Publications

Abstract

Background

Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled ‘chronogeneity’. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample.
Methods

Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups.
Results

The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male.
Conclusions

Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence.

Abstract

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

Abstract

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Abstract

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Abstract

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

Abstract

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Abstract

Many mental health conditions present a spectrum of social difficulties that overlaps with social behaviour in the general population including shared but little characterised genetic links. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia across a spectrum of different social symptoms. Longitudinally assessed low-prosociality and peer-problem scores in two UK population-based cohorts (4–17 years; parent- and teacher-reports; Avon Longitudinal Study of Parents and Children(ALSPAC): N ≤ 6,174; Twins Early Development Study(TEDS): N ≤ 7,112) were regressed on polygenic risk scores for disorder, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD and schizophrenia. Modelling variation in univariate genetic effects jointly using random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP. Differences in age, reporter and social trait captured 45–88% in univariate effect variation. Cross-disorder adjusted analyses demonstrated that age-related heterogeneity in univariate effects is shared across mental health conditions, while reporter- and social trait-specific heterogeneity captures disorder-specific profiles. In particular, ADHD, MD, and ASD polygenic risk were more strongly linked to peer problems than low prosociality, while schizophrenia was associated with low prosociality only. The identified association profiles suggest differences in the social genetic architecture across mental disorders when investigating polygenic overlap with population-based social symptoms spanning 13 years of child and adolescent development.

Abstract

Background

Head circumference is associated with intelligence and tracks from childhood into adulthood.
Methods

We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age.
Results

Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes.
Conclusions

The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.

Abstract

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10−5), 3.5% (P=10−3) and 0.5% (P=6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Abstract

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

Abstract

Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype (“maternal effects”, M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ~4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.

Abstract

We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC ). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β=0.19 [0.13, 0.24]) (coefficient=SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β=-0.46 [-0.52,-0.40]) and cortical thickness [β=-0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) (β=0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p<}0.05 cut-off) (n=2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n=3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n=938), and the Young Finns Study (YFS) (n=1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p{<0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion.

Abstract

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

Abstract

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.

Abstract

OBJECTIVE: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " 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/height(x) ), 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/m(3.1) 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/m(2) (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.

Abstract

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.