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The Molecular Genetic Architecture of Attention Deficit Hyperactivity Disorder

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The Molecular Genetic Architecture of Attention Deficit Hyperactivity Disorder Molecular Psychiatry (2015) 20, 289–297 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp EXPERT REVIEW The molecular genetic architecture of attention deficit hyperactivity disorder Z Hawi1, TDR Cummins1, J Tong1, B Johnson1, R Lau1, W Samarrai2 and MA Bellgrove1 Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition which affects 2–10% of school age children worldwide. Although the underlying molecular mechanism for the disorder is poorly understood, familial, twin and adoption studies suggest a strong genetic component. Here we provide a state-of-the-art review of the molecular genetics of ADHD incorporating evidence from candidate gene and linkage designs, as well as genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) and rare copy number variations (CNVs). Bioinformatic methods such as functional enrichment analysis and protein–protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Candidate gene associations of minor effect size have been replicated across a number of genes including SLC6A3, DRD5, DRD4, SLC6A4, LPHN3, SNAP-25, HTR1B, NOS1 and GIT1. Although case-control SNP-GWAS have had limited success in identifying common genetic variants for ADHD that surpass critical significance thresholds, quantitative trait designs suggest promising associations with Cadherin13 and glucose–fructose oxidoreductase domain 1 genes. Further, CNVs mapped to glutamate receptor genes (GRM1, GRM5, GRM7 and GRM8) have been implicated in the aetiology of the disorder and overlap with bioinformatic predictions based on ADHD GWAS SNP data regarding enriched pathways. Although increases in sample size across multi-center cohorts will likely yield important new results, we advocate that this must occur in parallel with a shift away from categorical case-control approaches that view ADHD as a unitary construct, towards dimensional approaches that incorporate endophenotypes and statistical classification methods. Molecular Psychiatry (2015) 20, 289–297; doi:10.1038/mp.2014.183; published online 20 January 2015 INTRODUCTION endophenotypes and data-driven classification techniques, must Attention deficit hyperactivity disorder (ADHD) is the most now be used to advance the field. prevalent psychiatric condition of childhood, affecting 2–10% of school age children worldwide. Its features include extreme levels THE MOLECULAR GENETICS OF ADHD of motor activity, impulsivity and inattention. Individuals with ADHD may present with predominantly inattentive or hyperactive The last two decades of molecular genetic research in complex symptoms or, more commonly, a combination of both (ADHD- diseases including psychiatric conditions has been fuelled by the combined type). These symptoms are chronic and persist into common disease common variant (CDCV) hypothesis. The CDCV adulthood in ~ 30–60% of cases and are associated with lowered hypothesis argues that common genetic variations (allele fre- 4 academic functioning, increased risk for drug abuse and negative quency 5%) of low penetrance in the population are the major consequences for family and peer relations.1,2 Although environ- contributors to genetic susceptibility to common diseases. Although there are examples where the CDCV hypothesis has mental influences (such as low birth weight, delivery complica- proven useful for mapping genes underlying complex diseases tions, toxin exposure and food additives) have been identified, such as Crohn's disease and Alzheimer's disease,4,5 most of the genetic factors are recognised as the critical etiological compo- reported associations are of minor/modest effect size and account nent of ADHD. Large twin studies have consistently shown higher for a small proportion of the heritability of the associated disease/ monozygotic than dizygotic concordance rates with heritability trait.6 An alternative hypothesis is the common disease rare – 3 estimates ~ 75 90%. Although the genetic architecture of ADHD variant (CDRV) hypothesis which predicts that multiple rare is not known, a multi-factorial model is consistent with the high variations (⩽5% frequency) have a cumulative effect that accounts prevalence of ADHD in the general population and the high for a significant proportion of the genetic risk for common – concordance rate in monozygotic twins (68 81%) but modest risk conditions7 and that much of the genetic association signals to first-degree relatives (~20%). This article provides a state-of-the- reported under the CDCV approach actually represent diluted risk art review of the molecular genetics of ADHD. Findings from signals of rare, highly penetrant causal