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Genetic influences on ADHD symptom dimensions: Examination of a priori candidates, gene-based tests, genome-wide variation, and SNP heritability.

ABSTRACT: Although the heritability of ADHD is estimated to be high, identifying specific genetic markers remains challenging. Most studies to date have examined the genetic basis of ADHD by employing dichotomous diagnostic phenotypes, but, as ADHD symptoms tend to be phenotypically dimensional, an alternative and potentially informative approach is to examine continuous indices of inattention and hyperactivity-impulsivity symptoms. The current study aimed to identify genetic effects on dimensionally-focused adult ADHD-related phenotypes in 990 individuals of European ancestry with intentionally low levels of substance misuse to avoid confounding. The study used four complementary approaches: (1) analysis of a priori candidate loci identified in prior meta-analytic work; (2) gene-based analysis; (3) hypothesis-free genome-wide association testing; and (4) single nucleotide polymorphism (SNP) heritability via genomic-relatedness-matrix restricted maximum likelihood analysis (GREML). The GREML analysis included a bivariate model to test whether the ADHD symptom dimensions index the same genetic liability. The results revealed significant differential associations between two a priori loci and ADHD phenotypes, rs6296 in HTR1B with inattention and rs3746544 in SNAP-25 with hyperactivity-impulsivity. No significant gene-based or genome-wide associations were detected, but SNP heritability revealed that a large portion of genetic variance was accounted for by common SNPs (44%, 55%, and 59% for inattention, hyperactivity-impulsivity, and total ADHD, respectively) and substantial shared genetic variance across inattention and hyperactivity-impulsivity (86%). These findings reveal both unique and common patterns of genetic influences across dimensional ADHD-related phenotypes. More broadly, these findings reveal the value in using multiple methods to understand the genetic etiology of ADHD.

SUBMITTER: Bidwell LC

PROVIDER: S-EPMC5690554 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Genetic influences on ADHD symptom dimensions: Examination of a priori candidates, gene-based tests, genome-wide variation, and SNP heritability.

Bidwell L Cinnamon LC Gray Joshua C JC Weafer Jessica J Palmer Abraham A AA de Wit Harriet H MacKillop James J

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20170601 4

Although the heritability of ADHD is estimated to be high, identifying specific genetic markers remains challenging. Most studies to date have examined the genetic basis of ADHD by employing dichotomous diagnostic phenotypes, but, as ADHD symptoms tend to be phenotypically dimensional, an alternative and potentially informative approach is to examine continuous indices of inattention and hyperactivity-impulsivity symptoms. The current study aimed to identify genetic effects on dimensionally-focu ...[more]

PMID: 28512748

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Project description:Backgroundattention-deficit/hyperactivity disorder (ADHD) is associated with both polygenic liability and environmental exposures, both intrinsic to the family, such as family conflict, and extrinsic, such as air pollution. However, much less is known about the interplay between environmental and genetic risks relevant to ADHD-a better understanding of which could inform both mechanistic models and clinical prediction algorithms.MethodsTwo independent data sets, the population-based Adolescent Brain Cognitive Development Study (ABCD) (N = 11,876) and the case-control Oregon-ADHD-1000 (N = 1449), were used to examine additive (G + E) and interactive (GxE) effects of selected polygenic risk scores (PRS) and environmental factors in a cross-sectional design. Genetic risk was measured using PRS for nine mental health disorders/traits. Exposures included family income, family conflict/negative sentiment, and geocoded measures of area deprivation, lead exposure risk, and air pollution exposure (nitrogen dioxide and fine particulate matter).ResultsADHD PRS and family conflict jointly predicted concurrent ADHD symptoms in both cohorts. Additive-effects models, including both genetic and environmental factors, explained significantly more variation in symptoms than any individual factor alone (joint R 2 = .091 for total symptoms in ABCD; joint R 2 = .173 in Oregon-ADHD-1000; all delta-R 2 p-values <2e-7). Significant effect size heterogeneity across ancestry groups was observed for genetic and environmental factors (e.g., Q = 9.01, p = .011 for major depressive disorder PRS; Q = 13.34, p = .001 for area deprivation). GxE interactions observed in the full ABCD cohort suggested stronger environmental effects when genetic risk is low, though they did not replicate.ConclusionsReproducible additive effects of PRS and family environment on ADHD symptoms were found, but GxE interaction effects were not replicated and appeared confounded by ancestry. Results highlight the potential value of combining exposures and PRS in clinical prediction algorithms. The observed differences in risks across ancestry groups warrant further study to avoid health care disparities.

Project description:The goal of this article is to investigate the symptom dimensions of oppositional defiant disorder (ODD; irritability, defiance) and attention deficit/hyperactivity disorder (ADHD; inattention, hyperactivity-impulsivity) as predictors of academic performance, depressive symptoms, and peer functioning in middle childhood. Children (N = 346; 51% female) were assessed via teacher-report on measures of ODD/ADHD symptoms at baseline (Grades K-2) and academic performance, depressive symptoms, peer rejection, and victimization on 7 occasions over 4 school years (K-2 through 3-5). Self-report and grade point average data collected in Grades 3-5 served as converging outcome measures. Latent growth curve and multiple regression models were estimated using a hierarchical/sensitivity approach to assess robustness and specificity of effects. Irritability predicted higher baseline depressive symptoms, peer rejection, and victimization, whereas defiance predicted higher baseline peer rejection; however, none of these ODD-related effects persisted 3 years later to Grades 3-5. In contrast, inattention predicted persistently poorer academic performance, persistently higher depressive symptoms, and higher baseline victimization; hyperactivity-impulsivity predicted subsequent peer rejection and victimization in Grades 3-5. In converging models, only inattention emerged as a robust predictor of 3-year outcomes (viz., grade point average, depressive symptoms, peer rejection, and relational victimization). Broadly, ODD dimensions-particularly irritability-may be linked to acute disturbances in social-emotional functioning in school-age children, whereas ADHD dimensions may predict more persistent patterns of peer, affective, and academic problems. By examining all 4 ODD/ADHD symptom dimensions simultaneously, the present analyses offer clarity and specificity regarding which dimensions affect what outcomes, and when. Findings underscore the importance of multidimensional approaches to research, assessment, and intervention.

Project description:Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case-control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 × 10-6). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism can be significantly predicted across ancestry, and highlight the importance of studying polygenic contributions to personality in non-European populations.

Dataset Information

Genetic influences on ADHD symptom dimensions: Examination of a priori candidates, gene-based tests, genome-wide variation, and SNP heritability.

Publications

Genetic influences on ADHD symptom dimensions: Examination of a priori candidates, gene-based tests, genome-wide variation, and SNP heritability.

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