Association between polygenic risk scores for attention-deficit hyperactivity disorder and educational and cognitive outcomes in the general population

Background: Children with a diagnosis of attention-deficit hyperactivity disorder (ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement. Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N: 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers. Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13–14 years; β = −1.4 (−2.0 to −0.8), P = 2.3 × 10−6), at General Certificate of Secondary Education exams at age 15–16 years (β = −4.0 (−6.1 to −1.9), P = 1.8 × 10−4], reduced odds of sitting Key Stage 5 examinations at age 16–18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P = 0.001] and lower IQ scores at age 15.5 [β = −0.8 (−1.2 to −0.4), P = 2.4 × 10−4]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = −0.09 (−0.10 to −0.06), P = 0.005] and lower maternal IQ [β = −0.6 (−1.2 to −0.1), P = 0.03]. Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects

Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development

Abstract Background Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. Methods Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. Results In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait r g ≤ 1, p min  = 3 × 10−4) as those between repeated measures of the same trait (within-trait r g ≤ 0.94, p min  = 7 × 10−4). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (p-meta = 6.4 × 10−4). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R 2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. Conclusions In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships

Common variation near ROBO2 is associated with expressive vocabulary in infancy

Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15–18 months, ‘one-word stage’, NTotal=8,889) and a later (24–30 months, ‘two-word stage’, NTotal=10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P=1.3 × 10−8) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h215–18-months=0.13, meta-GCTA h224–30-months=0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h224-months=0.20)

Promoting ecosystem and human health in urban areas using green infrastructure: A literature review

Europe is a highly urbanised continent. The consequent loss and degradation of urban and peri-urban green space could adversely affect ecosystems as well as human health and well-being. The aim of this paper is to formulate a conceptual framework of associations between urban green space and ecosystem and human health. Through an interdisciplinary literature review the concepts of Green Infrastructure, ecosystem health, and human health and well-being are discussed. The possible contributions of urban and peri-urban green space systems, or Green Infrastructure, on both ecosystem and human health are critically reviewed. Finally, based on a synthesis of the literature a conceptual framework is presented. The proposed conceptual framework highlights many dynamic factors, and their complex interactions, affecting ecosystem health and human health in urban areas. This framework forms the context into which extant and new research can be placed. In this way it forms the basis for a new interdisciplinary research agenda

Exploring the equity of GP practice prescribing rates for selected coronary heart disease drugs: a multiple regression analysis with proxies of healthcare need

Background There is a small, but growing body of literature highlighting inequities in GP practice prescribing rates for many drug therapies. The aim of this paper is to further explore the equity of prescribing for five major CHD drug groups and to explain the amount of variation in GP practice prescribing rates that can be explained by a range of healthcare needs indicators (HCNIs). Methods The study involved a cross-sectional secondary analysis in four primary care trusts (PCTs 1–4) in the North West of England, including 132 GP practices. Prescribing rates (average daily quantities per registered patient aged over 35 years) and HCNIs were developed for all GP practices. Analysis was undertaken using multiple linear regression. Results Between 22–25% of the variation in prescribing rates for statins, beta-blockers and bendrofluazide was explained in the multiple regression models. Slightly more variation was explained for ACE inhibitors (31.6%) and considerably more for aspirin (51.2%). Prescribing rates were positively associated with CHD hospital diagnoses and procedures for all drug groups other than ACE inhibitors. The proportion of patients aged 55–74 years was positively related to all prescribing rates other than aspirin, where they were positively related to the proportion of patients aged >75 years. However, prescribing rates for statins and ACE inhibitors were negatively associated with the proportion of patients aged >75 years in addition to the proportion of patients from minority ethnic groups. Prescribing rates for aspirin, bendrofluazide and all CHD drugs combined were negatively associated with deprivation. Conclusion Although around 25–50% of the variation in prescribing rates was explained by HCNIs, this varied markedly between PCTs and drug groups. Prescribing rates were generally characterised by both positive and negative associations with HCNIs, suggesting possible inequities in prescribing rates on the basis of ethnicity, deprivation and the proportion of patients aged over 75 years (for statins and ACE inhibitors, but not for aspirin)

Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption we performed a population based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals respectively from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2,446,724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of fifteen independent loci, with ten loci reaching genome-wide significance (p<5x10−8) for ‘age at first tooth’ and eleven loci for ‘number of teeth’. Together these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including a SNP in the protein-coding region of BMP4 (rs17563, P= 9.080x10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development

On the Nature and Genesis of EUV Waves: A Synthesis of Observations from SOHO, STEREO, SDO, and Hinode

A major, albeit serendipitous, discovery of the SOlar and Heliospheric Observatory mission was the observation by the Extreme Ultraviolet Telescope (EIT) of large-scale Extreme Ultraviolet (EUV) intensity fronts propagating over a significant fraction of the Sun's surface. These so-called EIT or EUV waves are associated with eruptive phenomena and have been studied intensely. However, their wave nature has been challenged by non-wave (or pseudo-wave) interpretations and the subject remains under debate. A string of recent solar missions has provided a wealth of detailed EUV observations of these waves bringing us closer to resolving their nature. With this review, we gather the current state-of-art knowledge in the field and synthesize it into a picture of an EUV wave driven by the lateral expansion of the CME. This picture can account for both wave and pseudo-wave interpretations of the observations, thus resolving the controversy over the nature of EUV waves to a large degree but not completely. We close with a discussion of several remaining open questions in the field of EUV waves research.Comment: Solar Physics, Special Issue "The Sun in 360",2012, accepted for publicatio

Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children

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

Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3

Objective: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m2" is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children. Methods: A GWAS of height-adjusted BMI (BMI[x]=weight/heightx), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed. Results: GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m3.1 change per allele G (0.19, 0.38), P=6 × 10-9). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m2 (0.15, 0.35), P=6 × 10-7)]. Results were replicated in an independent sample, the Generation R study. Conclusions: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits

Microsatellite discovery in an insular amphibian (Grandisonia alternans) with comments on cross-species utility and the accuracy of locus identification from unassembled Illumina data

The Seychelles archipelago is unique among isolated oceanic islands because it features an endemic radiation of caecilian amphibians (Gymnophiona). In order to develop population genetics resources for this system, we identified microsatellite loci using unassembled Illumina MiSeq data generated from a genomic library of Grandisonia alternans, a species that occurs on multiple islands in the archipelago. Applying a recently described method (PALFINDER) we identified 8001 microsatellite loci that were potentially informative for population genetics analyses. Of these markers, we screened 60 loci using five individuals, directly sequenced several amplicons to confirm their identity, and then used eight loci to score allele sizes in 64 G. alternans individuals originating from five islands. A number of these individuals were sampled using non-lethal methods, demonstrating the efficacy of non-destructive molecular sampling in amphibian research. Although two loci satisfied our criteria as diploid, neutrally evolving loci with the statistical power to detect population structure, our success in identifying reliable loci was very low. Additionally, we discovered some issues with primer redundancy and differences between Illumina and Sanger sequences that suggest some Illumina-inferred loci are invalid. We investigated cross-species utility for eight loci and found most could be successfully amplified, sequenced and aligned across other species and genera of caecilians from the Seychelles. Thus, our study in part supported the validity of using PALFINDER with unassembled reads for microsatellite discovery within and across species, but importantly identified major limitations to applying this approach to small datasets (ca. 1 million reads) and loci with small tandem repeat sizes