Evie Stergiakouli

Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population

IMPORTANCE Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population. OBJECTIVE To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14,062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015. EXPOSURES Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set. MAIN OUTCOMES AND MEASURES Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence. RESULTS Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R(2) = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R(2) = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R(2) = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R(2) = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes. CONCLUSIONS AND RELEVANCE This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.

Shared Genetic Influences Between Attention-Deficit/Hyperactivity Disorder (ADHD) Traits in Children and Clinical ADHD

Objective Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample. Method Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample. Results Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08–1.28], p = .0003), higher ADHD symptom severity (β = 0.29 [95% CI = 0.04–0.54], p = 0.02), and symptom domain severity in the clinical sample. Conclusion This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD.

Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population

Importance Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder that shows clinical and genetic overlap with other childhood neurodevelopmental disorders. Levels of ADHD symptoms typically decline across childhood and adolescence, although they remain elevated for some individuals. The determinants of symptom persistence and decline are not yet fully understood. Objectives To test the hypothesis that genetic risk variant load for ADHD (indexed by polygenic risk scores [PRS]), but not for other psychiatric disorders, is associated with population-based ADHD symptom trajectories across childhood and adolescence, and to examine whether higher genetic liability for ADHD is correlated with total number of additional neurodevelopmental disorders (multimorbidity) in childhood. Design, Setting, and Participants The Avon Longitudinal Study of Parents and Children, an ongoing prospective population-based cohort study, has been collecting data on 14 701 children, including 9757 with data on symptoms of ADHD at multiple time points, since September 6, 1990. The primary exposure variables, PRS, were generated using results of a genome-wide association study from the Psychiatric Genomics Consortium. Childhood multimorbidity scores (ages 7-9 years) were measured by total impairments in 4 domains known to share genetic liability with ADHD: IQ, social communication, pragmatic language, and conduct. Data analysis was conducted from March 1 to September 8, 2016. Main Outcomes and Measures Attention-deficit/hyperactivity disorder symptom trajectories from ages 4 to 17 years (7 time points). Results Among 9757 children with data on symptoms of ADHD at multiple time points (age range, 4-17 years; 4968 boys and 4789 girls), 4 ADHD symptom trajectories were identified: low (82.6%), intermediate (7.7%), childhood-limited (5.8%), and persistent (3.9%). Mean (SE) PRS for ADHD were higher in children in the persistent trajectory (0.254 [0.069]) compared with each of the other 3 trajectories (low, -0.018 [0.014], χ21 = 14.67, P < .001, odds ratio, 1.31; intermediate, 0.054 [0.055], χ21 = 4.70, P = .03, odds ratio, 1.22; and childhood-limited, 0.017 [0.060], χ21 = 6.50, P = .01, odds ratio, 1.27). Findings were specific to PRS for ADHD; PRS for other psychiatric conditions did not differ across trajectories. The proportion of children with multimorbidity was also highest in those in the persistent trajectory (42.5%; 95% CI, 33.9%-51.1%; P < .001) and was associated with persistence of ADHD symptoms independent of PRS. Conclusions and Relevance Persistence of ADHD symptoms across childhood and adolescence in the general population is associated with higher PRS for ADHD. Childhood multimorbidity was also associated with persistence of ADHD symptoms and may help to identify children with ADHD whose symptoms are most likely to continue into adolescence.

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

Abstract 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.

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 = 2x10-5). 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.

Y Chromosome, Mitochondrial DNA and Childhood Behavioural Traits

Many psychiatric traits are sexually dimorphic in terms of prevalence, age of onset, progression and prognosis; sex chromosomes could play a role in these differences. In this study we evaluated the association between Y chromosome and mitochondrial DNA haplogroups with sexually-dimorphic behavioural and psychiatric traits. The study sample included 4,211 males and 4,009 females with mitochondrial DNA haplogroups and 4,788 males with Y chromosome haplogroups who are part of the Avon Longitudinal Study of Parents and Children (ALSPAC) based in the United Kingdom. Different subsets of these populations were assessed using measures of behavioural and psychiatric traits with logistic regression being used to measure the association between haplogroups and the traits. The majority of behavioural traits in our cohort differed between males and females; however Y chromosome and mitochondrial DNA haplogroups were not associated with any of the variables. These findings suggest that if there is common variation on the Y chromosome and mitochondrial DNA associated with behavioural and psychiatric trait variation, it has a small effect.

