ebook_ADHD2019

12 Rohde, Buitelaar, Gerlach & Faraone ADHD is inherited and that, for most cases of ADHD, many DNA risk variants are needed before the disorder becomes evident. These risk variants combine and interact with environmental risk factors to create the pathophysiology of the disor- der. In the coming decades, scientists will discover more common and rare genetic and environmental risk factors. This process will set the stage for discoveries that will improve treatment and, perhaps, allow for preventive measures. It is humbling to realize that none of the genome-wide significant variants dis- covered by GWAS had been predicted by models of ADHD’s pathophysiology. The loci discovered challenge the idea that ADHD’s etiology will be explained by events that proximally dysregulate catecholaminergic transmission. As suggested by Hess et al., 28 such dysregulation may be secondary to ADHD’s primary etiolo- gy. In this model, etiologic events that have effects on early development lead to secondary adjustments by the brain, which dysregulate catecholaminergic systems and cause the symptoms of ADHD. One of the most remarkable findings from genetic studies, both epidemiologic and molecular, is the conclusion that the diagnosis of ADHD is the extreme of a dimensional trait in the population. This finding suggests that ADHD is analo- gous to hypertension and that diagnostic approaches should consider defining the full continuum of “ADHD-traits” along with the threshold for defining clinically meaningful manifestations of that trait. Describing this continuum in future diag- nostic systems should help clinicians determine how to diagnose and treat patients who fall just below the current threshold for diagnosis. An apt comparison is with intellectual disability (ID). Most forms of ID fall along the normal distribution of intelligence with rare cases being categorically different. 29 A dimensional view of ADHD will change the question “Is ADHD underdiagnosed or overdiagnosed” to “where should we place the diagnostic threshold for ADHD?”. Because sub- threshold ADHD can be associated with substantial morbidity, 2,30-33 demarcating a diagnostic range that one might refer to as “borderline ADHD” (following the analogy with hypertension), might be useful. Faraone et al. 34 described two competing models of ADHD’s etiology: etiologic heterogeneity and multifactorial causation. Much research shows that ADHD is a clinically heterogeneous disorder as regards the nature and severity of ADHD symptoms, the extent of psychiatry comorbidity, the degree of impairment, the presence of neuropsychological impairments and the course and outcome of the disorder. The etiologic heterogeneity hypothesis posits that clinical heterogenei- ty is mirrored by heterogeneity in the events that cause ADHD. It predicts that ADHD can be separated into two or more classes having different genetic and/or environmental etiologies. In contrast to the etiologic heterogeneity model, the multifactorial model po- sits all cases of ADHD to arise from a single pool of genetic and environmental va- riables – each of small effect – that combine to produce a vulnerability to ADHD. As cumulative vulnerability increases, the expression of ADHD’s symptoms and