.
Aims
To assess the feasibility and reproducibility of non-invasive vascular assessment in a childhood population setting and identify the determinants of vascular phenotype in early life.
Methods and results
We studied 7557 children (age 9.8–12.3 years) participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Six research technicians underwent a 5-month training protocol to enable study of brachial artery endothelial function by flow-mediated dilatation (FMD) and arterial stiffness by carotid to radial pulse wave velocity (PWV) and brachial distensibility [distensibility coefficient (DC)]. Reproducibility studies were performed at the beginning, the middle, and the end of the study. A blinded repeat evaluation of a random selection of 3% of the cohort was also undertaken throughout the study. The effect of anthropometric and environmental factors on each measure was examined. Successful measures were obtained in 88, 95, and 87% of the studied children for FMD, PWV, and DC, respectively. The coefficients of variation between technicians for FMD, PWV, and DC were 10.5, 4.6, and 6.6% at the beginning of the study and reached 7.7, 4.1, and 10% at the end. Baseline vessel diameter and gender were important determinants of all the vascular measures, with a small effect of room and skin temperatures on FMD and PWV. Boys consistently had lower FMD and DC and higher PWV measures (P < 0.01 for all).
Conclusion
Reproducible, high-quality assessments of vascular structure and function in children can be made on a large scale in field studies by suitably trained non-specialist operators. This study provides an invaluable resource for assessing the impact of early influences, genetic, and environmental factors on arterial phenotype.
doi:10.1093/eurheartj/ehq062
PMCID: PMC2912638  PMID: 20421227
ALSPAC; Vascular; Children; Endothelial function; Reproducibility
The American journal of psychiatry  2010;167(11):1364-1372.
Objective
Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.
Method
Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.
Results
Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple subthreshold social, communicative, and cognitive impairments.
Conclusions
Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
doi:10.1176/appi.ajp.2010.09121789
PMCID: PMC3008767  PMID: 20634369

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