Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: utilizing electronic health records in a Phenome-Wide Association Study.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history. METHODS: We used data from the Estonian Biobank cohort (N = 111 261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRSADHD and 1515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with (1) ADHD diagnosis and (2) questionnaire-based high ADHD risk analyses. RESULTS: After Bonferroni correction (p = 3.3 × 10-5) we identified 80 medical conditions associated with PRSADHD. The strongest evidence was seen with chronic obstructive pulmonary disease (OR 1.15, CI 1.11-1.18), obesity (OR 1.13, CI 1.11-1.15), and type 2 diabetes (OR 1.11, CI 1.09-1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor. CONCLUSIONS: Overall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.

Overview of CAPICE-Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie Sklodowska-Curie International Training Network.

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

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.

The role of depression and antidepressant treatment in antihypertensive medication adherence and persistence: Utilising electronic health record data.

Higher blood pressure levels in patients with depression may be associated with lower adherence to antihypertensive medications (AHMs). Here, we use electronic health record (EHR) data from the Estonian Biobank (EstBB) to investigate the role of lifetime depression in AHM adherence and persistence. We also explore the relationship between antidepressant initiation and intraindividual change in AHM adherence among hypertension (HTN) patients with newly diagnosed depression. Diagnosis and pharmacy refill data were obtained from the National Health Insurance database. Adherence and persistence to AHMs were determined for hypertension (HTN) patients initiating treatment between 2009 and 2017 with a three-year follow-up period. Multivariable regression was used to explore the associations between depression and AHM adherence or persistence, adjusting for sociodemographic, genetic, and health-related factors. A linear mixed-effects model was used to estimate the effect of antidepressant treatment initiation on antihypertensive medication adherence, adjusting for age and sex. We identified 20,724 individuals with newly diagnosed HTN (6294 depression cases and 14,430 controls). Depression was associated with 6% lower probability of AHM adherence (OR = 0.943, 95%CI = 0.909-0.979) and 12% lower odds of AHM persistence (OR = 0.876, 95%CI = 0.821-0.936). Adjusting for sociodemographic, genetic, and health-related factors did not significantly influence these associations. AHM adherence increased 8% six months after initiating antidepressant therapy (N = 132; ß = 0.078; 95%CI = 0.025-0.131). Based on the EHR data on EstBB participants, depression is associated with lower AHM adherence and persistence. Additionally, antidepressant therapy may help improve AHM adherence in patients with depression.

Prenatal smoking, alcohol and caffeine exposure and offspring externalizing disorders: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Several studies have indicated an association between maternal prenatal substance use and offspring externalizing disorders; however, it is uncertain whether this relationship is causal. We conducted a systematic review to determine: (1) if the literature supports a causal role of maternal prenatal substance use on offspring externalizing disorders diagnosis and (2) whether these associations differ across externalizing disorders. METHODS: We searched Web of Science, Embase, PsycINFO and Medline databases. Risk of bias assessment was conducted using the Newcastle-Ottawa Scale (NOS), and where possible meta-analysis was conducted for studies classed as low risk of bias. We included studies of any design that examined prenatal smoking, alcohol or caffeine use. Studies in non-English language, fetal alcohol syndrome and comorbid autism spectrum disorders were excluded. Participants in the included studies were mothers and their offspring. Measurements included prenatal smoking, alcohol or caffeine use as an exposure, and diagnosis of attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) in offspring as an outcome. RESULTS: We included 63 studies, 46 of which investigated smoking and ADHD. All studies were narratively synthesized, and seven studies on smoking and ADHD were meta-analysed. The largest meta-analysis based on genetically sensitive design included 1 011 546 participants and did not find evidence for an association [odds ratio (OR)1-9 cigarettes = 0.90, 95% confidence interval (CI) = 0.83-1.11; OR > 10 cigarettes = 1.04, 95% CI = 0.79-1.36). Studies on alcohol exposure in all the outcomes reported inconsistent findings and no strong conclusions on causality can be made. Studies on caffeine exposure were mainly limited to ADHD and these studies do not support a causal effect. CONCLUSIONS: There appears to be no clear evidence to support a causal relationship between maternal prenatal smoking and offspring attention-deficit hyperactivity disorder. Findings with alcohol and caffeine exposures and conduct disorder and oppositional-defiant disorder need more research, using more genetically sensitive designs.

The role of ADHD genetic risk in mid-to-late life somatic health conditions.

Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42-88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.

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 child genetic liability for smoking and caffeine consumption and child mental health: an intergenerational genetic risk score analysis in the ALSPAC cohort.

