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1.  Genome-wide association study identifies loci affecting blood copper, selenium and zinc 
Human Molecular Genetics  2013;22(19):3998-4006.
Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10−10, and rs2769264, P = 2.63 × 10−20); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10−28 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10−12; rs2120019, P = 1.55 × 10−18; and rs4826508, P = 1.40 × 10−12, respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
PMCID: PMC3766178  PMID: 23720494
2.  Perinatal depression and omega-3 fatty acids: A Mendelian randomisation study 
Journal of Affective Disorders  2014;166(100):124-131.
There have been numerous studies investigating the association between omega-3 fatty acids (FAs) and depression, with mixed findings. We propose an approach which is largely free from issues such as confounding or reverse causality, to investigate this relationship using observational data from a pregnancy cohort.
The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort collected information on FA levels from antenatal blood samples and depressive symptoms at several time points during pregnancy and the postnatal period. Conventional epidemiological analyses were used in addition to a Mendelian randomisation (MR) approach to investigate the association between levels of two omega-3 FAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and perinatal onset depression, antenatal depression (AND) and postnatal depression (PND).
Weak evidence of a positive association with both EPA (OR=1.07; 95% CI: 0.99–1.15) and DHA (OR=1.08; 95% CI: 0.98–1.19) with perinatal onset depression was found using a multivariable logistic regression adjusting for social class and maternal age. However, the strength of association was found to attenuate when using an MR analysis to investigate DHA.
Pleiotropy is a potential limitation in MR analyses; we assume that the genetic variants included in the instrumental variable are associated only with our trait of interest (FAs) and thus cannot influence the outcome via any other pathway.
We found weak evidence of a positive association between omega-3 FAs and perinatal onset depression. However, without confirmation from the MR analysis, we are unable to draw conclusions regarding causality.
PMCID: PMC4101243  PMID: 25012420
Depression; Perinatal; Mendelian randomisation; Omega-3; ALSPAC
3.  Birth weight is positively related to bone size in adolescents but inversely related to cortical bone mineral density: Findings from a large prospective cohort study 
Bone  2014;65(100):77-82.
To examine the influence of intrauterine environment on subsequent bone development, we investigated the relationship between birth weight and cortical bone parameters, and the role of puberty, bone resorption and insulin as possible mediators. Bone outcomes were obtained from mid-tibial pQCT scans performed at age 15.5 years in 1960 males and 2192 females from the ALSPAC birth cohort. Birth weight was positively related to periosteal circumference (PC) [beta = 0.40 (0.34, 0.46)], which was largely but not completely attenuated after adjustment for height and weight [beta = 0.07 (0.02, 0.12)] (SD change in outcome per 1 kg increase in birth weight with 95% CI). Based on our height and weight adjusted model, the association was stronger in females compared to males (P = 0.02 for gender interaction), and persisted in 2842 participants with equivalent results at age 17.7 years. Conversely, birth weight was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after adjusting for height and weight [beta = − 0.18 (− 0.23, − 0.13)], with a stronger association in males compared to females (P = 0.01 for gender interaction), but an equivalent association was not seen at 17.7 years. In further analyses performed on data from age 15.5 years, the association between birth weight and PC was unaffected by adjustment for puberty (Tanner stage at age 13.5 years), bone resorption (fasting beta-carboxyterminal cross linking telopeptide (βCTX) at age 15.5 years) or insulin (fasting insulin at age 15.5 years). In contrast, the association with BMDC was attenuated by approximately 30% after adjustment for puberty or bone resorption, and by 50% after adjustment for both factors combined. We conclude that the inverse relationship between birth weight and BMDC is in part mediated by effects of puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.
•Birth weight (BW) was positively related to periosteal circumference (PC) at age 15, even after height and weight adjustment.•The association of BW with PC was stronger in females, and was also seen at age 17.7 years.•BW was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after height and weight adjustment.•The inverse association of BW with BMDC was stronger in males, but there was no association at 17.7 years.•The association of BW with BMDC was attenuated by approximately 50% after adjustment for puberty and bone resorption.
PMCID: PMC4073227  PMID: 24840816
pQCT; Periosteal circumference; Tibia; Puberty; Bone resorption
5.  Glue Ear, Hearing Loss and IQ: An Association Moderated by the Child’s Home Environment 
PLoS ONE  2014;9(2):e87021.
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.
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.
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).
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.
The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss.
PMCID: PMC3911938  PMID: 24498289
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;
PMCID: PMC3801454  PMID: 23811414
8.  Dependence of deodorant usage on ABCC11 genotype: Scope for personalised genetics in personal hygiene 
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.
