Biology subjects

Stergiakouli, E.

Publications and source records attributed to Stergiakouli, E..

10 recordsLinked to original sources

bioRxiv2018

Cleft lip/palate and educational attainment: cause, consequence, or correlation? A Mendelian randomization study

ImportancePrevious studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. A clearer understanding of this mechanism will inform development of interventions to improve educational attainment in individuals born with a cleft, which could have wide-ranging knock-on effects on their quality of life.\n\nObjectiveTo assess evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.\n\nDesignUsing summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828).\n\nResultsThere was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg -0.03, 95% CI -0.14 to 0.08, P 0.58; {beta}MR 0.002, 95% CI -0.001 to 0.005, P 0.417) or intelligence (rg -0.01, 95% CI -0.12 to 0.10, P 0.85; {beta}MR 0.002, 95% CI -0.010 to 0.014, P 0.669).\n\nConclusions and relevanceCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo children born with a non-syndromic cleft lip with or without palate (nsCL/P) have lower-than average academic achievement because of an underlying genetic predisposition to educational attainment and/or intelligence?\n\nFindingsThere was little evidence for shared common variant genetic correlation between nsCL/P, educational attainment and intelligence.\n\nMeaningCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

genetics↗

bioRxiv2018

The contribution of psychiatric risk alleles to a general liability to psychopathology in early life

BackgroundPsychiatric disorders show phenotypic as well as genetic overlaps. Factor analyses of child and adult psychopathology have found that phenotypic overlaps largely can be explained by a latent general \"p\" factor that reflects general liability to psychopathology. We investigated whether shared genetic liability across disorders would be reflected in associations between multiple different psychiatric polygenic risk scores (PRS) and a general psychopathology factor in childhood.\n\nMethodsThe sample was a UK, prospective, population-based cohort (ALSPAC), including data on psychopathology at age 7 (N=8161) years. PRS were generated from large published genome-wide association studies.\n\nOutcomesThe general psychopathology factor was associated with both schizophrenia PRS and attention-deficit/hyperactivity disorder (ADHD) PRS, whereas there was no strong evidence of association with major depressive disorder and autism spectrum disorder PRS. Schizophrenia PRS was also associated with a specific \"emotional\" problems factor.\n\nInterpretationOur findings suggest that genetic liability to schizophrenia and ADHD may contribute to shared genetic risks across childhood psychiatric diagnoses at least partly via the general psychopathology factor. However, the pattern of observations could not be explained by a general \"p\" factor on its own.\n\nFundingThis work was supported by the Wellcome Trust (204895/Z/16/Z).Introduction

genetics↗

bioRxiv2018

Education, intelligence and Alzheimer’s disease: Evidence from a multivariable two-sample Mendelian randomization study

ObjectivesTo examine whether educational attainment and intelligence have causal effects on risk of Alzheimers disease (AD), independently of each other.\n\nDesignTwo-sample univariable and multivariable Mendelian Randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on risk of AD.\n\nParticipants17,008 AD cases and 37,154 controls from the International Genomics of Alzheimers Project (IGAP) consortium\n\nMain outcome measureOdds ratio of AD per standardised deviation increase in years of schooling and intelligence\n\nResultsThere was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23% to 49%) and 35% (95% CI: 25% to 43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account, but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis.\n\nConclusionsThere is robust evidence for an independent, causal effect of intelligence in lowering AD risk, potentially supporting a role for cognitive training interventions to improve aspects of intelligence. However, given the observed causal effect of educational attainment on intelligence, there may also be support for policies aimed at increasing length of schooling to lower incidence of AD.

genetics↗

bioRxiv2018

Disentangling genetic overlap between Attention-Deficit/Hyperactivity Disorder, literacy and language

Interpreting polygenic overlap between ADHD and both literacy- and language-related impairments is challenging as genetic confounding can bias associations. Here, we investigate evidence for links between polygenic ADHD risk and multiple literacy- and language-related abilities (LRAs), assessed in UK children (N[≤]5,919), conditional on genetic effects shared with educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years-of-schooling were obtained from large consortia (N[≤]326,041). ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained [≤]1.6% phenotypic variation. Polygenic links were then dissected into both genetic effects shared with and independent of EA using multivariable regressions (MVR), analogous to Mendelian Randomization approaches accounting for mediating effects. Conditional on EA, polygenic ADHD risk remained associated with multiple literacy-related skills, phonemic awareness and verbal intelligence, but not language-related skills such as listening comprehension and non-word repetition. Pooled reading performance showed the strongest overlap with ADHD independent of EA. Using conservative ADHD-instruments (P-threshold<5x10-8) this corresponded to a 0.35 decrease in Z-scores per log-odds in ADHD-liability (P=9.2x10-5). Using subthreshold ADHD-instruments (P-threshold<0.0015), these associations had lower magnitude, but higher predictive accuracy, with a 0.03 decrease in Z-scores (P=1.4x10-6). Polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and only detectable using subthreshold instruments. Thus, ADHD-related polygenic links are highly susceptible to genetic confounding, concealing an ADHD-specific association profile that primarily involves reading-related impairments, but few language-related problems.