BACKGROUND AND AIMS: Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We aimed to separate effects of the maternal environment (intrauterine or postnatal) from pleiotropic genetic effects. DESIGN: Secondary analysis of a longitudinal study. We (i) validated smoking and caffeine genetic risk scores (GRS) derived from published genome-wide association study (GWAS) for use during pregnancy, (ii) compared estimated effects of maternal and offspring GRS on childhood mental health outcomes and (iii) tested associations between maternal and offspring GRS on their respective outcomes. SETTING: We used data from a longitudinal birth cohort study from England, the Avon Longitudinal Study of Parents and Children (ALSPAC). PARTICIPANTS: Our sample included 7921 mothers and 7964 offspring. MEASUREMENTS: Mental health and non-mental health phenotypes were derived from questionnaires and clinical assessments: 79 maternal phenotypes assessed during and outside of pregnancy and 71 offspring phenotypes assessed in childhood (<10 years) and adolescence (11-18 years). FINDINGS: The maternal smoking and caffeine GRS were associated with maternal smoking and caffeine consumption during pregnancy (2nd trimester: Psmoking  = 3.0 × 10-7 , Pcaffeine  = 3.28 × 10-5 ). Both the maternal and offspring smoking GRS showed evidence of association with reduced childhood anxiety symptoms (ßmaternal  = -0.033; ßoffspring  = -0.031) and increased conduct disorder symptoms (ßmaternal  = 0.024; ßoffspring  = 0.030), after correcting for multiple testing. Finally, the maternal and offspring smoking GRS were associated with phenotypes related to sensation seeking behaviours in mothers and adolescence (e.g. increased symptoms of externalising disorders, extraversion and monotony avoidance). The caffeine GRS showed weaker evidence for associations with mental health outcomes. CONCLUSIONS: We did not find strong evidence that maternal smoking and caffeine genetic risk scores have a causal effect on offspring mental health outcomes. Our results confirm that the smoking genetic risk scores also captures liability for sensation seeking personality traits.

Characterization of alcohol polygenic risk scores in the context of mental health outcomes: Within-individual and intergenerational analyses in the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Heavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages. DESIGN: We characterized a PRS reliably associated with patterns of adult alcohol consumption by 1) validating whether it predicts own alcohol use at different life-stages (pregnancy, adolescence) of interest for mental health impact. Additionally, we explored associations of alcohol PRS on mental health phenotypes 2) within-individuals (using own alcohol PRS on own phenotypes) and 3) intergenerationally (using maternal alcohol PRS on offspring phenotypes). We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 960-7841). Additional substance abuse behaviors and mental health/behavioral outcomes were investigated (alcohol phenotypes n = 22; health phenotypes n = 91). FINDINGS: Maternal alcohol PRS was associated with consumption during pregnancy (strongest signal: alcohol frequency at 18 weeks' gestation: ß = 0.041, 95%CI = 0.0.02-0.06), p = 1.01 × 10-5, adjusted R2 = 1.6 %), offspring alcohol PRS did not predict offspring alcohol consumption. We found evidence for an association of maternal alcohol PRS with own perinatal depression (OR = 1.10, 95% CI = 1.02 to 1.18, p = 0.022) and decreased offspring intellectual ability (ß=-0.209, 95% CI -0.38 to -0.04, p= 0.016). CONCLUSIONS: These alcohol PRS are a valid proxy for maternal alcohol use in pregnancy. Offspring alcohol PRS was not associated with drinking in adolescence. Consistently with results from different study designs, we found evidence that maternal alcohol PRS are associated with both prenatal depression and decreased offspring intellectual ability.

Early vocabulary in full term and preterm Estonian children.

BACKGROUND: Preterm birth is considered to be a high risk factor for child development and early vocabulary can be used as an indicator for later development. AIMS: The aim of the present study is to compare the size of early vocabulary, proportional use of different word categories, and mean length of utterance (henceforth MLU) of preterm and full term children. METHOD: The sample consisted of 40 preterm (corrected ages 16-25 months) and two matched groups of full term children. First full term group consisted of 120 children who were matched by age and gender. Second full term group consisted of 109 children who were matched by age, gender and size of productive vocabulary. The data for this study were gathered using the Estonian adaptation of MacArthur-Bates Communicative Development Inventory: Words and Sentences. RESULTS: Full term children who were matched by age and gender had larger vocabulary as compared to the preterm children's vocabulary (U = 1758.5, p = 0.01). Poisson regression yielded that age, gender, and preterm birth explained significantly the variance in the vocabulary size. Poisson regressions showed that all three variables explained significantly variance in proportional use of social terms and predicates. Age had significant effect for proportional use of common nouns. Age and preterm birth had a significant effect on the proportional use of function words. MLU was shorter in preterm than in full term children (U = 1125.0, p = 0.002). CONCLUSIONS: Estonian preterm children's vocabulary is slightly smaller than full term children's vocabulary. There is a difference in the proportions of word categories used, as preterm children use more social terms, and less predicates, and function words.