PMCID: PMC3674910  PMID: 23325016
ABCC11 gene; deodorant usage; axillary odor; personalised genetics
9.  Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC) 
The British journal of nutrition  2012;109(7):1196-1210.
Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno–fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.
PMCID: PMC3600399  PMID: 22877655
FADS; Fetal fatty acid supply; Cord blood; Avon Longitudinal Study of Parents and Children (ALSPAC)
10.  Polyunsaturated fatty acid levels in blood during pregnancy, at birth and at 7 years: their associations with two common FADS2 polymorphisms 
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.
PMCID: PMC3465695  PMID: 22194195
11.  Maternal smoking and child psychological problems: Disentangling causal and non-causal effects 
Pediatrics  2010;126(1):e57-e65.
To explore associations of maternal prenatal smoking and child psychological problems and determine the role of causal intrauterine mechanisms.
Patients and Methods
Maternal smoking and child psychological problems were explored in 2 birth cohorts in Pelotas, Brazil (n=509; random sub-sample) and Avon Longitudinal Study of Parents and Children (ALSPAC), Britain (n=6,735). Four approaches for exploring causal mechanisms were applied: 1) cross-population comparisons between a high-income and a middle-income country, 2) multiple adjustment for socioeconomic and parental psychological factors, 3) maternal-paternal comparisons as a test of putative intrauterine effects; and 4) search for specific effects on different behavioural subscales.
Socioeconomic patterning of maternal prenatal smoking was stronger in the ALSPAC compared with the Pelotas cohort. Despite this difference in a key confounder, consistency in observed associations was found between these cohorts. In both cohorts, unadjusted, maternal smoking was associated with greater offspring hyperactivity, conduct/externalizing problems, and peer problems, but not with emotional/internalizing problems. After adjusting for confounders and paternal prenatal smoking, only the association with conduct/externalizing problems persisted in both cohorts (conduct problems in the ALSPAC cohort, odds ratio OR: 1.24 [95% confidence interval (CI): 1.07–1.46], p= .005; externalizing problems in the Pelotas cohort, OR:1.82 [95% CI:1.19–2.78], p=.005; ORs reflect ordinal ORs of maternal smokers having offspring with higher scores). Maternal smoking associations were stronger than paternal smoking associations, although statistical evidence for differences was weak in 1 cohort.
Evidence from 4 approaches suggests a possible intrauterine effect of maternal smoking on offspring conduct/externalizing problems.
PMCID: PMC3605780  PMID: 20587678
ALSPAC; Pelotas; prenatal smoking; child; behavioral problems; developmental origins
12.  Do ω-3 or other fatty acids influence the development of ‘growing pains’? A prebirth cohort study 
BMJ Open  2012;2(4):e001370.
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.
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.
Avon Longitudinal Study of Parents & Children.
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.
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.
Thus, there is no evidence that ω-3 fatty acid status protects against the development of growing pains in childhood.
PMCID: PMC3432839  PMID: 22923631
Epidemiology; Genetics; Paediatric clinical genetics & dysmorphology; Nutrition & Dietetics; Orthopaedic & Trauma Surgery; Musculoskeletal disorders; Pain Management
13.  Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study 
BMJ Open  2012;2(4):e001238.
To determine the carrier rate of the GJB2 mutation c.35delG and c.101T>C in a UK population study; to determine whether carriers of the mutation had worse hearing or otoacoustic emissions compared to non-carriers.
Prospective cohort study.
University of Bristol, UK.
Children in the Avon Longitudinal Study of Parents and Children. 9202 were successfully genotyped for the c.35delG mutation and c.101>T and classified as either carriers or non-carriers.
Outcome measures
Hearing thresholds at age 7, 9 and 11 years and otoacoustic emissions at age 9 and 11.
The carrier frequency of the c.35delG mutation was 1.36% (95% CI 1.13 to 1.62) and c.101T>C was 2.69% (95% CI 2.37 to 3.05). Carriers of c.35delG and c.101T>C had worse hearing than non-carriers at the extra-high frequency of 16 kHz. The mean difference in hearing at age 7 for the c.35delG mutation was 8.53 dB (95% CI 2.99, 14.07) and 12.57 dB at age 9 (95% CI 8.10, 17.04). The mean difference for c.101T>C at age 7 was 3.25 dB (95% CI −0.25 to 6.75) and 7.61 dB (95% CI 4.26 to 10.96) at age 9. Otoacoustic emissions were smaller in the c.35delG mutation carrier group: at 4 kHz the mean difference was −4.95 dB (95% CI −6.70 to −3.21) at age 9 and −3.94 dB (95% CI −5.78 to −2.10) at age 11. There was weak evidence for differences in otoacoustic emissions amplitude for c.101T>C carriers.