Investigating late-onset ADHD: a population cohort investigation

Background Adult ADHD has been assumed to be a continuation of childhood‐onset ADHD. However, recent studies have identified individuals with ADHD in adulthood who have not had ADHD in childhood. Whether or not these individuals have a ‘typical’ neurodevelopmental profile is not clear. Methods We tested two explanations for the emergence of apparent late‐onset ADHD symptomatology using the ALSPAC epidemiological cohort, by grouping individuals according to their scores on the Strengths and Difficulties Questionnaire (SDQ) hyperactivity subscale at ages 12 and 17 years. First, we tested whether some of those with apparent late‐onset ADHD symptoms had been potentially misclassified on the basis of earlier SDQ hyperactivity scores (ages 7, 8 and 9 years) or of subthreshold symptoms at age 12 years. Second, we investigated the possibility that those with ‘genuine’ late‐onset ADHD symptoms had a delayed manifestation of the same liability that underlies childhood‐onset symptoms, by investigating whether they had a similar profile of neurodevelopmental impairments (in the domains of autistic symptomatology, language, reading, spelling, executive functioning and IQ) as those with typical childhood‐onset ADHD. Results N = 56/75 (75%) of those with apparent late‐onset ADHD had had high ADHD scores at least one point in childhood, suggesting that they may have been misclassified on the basis of their score at age 12 years. The remaining 19 individuals (25%) with genuine late‐onset ADHD symptoms did not show a profile of neurodevelopmental impairment typically seen in ADHD, instead showing similar levels of autistic symptoms, language skills, executive functioning ability and IQ to those without ADHD symptoms. The only exceptions were that this group showed reading and spelling problems at age 9 years. Conclusions Our work suggests that this small number of individuals with genuine late‐onset symptoms may not be most appropriately considered as having a typical neurodevelopmental disorder.

Association of copy number variation across the genome with neuropsychiatric traits in the general population

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism‐array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (<1%) CNV burden (total number of genes affected by CNVs, total length of CNVs, and largest CNV carried) was analyzed in relation to: psychotic experiences (PEs) and anxiety/depression in adolescence; autism spectrum disorder (ASD) and attention‐deficit hyperactivity disorder (ADHD), ASD and ADHD traits, and cognitive measures during childhood. Outcomes were also assessed in relation to known SCZ CNVs. The number of genes affected by rare CNVs was associated with a continuous measure of ASD: the standardized mean difference [SMD] per gene affected was increased by 0.018 [95%CI 0.011,0.025], p = 3e‐07 for duplications and by 0.021 [95%CI 0.010, 0.032], p = 1e‐04 for deletions. In line with our published results on educational attainment in ALSPAC, intelligence quotient (IQ) was associated with CNV burden: the SMD per gene affected was −0.017 [95%CI −0.025, −0.008] p = 1e‐04 for duplications and −0.023 [95%CI −0.037, −0.009], p = .002 for deletions. Associations were also observed for measures of coherence, attention, memory, and social cognition. SCZ‐associated deletions were associated with IQ (SMD: −0.617 [95%CI −0.936, −0.298], p = 2e‐04), but not with PEs or other traits. We found that rare CNV burden and known SCZ candidate CNVs are associated with neuropsychiatric phenotypes in a nonclinically ascertained sample of young people.

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

Objectives To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other. Design Two-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. Participants 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortium Main outcome measure Odds ratio of AD per standardised deviation increase in years of schooling and intelligence Results There 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. Conclusions There 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.

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<5×10−8) this corresponded to a 0.35 decrease in Z-scores per log-odds in ADHD-liability (P=9.2×10−5). 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=1.4×10−6). 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.