genetics↗

bioRxiv2018

Identifying Critical Points of Trajectories of Depressive Symptoms From Childhood to Young Adulthood: Evidence of Sex Differences from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Depression is a common mental illness associated with increased substance misuse and risk of suicide. Potential risk factors for depression include sex and depressive symptoms in early life, however the mechanisms responsible are not yet understood. Research has focused on late childhood and adolescence as this developmental period may be a modifiable risk factor that prevents or reduces depression at a later stage. It is also important to establish at what ages the level of depression is changing as this will help identify critical points to intervene with treatment. We used multilevel growth-curve models to explore adolescent trajectories of depressive symptoms in the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Using data from 9301 individuals, trajectories of depressive symptoms were constructed for males and females between 10.6 and 22.8 years old. We calculated the age of peak velocity for depressive symptoms (the age at which depressive symptoms increases most rapidly) and the age of maximum depressive symptoms. Adjusted results suggested that being female was associated with a steeper trajectory compared to being male (per 1 year increase in relation to depressive symptoms: 0.128, SE = 0.035, [95% CI: 0.059, 0.198]; p <0.001). We found evidence suggesting that females had an earlier age of peak velocity of depressive symptoms (females 13.7 years old, SE = 0.321, [95% CI: 12.9, 14.4] and males 16.4 years old, SE = 0.096, [95% CI: 16.2, 16.6]; p <0.001), but weak evidence of an earlier age of maximum depressive symptoms (p = 0.125). Possible mechanisms that underlie this sex difference include the roles of pubertal development and timing. Using multilevel growth curve models to estimate the age of peak velocity and maximum depressive symptoms for different population subgroups may provide useful knowledge for treating and preventing later depression.

epidemiology↗

bioRxiv2018

DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

BackgroundNon-syndromic cleft lip/palate (nsCL/P) is a complex trait with genetic and environmental risk factors. Around 40 distinct genetic risk loci have been identified for nsCL/P, but many reside in non-protein-coding regions with an unclear function. We hypothesised that one possibility is that the genetic risk variants influence susceptibility to nsCL/P through gene regulation pathways, such as those involving DNA methylation.\n\nMethodsUsing nsCL/P Genome-wide association study summary data and methylation data from four studies, we used Mendelian randomization and joint likelihood mapping to identify putative loci where genetic liability to nsCL/P may be mediated by variation in DNA methylation in blood.\n\nResultsThere was evidence at three independent loci, VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant. Follow up analyses using DNA methylation data, derived from lip and palate tissue, and gene expression catalogues provided further insight into possible biological mechanisms.\n\nConclusionsGenetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.

genetics↗

bioRxiv2018

Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 0.00002). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.

genetics↗

bioRxiv2017

The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children

BackgroundIt is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation.\n\nMethodsUsing data on mothers (N=7,486) and children (N=7,508) from the Avon Longitudinal Study of Parents and Children, we 1) examined the association of polygenic risk scores for a range of socio-demographic, lifestyle characteristics and health conditions related to continued participation, 2) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a sub-sample who participated in a recent follow-up and 3) determined the proportion of variation in participation explained by common genetic variants using genome-wide data.\n\nResultsWe found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, ADHD and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data (OR for ever smoking per SD increase in polygenic score:0.85, 95% CI:0.81,0.89) and sub-sample (OR:0.95, 95% CI:0.88,1.02). In genome-wide analysis, single nucleotide polymorphism based heritability explained 17-31% of variability in participation.\n\nConclusionsGenetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.

genetics↗

bioRxiv2017

The causal effect of educational attainment on Alzheimer’s disease: A two-sample Mendelian randomization study

BackgroundObservational evidence suggests that higher educational attainment is protective for Alzheimers disease (AD). It is unclear whether this association is causal or confounded by demographic and socioeconomic characteristics. We examined the causal effect of educational attainment on AD in a two-sample MR framework.\n\nMethodsWe extracted all available effect estimates of the 74 single nucleotide polymorphisms (SNPs) associated with years of schooling from the largest genome-wide association study (GWAS) of educational attainment (N=293,723) and the GWAS of AD conducted by the International Genomics of Alzheimers Project (n=17,008 AD cases and 37,154 controls). SNP-exposure and SNP-outcome coefficients were combined using an inverse variance weighted approach, providing an estimate of the causal effect of each SD increase in years of schooling on AD. We also performed appropriate sensitivity analyses examining the robustness of causal effect estimates to the various assumptions and conducted simulation analyses to examine potential survival bias of MR analyses.\n\nFindingsWith each SD increase in years of schooling (3.51 years), the odds of AD were, on average, reduced by approximately one third (odds ratio= 0.63, 95% confidence interval [CI]: 0.48 to 0.83, p<0.001). Causal effect estimates were consistent when using causal methods with varying MR assumptions or different sets of SNPs for educational attainment, lending confidence to the magnitude and direction of effect in our main findings. There was also no evidence of survival bias in our study.\n\nInterpretationOur findings support a causal role of educational attainment on AD, whereby an additional [~]3.5 years of schooling reduces the odds of AD by approximately one third.

epidemiology↗

bioRxiv2017

Distinct Blood DNA Methylation Profiles In Subtypes Of Orofacial Cleft

BackgroundThere is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts.\n\nMethodsIn this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.\n\nIn whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50).\n\nResultsWe found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA) and over 250 novel associations.\n\nConclusionOur finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.

epidemiology↗