Carriers of the c.35delG mutation and c.101T>C have worse extra-high-frequency hearing than non-carriers. This may be a predictor for changes in lower-frequency hearing in adulthood. The milder effects observed in carriers of c.101T>C are in keeping with its classification as a mutation causing mild/moderate hearing loss in homozygosity or compound heterozygosity.
PMCID: PMC3449272  PMID: 22855627
Otolaryngology; Audiology; Genetics; Otolaryngology; Paediatric otolaryngology
14.  Prenatal and Early Life Exposure to Stressful Life Events and Risk of Autism Spectrum Disorders: Population-Based Studies in Sweden and England 
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.
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.
PMCID: PMC3374800  PMID: 22719977
15.  Early Life Stress, MAOA, and Gene-Environment Interactions Predict Behavioral Disinhibition in Children 
Genes, brain, and behavior  2009;9(1):65-74.
Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth – 3 years) stressors to influence behavior in pre-pubertal children.
The Avon Longitudinal Study of Parents and Children, U.K., is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years.
In both sexes, exposure to family adversity and stressful life events in the first three years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3 ½ years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1 ½ and 2 ½ years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity.
In a general population sample of pre-pubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR - stressful life event interactions specifically predicted hyperactivity.
PMCID: PMC2824071  PMID: 19804559
ALSPAC; hyperactivity; conduct disturbances; ADHD; SDQ; MAOA-LPR
16.  Association Between a High-Risk Autism Locus on 5p14 and Social Communication Spectrum Phenotypes in the General Population 
The American journal of psychiatry  2010;167(11):1364-1372.
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.
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.
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.
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.
PMCID: PMC3008767  PMID: 20634369
17.  Infant feeding in the second 6 months of life related to iron status: an observational study 
Archives of Disease in Childhood  2007;92(10):850-854.
To investigate the relationship between iron status in infancy and type of milk and weaning solids consumed.
An observational cohort study.
928 term infants from the Avon Longitudinal Study of Parents and Children in 1993–94.
Haemoglobin and ferritin concentrations at 8 and 12 months were assessed in relation to type and quantity of milk intake at 8 months.
By WHO criteria, 22.7% of the infants were anaemic at 8 months and 18.1% at 12 months. More breast‐ than formula‐fed infants were anaemic at 8 and 12 months. Cows' milk as the main drink was associated with increased anaemia at 12 months and low ferritin at 8 and 12 months. No association was found between any nutrients and haemoglobin concentrations. Protein and non‐haem iron intakes were positively associated with ferritin concentrations and calcium intake negatively. This effect was more marked in infants being fed cows' milk. More than 25% of infants in the breast milk and cows' milk groups and 41% of infants having >6 breast feeds per day had iron intakes below the lower reference nutrient intake. Feeding cows' milk or formula above 600 ml or >6 breast feeds per day was associated with lower intakes of solids.
Both breast and cows' milk feeding were associated with higher levels of anaemia. Satisfactory iron intake from solids in later infancy is more likely if formula intake is <600 ml per day and breast feeds are limited to <6 feeds per day. Cows' milk should be strongly discouraged as a main drink before 12 months.
PMCID: PMC2083241  PMID: 17537759
ALSPAC; cows' milk; breast milk; formula; iron deficiency
18.  Is there an intrauterine influence on obesity? Evidence from parent–child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC) 
Archives of Disease in Childhood  2007;92(10):876-880.
It has been suggested that increasing obesity levels in young women lead to intrauterine environments that, in turn, stimulate increased obesity among their offspring, generating an intergenerational acceleration of obesity levels. If this mechanism is important, the association of maternal body mass index (BMI) with offspring BMI should be stronger than the association of paternal with offspring BMI.
To compare the relative strengths of association of maternal and paternal BMI with offspring BMI at age 7.5, taking into account the possible effect of non‐paternity.
We compared strength of association for maternal–offspring and paternal–offspring BMI for 4654 complete parent–offspring trios in the Avon Longitudinal Study of Parents and Children (ALSPAC), using unstandardised and standardised regression analysis. We carried out a sensitivity analysis to investigate the influence of non‐paternity on these associations.
The strength of association between parental BMI and offspring BMI at age 7.5 was similar for both parents. Taking into account correlations between maternal and paternal BMI, performing standardised rather than unstandardised regression and carrying out a sensitivity analysis for non‐paternity emphasised the robustness of the general similarity of the associations. The associations between high parental BMI (top decile) and offspring BMI are also similar for both parents.
