Association between inflammation and cognition: Triangulation of evidence using a population-based cohort and Mendelian randomization analyses.

BACKGROUND: Inflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear. METHODS: In a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability. RESULTS: In the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, -0.02 [95 % confidence interval (CI) -0.06 to 0.02, p = 0.27] to 0.02 [95 % CI -0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, -0.73 [95 % CI -2.47 to 1.01, p = 0.41] to 0.21 [95 % CI -1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, -0.02 [95 % CI -0.05 to 0.01, p = 0.12] to 0.03 [95 % CI -0.01 to 0.07, p = 0.19]). CONCLUSIONS: Our MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.

Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study.

BACKGROUND: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. METHODS: We used data from a UK-based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising 7689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age-adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder-adjusted regression models. Multiple imputation was used to account for missing data, and restricted cubic splines were used to investigate nonlinear associations. Mendelian randomization was used to strengthen causal inference. RESULTS: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR = 0.98, 95% CI = 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR = 0.99, 95% CI = 0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR = 1.08, 95% CI = 0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. LIMITATIONS: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. CONCLUSIONS: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer's disease.

Few studies suggest possible links between attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and Alzheimer's disease but they have been limited by small sample sizes, diagnostic and recall bias. We used two-sample Mendelian randomization (MR) to estimate the bidirectional causal association between genetic liability to ADHD and ASD on Alzheimer's disease. In addition, we estimated the causal effects independently of educational attainment and IQ, through multivariable Mendelian randomization (MVMR). We employed genetic variants associated with ADHD (20,183 cases/35,191 controls), ASD (18,381 cases/27,969 controls), Alzheimer's disease (71,880 cases/383,378 controls), educational attainment (n = 766,345) and IQ (n = 269,867) using the largest GWAS of European ancestry. There was limited evidence to suggest a causal effect of genetic liability to ADHD (odds ratio [OR] = 1.00, 95% CI: 0.98-1.02, P = 0.39) or ASD (OR = 0.99, 95% CI: 0.97-1.01, P = 0.70) on Alzheimer's disease. Similar causal effect estimates were identified as direct effects, independent of educational attainment (ADHD: OR = 1.00, 95% CI: 0.99-1.01, P = 0.76; ASD: OR = 0.99, 95% CI: 0.98-1.00, P = 0.28) and IQ (ADHD: OR = 1.00, 95% CI: 0.99-1.02. P = 0.29; ASD: OR = 0.99, 95% CI: 0.98-1.01, P = 0.99). Genetic liability to Alzheimer's disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR = 1.12, 95% CI: 0.86-1.44, P = 0.37; ASD: OR = 1.19, 95% CI: 0.94-1.51, P = 0.14). We found limited evidence to suggest a causal effect of genetic liability to ADHD or ASD on Alzheimer's disease; and vice versa.

Parental inflammatory bowel disease and autism in children.

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses.

Higher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring's own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73-1.07, p = 0.21; offspring's own PRS on autism: RR 1.11, 95%CI 0.88-1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98-1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

Is genetic liability to ADHD and ASD causally linked to educational attainment?

BACKGROUND: The association patterns of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) with educational attainment (EA) are complex; children with ADHD and ASD are at risk of poor academic outcomes, and parental EA has been associated with risk of ADHD/ASD in the offspring. Little is known on the causal links between ADHD, ASD, EA and the potential contribution of cognitive ability. METHODS: Using the latest genome-wide association studies (GWAS) summary data on ADHD, ASD and EA, we applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to ADHD and ASD on EA. Reverse direction analyses were additionally performed. Multivariable MR was performed to estimate any effects independent of cognitive ability. RESULTS: Genetic liability to ADHD had a negative effect on EA, independently of cognitive ability (MVMRIVW: -1.7 months of education per doubling of genetic liability to ADHD; 95% CI: -2.8 to -0.7), whereas genetic liability to ASD a positive effect (MVMRIVW: 30 days per doubling of the genetic liability to ASD; 95% CI: 2 to 53). Reverse direction analyses suggested that genetic liability to higher EA had an effect on lower risk of ADHD, independently of cognitive ability (MVMRIVWOR: 0.33 per SD increase; 95% CI: 0.26 to 0.43) and increased risk of ASD (MRIVWOR: 1.51 per SD increase; 95% CI: 1.29 to 1.77), which was partly explained by cognitive ability (MVMRIVWOR per SD increase: 1.24; 95%CI: 0.96 to 1.60). CONCLUSIONS: Genetic liability to ADHD and ASD is likely to affect educational attainment, independently of underlying cognitive ability.