variants.8 candidate gene and genome-wide association studies (GWAS) are Earlier psychiatric genetic association studies pursued the CDCV integrated using bioinformatics and complex network analysis. hypothesis with a candidate gene approach (pre-specified gene Whereas the vast majority of genetic studies have treated ADHD of interest), using a single or limited number of genetic markers, as a unitary construct, we argue that a shift towards hetero- to examine the relationship between a gene and a disease geneity reduction, including the use of empirically derived condition. Advances in microarray technologies (high throughput 1School of Psychological Sciences, Monash University, Melbourne, VIC, Australia and 2New York City College of Technology, City University of New York, New York, NY, USA. Correspondence: Dr Z Hawi, School of Psychological Sciences, Monash University, Building 17, Clayton Campus, Wellington Road, Melbourne,VIC 3800, Australia. E-mail: [email protected] Received 18 April 2014; revised 14 November 2014; accepted 19 November 2014; published online 20 January 2015 Attention deficit hyperactivity disorder Z Hawi et al 290 Table 1. Candidate genes showing replicated evidence of association with ADHD Gene Associated variant Location Biological function References SLC6A3 40 bp VNTR 3′ UTR Regulator of extracellular dopamine and mediates the reuptake of Cook et al.91a; Gizer dopamine from the synapse. et al.92b DRD4 48 bp VNTR Exon GPCR activated by the neurotransmitter dopamine. La Hoste et al.93a; Gizer et al.92b DRD5 148 bp 5ʹ flanking Transduces extracellular signals in the form of dopamine into several Daly et al.94a; dinucleotide intracellular responses, including effects on adenylate cyclase, Ca2+ Gizer et al.92b repeats levels and K+ conductance. SLC6A4 40 bp indel 5ʹ flanking A member of a transporter family that is Na+ and Cl dependent. Manor et al.95a; Mediates the reuptake of serotonin from synapses. Gizer et al.92b HTR1B rs6296 Exon1 GPCR for serotonin. A prime target for antidepressant drugs and Hawi et al.96a; psychoactive substances Gizer et al.92b SNAP25 rs3746544 3ʹ UTR Plasma membrane protein essential for synaptic vesicle fusion and Brophy et al.97a; neurotransmitter release Gizer et al.92b SLC9A9 Inversion Region A member of large solute carrier family 9. Acts in electroneutral de Silva et al.98a; breakpoints 3p14—q21 exchange of hydrogen/sodium ions across membranes. Lasky-Su et al.21c; Mick et al.23c LPHN3 Haplotype Exon 4–19 Encodes a member of the latrophilin subfamily of GPCR. May act in Arcos-Burgos encompassing signal transduction and cell adhesion. et al.99a; Ribases exons et al.100d GIT1 rs550818 Intron GPCR kinase. Thought to be involved in vesicle trafficking, cell Won et al.101a adhesion and increasing the speed of cell migration. Overexpression of GIT1 is known to regulate the beta2-adrenergic receptor. NOS1 180–210 bp CA Exon Mediates several biological processes including neurotransmission Reif et al.102a; repeat and is reported to associate with neurodegenerative conditions. Franke et al.103c Abbreviations: ADHD, attention deficit hyperactivity disorder; GPCR, G-protein-coupled receptors; GWAS, genome wide association studies; UTR, untranslated region; VNTR, variable number tandem repeat. aFirst reported by. bMeta-analysis article. cGWAS finding. dAssociation in large sample or validation using animal model. genotyping) have now provided a powerful tool to investigate DAT1 VNTR influences neurocognitive measures in both ADHD genome-wide differences between patients and controls in and non-clinical samples.17,18 hypothesis-free designs. Like many candidate gene studies, the GWAS approach uses single-nucleotide polymorphisms (SNPs) to pursue the CDCV hypothesis. In contrast, the common disease rare GWAS IN ADHD variant approach has been interrogated at genome-wide level SNP-GWAS using copy number of variations (CNV) and only a limited number In childhood ADHD, four case-control GWAS19–22, two family- of single-nucleotide variant analyses have been performed across based GWAS23,24 and a quantitative trait loci GWAS25 have been 9,10 all psychiatric disorders. performed. One ADHD case-control GWAS has been performed in adults, while a further quantitative trait loci GWAS has been performed in a population-based cohort of adolescents and GENETIC ASSOCIATION STUDIES OF ADHD IN THE PRE-GWAS 26,27 ERA adults. In addition, a meta-analysis has been performed on the child studies28 however, neither the childhood or adult GWAS nor Dysregulation in biogenic neurotransmission has traditionally the subsequent meta-analysis have yielded genome-wide sig- been implicated in the aetiology of ADHD. The clinical effective- nificance (P ⩽ 5×10− 8). In contrast, a family-based association ness of stimulant medications (such as
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