Comparison of mother–offspring and father–offspring associations for BMI suggests that intergenerational acceleration mechanisms do not make an important contribution to levels of childhood BMI within the population. Associations at later ages and for different components of body composition now require study.
PMCID: PMC2083247  PMID: 17595200
19.  Traits Contributing to the Autistic Spectrum 
PLoS ONE  2010;5(9):e12633.
It is increasingly recognised that traits associated with autism reflect a spectrum with no clear boundary between typical and atypical behaviour. Dimensional traits are needed to investigate the broader autism phenotype.
Methods and Principal Findings
Ninety-three individual measures reflecting components of social, communication and repetitive behaviours characterising autistic spectrum disorder (ASD) were identified between the ages of 6 months and 9 years from the ALSPAC database. Using missing value imputation, data for 13,138 children were analysed. Factor analysis suggested the existence of 7 factors explaining 85% of the variance. The factors were labelled: verbal ability, language acquisition, social understanding, semantic-pragmatic skills, repetitive-stereotyped behaviour, articulation and social inhibition. Four factors (1, 3, 5 and 7) were specific to ASD being more strongly associated with this phenotype than other co-morbid conditions while other factors were more associated with learning difficulties and specific language impairment. Nevertheless, all 7 factors contributed independently to the explanation of ASD (p<0.001). Exploration of putative genetic causal factors such as variants in the CNTNAP2 gene showed a varying pattern of associations with these traits. An alternative predictive model of ASD was derived using four individual measures: the coherence subscale of the Children's Communication Checklist (9y), the Social and Communication Disorders Checklist (91 m), repetitive behaviour (69 m) and the sociability subscale of the Emotionality Activity and Sociability measure (38 m). Although univarably these traits performed better than some factors, their combined explanations of ASD were similar (R2 = 0.48).
Conclusions and Significance
These results support the fractional nature of ASD with different aetiological origins for these components despite pleiotropic genetic effects being observed. These traits are likely to be useful in the exploration of ASD.
PMCID: PMC2935882  PMID: 20838614
20.  FADS2 Polymorphisms Modify the Effect of Breastfeeding on Child IQ 
PLoS ONE  2010;5(7):e11570.
Breastfeeding is important for child cognitive development. A study by Caspi et al has suggested that rs174575 within the FADS2 gene moderates this effect so that children homozygous in the minor allele (GG genotype) have similar IQs irrespective of feeding method.
Methods and Principal Findings
In our study of 5934 children aged 8 years, no genetic main effect with IQ was found for rs174575. However, an interaction with this polymorphism was observed such that breastfed GG children performed better than their formula fed counterparts by an additional 5.8 points [1.4, 10.1] (interaction p = 0.0091). Interaction results were attenuated by about 10% after adjustment for 7 factors. This study also investigated rs1535, another FADS2 polymorphism in linkage disequilibrium with rs174575, together with performance and verbal IQ, finding similar results although effect sizes were generally reduced.
Conclusions and Significance
This study did not replicate the findings of Caspi et al. In contrast to their study, GG children exhibited the greatest difference between feeding methods such that breastfed children performed similarly irrespective of child genotype whereas formula fed GG children performed worse than other children on formula milk. Further studies are required to replicate these findings.
PMCID: PMC2903485  PMID: 20644632
21.  Parental and Grandparental Ages in the Autistic Spectrum Disorders: A Birth Cohort Study 
PLoS ONE  2010;5(4):e9939.
A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with grandparental ages.
Methods and Findings
We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.66[95%CI 1.16, 2.37] for each 10-year increase in the grandmother's age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother's age and the major autistic trait–the Coherence Scale (regression coefficient b = 0.142, [95%CI = 0.057, 0.228]P = 0.001). After allowing for confounders the effect size increased to b = 0.217[95%CI 0.125, 0.308](P<0.001) for each 10 year increase in age.
Although the relationship between maternal grandmother's age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild's genome during the grandmother's pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should be treated as hypothesis generating pending corroborative results from other studies.
PMCID: PMC2848579  PMID: 20376340
22.  Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Is Associated With Spinal BMD in 9-Year-Old Children 
The C677T MTHFR polymorphism has been associated with lumbar spine and hip BMD. In older adults, the genetic effect has been reported in women only. However, in younger adults, this influence may only be present in men. This study is the first to investigate associations between the C677T MTHFR polymorphism and bone phenotypes in children. Regression analyses were used to study the relationship between MTHFR genotype and bone phenotypes derived from total body DXA scans in children 9.9 yr of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 5816 children had both genetic and DXA data for the total body less head region (TBLH) and 3196 for the spine. A strong association was observed between the C677T MTHFR genotype and spine BMD (p < 0.001; 0.10 SD decrease per T allele). There was some evidence that this genetic effect was stronger in boys compared with girls (p = 0.04 for sex interaction). In contrast, there was no association between the C677T MTHFR genotype and TBLH BMD. The association between MTHFR genotype and spine BMD was attenuated particularly in girls by high maternal dietary intakes of vitamin B6 and folate during pregnancy but not by child dietary intakes at 7 yr. To the extent that these findings reflect known influences of C677T MTHFR genotype on plasma homocysteine levels, our results suggest that the latter is an important regulator of spinal BMD in childhood.
