Table 3.

Details of genetic studies investigating candidate predictive biomarkers for treatment response.

Authors, year	Country	N ADHD	N Control	Age	% Male	% White	Design	Candidate biomarker(s)	Key findings
Brikell et al. [64]	Denmark	Starting MPH (N = 7427) stopping MPH (N = 3370) or switching to non-stimulant (N = 1137) over 2 years	0	Range = 3–32 (age at first diagnosis)	71%	100%	Linked genetic and medical records	16q23.3 locus	16q23.3 locus (containing genes and variants associated with a range of neuropsychiatric phenotypes such as seasonal depression, alcohol intake and cerebellar volume) was significantly associated with switching medication. No genome-wide significant associations for starting or stopping treatment. No associations of ADHD PRS with treatment outcomes; bipolar disorder PRS and schizophrenia PRS predicted stopping stimulant medication.
Elia et al. [65]	Europe, USA	1013 (discovery sample) + 2493 (replication sample)	4105 + 9222(replication sample)	Range = 6–18	Not reported	100%	Multiple samples of ADHD cases and controls	CNVs within metabotropic glutamate receptor network genes	ADHD-associated CNVs were concentrated in genes within a network of metabotropic glutamate receptor genes, affecting 11.3% of ADHD cases compared to 1.2% of unaffected controls.
Elia et al. [66]	USA	30 (all harboring mutations in metabotropic glutamate receptor network genes)	0	Range = 12–17	66%	50%	5-week, open-label, single-blind, placebo-controlled trial of the metabotropic glutamate activator receptor fasoracetam	CNVs within metabotropic glutamate receptor network genes	Individuals who harbored CNVs within this glutamatergic gene network had better therapeutic response.
Gul et al. [59]	Turkey	100	80	Range = 6–15	66%	Not reported	2-month ATX, open label	A SNP (rs3785143) tagging the SLC6A2 gene	rs3785143 showed association with ATX response, with CC homozygotes showing superior response. OR ~3 with wide confidence intervals (1.1–13.4)
Myer et al. [60]	Multiple	3647	0	M = 9.5, range=4–13	83%	Multiple	Meta-analysis of candidate genes studies predicting MPH response	10 repeat VNTR within the SLC6A3 gene; SNPs tagging the SLC6A2 gene	Homozygotes for the 10 repeat VNTR within the SLC6A3 gene encoding the dopamine transporter targeted by MOH show worse response. SNPs tagging the gene coding for the norepinephrine transposer (SLC6A2) were tied to altered responsivity. Response was also moderated by variants within the DRD4 gene, that in silico alters receptor expression, and near the ADRA2 gene, coding for the alpha-2-adrenergic receptor. A polymorphism within the enzyme, COMT, which reduces its potency in degrading catecholamines, was tied to increased response.
Pagerols et al. [62]	Spain (children), Brazil (adult)	173 children (discovery sample) + 189 adults (replication sample)	0	Mean=9.6, SD = 2.9	84% (children), not reported (adults)	100%	PRS for MPH response derived in children and tested in adults to predict MPH response at 8 weeks	None	No genome-wise significant hits in children and no association between the PRS for treatment response in adults. The set of genes containing SNPs nominally associated with response (p < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome.
Zhong et al. [63]	China	241 (most medication naïve, 13 medication free for >1 week)	0	Mean=9.2, SD = 2.2	85%	Not reported	8/12-week MPH or ATX, open label	ADHD PRS	There were no genome-wide significant hits for treatment response. PRS for ADHD was found to predict a favorable response, explaining 2% of the variance.

ADHD attention deficit hyperactivity disorder, ATX atomoxetine, CNV copy number variant; COMT Catechol-o-methyltransferase, GWAS genome-wide association study, M mean age, MPH methylphenidate; PRS polygenic risk score; RCT randomized controlled trial, SD standard deviation, SNP single nucleotides polymorphism, VNTR variable number tandem repeat.