Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany

Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice.

The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genome-wideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction.

Knowledge about a patient’s genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder with symptoms of inattentiveness, impulsiveness, and hyperactivity, which leads to impairments in everyday life and manifests before the age of 12. The developmental trajectory shows a typical course of clinical symptoms, e.g., decrease of hyperactivity, occurrence of comorbid disorders, e.g., addiction and depression, as well as economic costs and social impairments [1]. ADHD has a worldwide prevalence of 5 to 7% of school-age children [2]. In childhood, impulsiveness and hyperactivity are leading symptoms, but decrease in adulthood, whereas inattentiveness becomes the leading symptom [3]. The extent to which symptoms completely remit or persist into adulthood is variable. While the cross-sectional prevalence of ADHD in adults was estimated between 2.5 and 3% [4], the persistence of symptoms with corresponding impairments into adulthood is about 65%.

Early on, clinicians noticed that ADHD-typical behavior occurs frequently in syndromic disorders, e.g., Klinefelter syndrome, Williams syndrome, fragile X syndrome, or tuberous sclerosis [5]. The high heritability [6] suggests a significant genetic component (see below). Genetic research can contribute not only to the elucidation of neurobiological mechanisms but also to clinical questions such as the effect of operationalization or the genetic correlation with comorbid disorders. Patients with ADHD show high comorbidity with autism, obesity, bipolar disorder and depression, anxiety, and substance use disorder [1, 7]. This suggests common underlying risk gene variants. Genetic correlations provide insights how biologic mechanisms manifest in different but related disorders (pleiotropy). In the following, we focus on general aspects of heredity and the complementary results of the analysis of common and rare variants of the genome.

There are several ways to investigate the heritability of ADHD. A classical strategy makes use of twin studies, due to the possibility of assessing the genetic effect (heritability) of the disorder. According to a recent meta-analysis of twin studies, the heritability of ADHD is estimated at 77–88% [8]. The magnitude is therefore similar to that of autism spectrum disorder (about 80%), bipolar disorder (about 75%), and schizophrenia (about 80%) [6].

By means of genome-wide complex trait analysis (GCTA), thousands of individuals are examined for hundreds of thousands of single-nucleotide polymorphisms (SNPs) and thus provide a measure of heritability, the so-called SNP-based heritability. A recent mega-analysis estimates SNP-based heritability (h2 snp = 22%) in a range comparable to previous estimates of h2 snp for ADHD in studies with fewer subjects (h2 snp, 10–28%) [9]. The proportion of heritability that explains this gap between approximately 74% in twin studies and 22% in SNP-based heritability is also referred to as “hidden heritability” in reference to the search for dark matter in astronomy. One explanation is the fact that statistical power of the performed genome-wide association studies (GWAS) is too small to reliably predict genetic associations. A core problem is the required number of test persons in order to reliably map a genetic association, preferably one with a high effect size. A higher number of participants, along with other measures such as the refinement of statistical methods, would certainly help to considerably increase the predictive power of GWAS. A stronger effect size of the SNPs, a higher allele frequency of the rare alleles of SNPs, and a higher LD lower the required number of subjects decisively [10, 11] which in turn means that, in ADHD, there are either very rare alleles or low effect sizes in action given as the latest and largest GWAS only gave 12 genome-wide significant hits by examining more than 20,000 cases.

In addition to the relationship between the number of subjects and the allele frequency of the SNPs, other DNA variants, such as copy number variations (CNV), may explain the missing heritability. CNVs are sections of DNA that either occur in multiple copies or deletions of certain chromosomal sections. CNVs occur at different frequencies but are quite common in patients with ADHD. Small CNVs of only a few kilobases are not detected with the necessary accuracy by GWAS, yet make up the considerably larger part of the genetic variability in ADHD. Large CNVs (> 500 kb) with a frequency of less than 1% can only be detected using sufficiently large sample sizes. In order to be able to map all possible CNVs, whole-genome sequencing (WGS) would be the method of choice.

Until the late 2000s, candidate gene studies on small samples were the method of choice for testing genetic associations. Genes coding for components of the monoamine transmitter systems was first investigated in ADHD. However, none of the candidate genes was replicated by larger genome-wide studies. A summary of these studies can be found in authoritative reviews [8, 12, 13]. While GWAS initially identified only a few loci for psychiatric disorders [14], the most recent collaborations succeeded in discovering a larger number of genome-wide significant loci (p ≤ 5 × 10−8) by significantly increasing the number of cases and control numbers (> 10,000).

A study of 909 parent-child trios with ADHD-affected children revealed strong genetic associations of the genes glucose-fructose oxidoreductase domain-containing 1 (GFOD1) and cadherin 13 (CHD13) [15–17] with ADHD. GFOD1 is expressed in the frontal cortex; the exact function of the gene is not yet known [18]. CDH13 encodes for a calcium-dependent cell-cell adhesion protein that influences neuronal development and synaptic plasticity [22]. In a knockout mouse model of Cdh13, mice showed hyperlocomotion and learning deficits [19]. These findings, together with evidence from other association studies in which CHD13 is associated with, e.g., autism, schizophrenia, bipolar disorder, and depression [20], make CDH13 an interesting candidate gene for ADHD.

Another ADHD candidate gene found in a large family by linkage analysis and replicated in parallel in a global case-control study (n = 2627 ADHD subjects, n = 2531 controls) is adhesion-G protein-coupled-receptor-L3 (ADGRL3, formerly LPHN3), a brain-specific G protein-coupled receptor with cell adhesion function [23]. ADGRL3 was confirmed as an ADHD candidate locus in two other independent case-control studies, by association of one haplotype in ADGRL3 [21] and single associations of several SNPs [22]. In the zebrafish model, the loss of adgrl3 leads to a reduction of dopaminergic neurons in the ventral diencephalon and a hyperactive/impulsive phenotype [23], whereas in Adgrl3-knockout mice, an increase in reward motivation and activity level as well as other ADHD-analogous behaviors was observed—parallel to dysregulation of the dopamine transporter [24, 25]. This suggests that the biological validation of an ADHD candidate gene from a GWAS in an animal model can elucidate potential mechanisms of pathogenesis. On the other side, it must be critically questioned whether behavioral traits such as hyperlocomotion in animals are equivalent ADHD-hyperactivity in humans.

In the most recent and comprehensive meta-analysis of ADHD GWAS data sets to date (20,183 cases, 35,191 controls), 12 genomic loci with genome-wide significance (p