PMCID: PMC2742728  PMID: 18715139
ALSPAC; DXA; MTHFR; genetic polymorphism
23.  The Effect of LRP5 Polymorphisms on Bone Mineral Density Is Apparent in Childhood 
Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2306862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.
PMCID: PMC2742716  PMID: 17505772
LRP5; Association; Growth; Height; Bone mineral density
24.  Habitual Levels of Physical Activity Influence Bone Mass in 11-Year-Old Children From the United Kingdom: Findings From a Large Population-Based Cohort 
We examined the influence of habitual levels of physical activity on bone mass in childhood by studying the relationship between accelerometer recordings and DXA parameters in 4457 11-year-old children. Physical activity was positively related to both BMD and bone size in fully adjusted models. However, further exploration revealed that this effect on bone size was modified by fat mass.
Exercise interventions have been reported to increase bone mass in children, but it is unclear whether levels of habitual physical activity also influence skeletal development.
Materials and Methods
We used multivariable linear regression to analyze associations between amount of moderate and vigorous physical activity (MVPA), derived from accelerometer recordings for a minimum of 3 days, and parameters obtained from total body DXA scans in 4457 11-year-old boys and girls from the Avon Longitudinal Study of Parents and Children. The influence of different activity intensities was also studied by stratification based on lower and higher accelerometer cut-points for moderate (3600 counts/minute) and vigorous (6200 counts/minute) activity, respectively.
MVPA was positively associated with lower limb BMD and BMC adjusted for bone area (aBMC; p < 0.001, adjusted for age, sex, socio-economic factors, and height, with or without additional adjustment for lean and fat mass). MVPA was inversely related to lower limb bone area after adjusting for height and lean mass (p = 0.01), whereas a positive association was observed when fat mass was also adjusted for (p < 0.001). Lower limb BMC was positively related to MVPA after adjusting for height and lean and fat mass (p < 0.001), whereas little relationship was observed after adjusting for height and lean mass alone (p = 0.1). On multivariable regression analysis using the fully adjusted model, moderate activity exerted a stronger influence on lower limb BMC compared with light activity (light activity: 2.9 [1.2–4.7, p = 0.001]; moderate activity: 13.1 [10.6–15.5, p < 0.001]; regression coefficients with 95% confidence intervals and p values).
Habitual levels of physical activity in 11-year-old children are related to bone size and BMD, with moderate activity exerting the strongest influence. The effect on bone size (as reflected by DXA-based measures of bone area) was modified by adjustment for fat mass, such that decreased fat mass, which is associated with higher levels of physical activity, acts to reduce bone size and thereby counteract the tendency for physical activity to increase bone mass.
PMCID: PMC2742715  PMID: 17014381
DXA; accelerometer; bone size; fat mass
25.  Selective drop-out in longitudinal studies and non-biased prediction of behaviour disorders 
The British Journal of Psychiatry  2009;195(3):249-256.
Participant drop-out occurs in all longitudinal studies, and if systematic, may lead to selection biases and erroneous conclusions being drawn from a study.
We investigated whether drop out in the Avon Longitudinal Study of Parents And Children (ALSPAC) was systematic or random, and if systematic, whether it had an impact on the prediction of disruptive behaviour disorders.
Teacher reports of disruptive behaviour among currently participating, previously participating and never participating children aged 8 years in the ALSPAC longitudinal study were collected. Data on family factors were obtained in pregnancy. Simulations were conducted to explain the impact of selective drop-out on the strength of prediction.
Drop out from the ALSPAC cohort was systematic and children who dropped out were more likely to suffer from disruptive behaviour disorder. Systematic participant drop-out according to the family variables, however, did not alter the association between family factors obtained in pregnancy and disruptive behaviour disorder at 8 years of age.
Cohort studies are prone to selective drop-out and are likely to underestimate the prevalence of psychiatric disorder. This empirical study and the simulations confirm that the validity of regression models is only marginally affected despite range restrictions after selective drop-out.
PMCID: PMC2802508  PMID: 19721116

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