The Association Between Locus of Control and Psychopathology: A Cross-Cohort Comparison Between a UK (Avon Longitudinal Study of Parents and Children) and a Japanese (Tokyo Teen Cohort) Cohort.

Background: An external locus of control (externality) is associated with poorer psychopathology in individualist cultures, but associations are reported to be weaker in collectivist cultures where an external style is less maladaptive. We investigated the prospective association between externality and psychotic-like experiences (PLE) and depressive symptoms (DS) and compared the strength of associations between a UK and a Japanese cohort. Method: Cross-cultural cohort study of a UK (Avon Longitudinal Study of Parents and Children) and a Japanese cohort (Tokyo Teen Cohort). Externality was assessed using the Children's Nowicki and Strickland Internal, External Scale and DS using the Short Moods and Feelings Questionnaire in both cohorts, PLE were assessed with the Psychosis-Like Experiences Questionnaire (ALSPAC), and the Adolescent Psychotic-Like Symptom Screener (TTC). Associations were investigated using multivariable regression models and bivariate regression models to compare the strength of associations. Results: Mean externality in both childhood and adolescence was higher in ALSPAC than in the TTC. Childhood externality was associated with PLE in late childhood and adolescence in both cohorts and adolescent externality was associated with PLE in young adulthood in the ALSPAC cohort. There was a more mixed pattern of association between externality and DS scores. There was little evidence of any differences in the strength of associations between externality and different psychopathologies, or between cohorts. In ALSPAC adolescent externality and early adult psychopathology were more strongly associated than childhood externality and adolescent and early adult psychopathology. There was no evidence that change in externality between childhood and adolescence was associated with new onset PLE or DS in early adulthood. Conclusion: An external locus of control is associated with poor mental health regardless of cultural context.

ADHD and depression: investigating a causal explanation.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods. METHODS: First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18-25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data. RESULTS: Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05-1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12-1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02-1.13). CONCLUSIONS: Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.

The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is important because comorbid health problems increase the serious social and economic impacts of ADHD. We used 2-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings underwent bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (odds ratio = 1.29, 95% confidence interval: 1.02, 1.63) and coronary artery disease (odds ratio = 1.11, 95% confidence interval: 1.03, 1.19) with consistent results across MR approaches. There was additional MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic, and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD, and suggest that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease.

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

BACKGROUND: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. RESULTS: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (ßMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; ßMR -0.009, 95% CI -0.02 to 0.002, P 0.11). CONCLUSIONS: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic.

An Autism Spectrum Disorder (ASD) diagnosis is often used to access services. We investigated whether ASD diagnostic outcome varied when DSM-5 was used compared to ICD-10R and DSM-IV-TR in a clinical sample of 150 intellectually able adults. Of those diagnosed with an ASD using ICD-10R, 56 % met DSM-5 ASD criteria. A further 19 % met DSM-5 (draft) criteria for Social Communication Disorder. Of those diagnosed with Autistic Disorder/Asperger Syndrome on DSM-IV-TR, 78 % met DSM-5 ASD criteria. Sensitivity of DSM-5 was significantly increased by reducing the number of criteria required for a DSM-5 diagnosis, or by rating 'uncertain' criteria as 'present', without sacrificing specificity. Reduced rates of ASD diagnosis may mean some ASD individuals will be unable to access clinical services.