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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: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.

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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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