Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment

Prenatal smoking, alcohol and caffeine exposure and maternal-reported attention deficit hyperactivity disorder symptoms in childhood:triangulation of evidence using negative control and polygenic risk score analyses

Background and aims Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors. Design First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner's substance use). The results were meta-analysed across the cohorts. Secondly, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. Setting We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. Participants Phenotype data available for children were: NALSPAC = 5455–7751; NGENR = 1537–3119; NMOBA = 28 053–42 206. Genotype data available for mothers was: NALSPAC = 7074; NMOBA = 14 583. Measurements A measure of offspring ADHD symptoms at age 7–8 years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. Findings The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms [odds ratio (OR)SMOKING = 1.11, 95% confidence interval (CI) = 1.00–1.23; ORALCOHOL = 1.27, 95% CI = 1.08–1.49; ORCAFFEINE = 1.05, 95% CI = 1.00–1.11], while not for fathers (ORSMOKING = 1.03, 95% CI = 0.95–1.13; ORALCOHOL = 0.83, 95% CI = 0.47–1.48; ORCAFFEINE = 1.02, 95% CI = 0.97–1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa. Conclusions There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms

Maternal and offspring genetic risk score analyses of fetal alcohol exposure and attention-deficit hyperactivity disorder risk in offspring

Background: Studies investigating the effects of prenatal alcohol exposure on childhood attention-deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7–8 years. Methods: We used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (NALSPAC = 8196; NMOBA = 13,614), fathers (NMOBA = 13,935), and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status. Results: The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97–1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING = 0.98, 95% CI 0.94–1.02; ORNO DRINKING = 0.99, 95% CI 0.97–1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa. Conclusions: We did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.publishedVersio

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

Do environmental effects indexed by parental genetic variation influence common psychiatric symptoms in childhood?

Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain individual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this sample, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining individual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale samples of genotyped families with information on childhood psychiatric outcomes

Modeling assortative mating and genetic similarities between partners, siblings, and in-laws

Assortative mating on heritable traits can have implications for the genetic resemblance between siblings and in-laws in succeeding generations. We studied polygenic scores and phenotypic data from pairs of partners (n = 26,681), siblings (n = 2,170), siblings-in-law (n = 3,905), and co-siblings-in-law (n = 1,763) in the Norwegian Mother, Father and Child Cohort Study. Using structural equation models, we estimated associations between measurement error-free latent genetic and phenotypic variables. We found evidence of genetic similarity between partners for educational attainment (rg = 0.37), height (rg = 0.13), and depression (rg = 0.08). Common genetic variants associated with educational attainment correlated between siblings above 0.50 (rg = 0.68) and between siblings-in-law (rg = 0.25) and co-siblings-in-law (rg = 0.09). Indirect assortment on secondary traits accounted for partner similarity in education and depression, but not in height. Comparisons between the genetic similarities of partners and siblings indicated that genetic variances were in intergenerational equilibrium. This study shows genetic similarities between extended family members and that assortative mating has taken place for several generations.publishedVersio

Examining intergenerational risk factors for conduct problems using polygenic scores in the Norwegian Mother, Father and Child Cohort Study

The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children's behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, β = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, β = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems-though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility

On the importance of parenting in externalizing disorders: an evaluation of indirect genetic effects in families

Background: Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems. Methods: The study used genome-wide single nucleotide polymorphism data from 9,675 parent–offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age. Results: Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene–environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems. Conclusions: This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene–environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors.publishedVersio

The importance of timing of socioeconomic disadvantage throughout development for depressive symptoms and brain structure

Prior studies have reported associations between socioeconomic disadvantage, brain structure and mental health outcomes, but the timing of these relations is not well understood. Using prospective longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC), this preregistered study examined whether socioeconomic disadvantage related differentially to depressive symptoms (n=3012–3530) and cortical and subcortical structures (n=460–733) in emerging adults, depending on the timing of exposure to socioeconomic disadvantage. Family income in early childhood and own income measured concurrently were both significantly related to depressive symptoms in emerging adulthood. Similar results were observed for perceived financial strain. In contrast, only family income in early childhood was associated with brain structure in emerging adulthood, with positive associations with intracranial volume and total and regional cortical surface area. The findings suggest that both objective and subjective aspects of one's financial standing throughout development relate to depressive symptoms in adulthood, but that specifically early life family income is related to brain structural features in emerging adulthood. This suggests that associations between socioeconomic disadvantage and brain structure originate early in neurodevelopment, highlighting the role of timing of socioeconomic disadvantage.</p

Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study

BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β =  − 0.11, 95% CI [− 0.12, − 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (β =  − 0.07, 95% CI [− 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general