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Hervas et al. J Transl Genet Genom 2021;5:278-87 https://dx.doi.org/10.20517/jtgg.2021.25 Page 282

Table 2. Summary of statistical analyses in group of ASD subjects treated with methylphenidate. Regression coefficient and P value
(within brackets) provided
Gene Polymorphism Response Side effects Aggress Shutd Irritab Mood Somnol BMI
ANKK1 rs1800497 0.67 (0.50) 1.83 (0.07) -0.93 (0.35) 1.29 (0.20) 0.33 (0.74) -1.46 (0.14) NA 0.52 (0.61)
BDNF rs6265 -0.01 (0.99) -2.25 (0.03) 1.51 (0.13) 1.14 (0.25) 1.48 (0.14) 1.42 (0.15) NA -0.78 (0.43)
COMT rs4680 1.53 (0.13) 1.42 (0.16) -1.65 (0.10) -1.90 (0.06) -0.48 (0.63) -0.52 (0.61) NA -0.05 (0.96)
DAT1 3’UTR-VNTR 2.21 (0.03) -0.24 (0.81) 0.71 (0.48) -1.10 (0.27) -0.35 (0.73) 0.33 (0.74) NA -1.52 (0.13)
DRD2 rs1801028 0.66 (0.51) -0.68 (0.50) -1.41 (0.16) -1.24 (0.22) -0.51 (0.61) -0.81 (0.42) NA -0.77 (0.44)
DRD3 rs167771 0.51 (0.61) -1.00 (0.32) 0.41 (0.68) 0.53 (0.60) -0.66 (.51) 0.71 (0.48) NA 0.74 (0.46)
rs6280 0.20 (0.84) -1.15 (0.25) -0.71 (0.48) 0.22 (0.83) -1.02 (0.30) -0.46 (0.64) NA -0.33 (0.74)
DRD4 48bp VNTR 0.06 (0.95) 0.46 (0.65) -0.42 (0.67) 0.84 (0.40) -0.05 (0.96) 0.13 (0.89) NA 0.77 (0.45)
HTR1A rs6295 0.76 (0.45) 1.43 (0.16) 0.53 (0.60) 0.29 (0.77) 0.44 (0.66) 0.86 (0.39) NA -0.12 (0.91)
rs878567 0.54 (0.59) 1.21 (0.23) 0.58 (0.56) 0.33 (0.74) 0.17 (0.86) 0.98 (0.33) NA 0.002 (0.99)
HTR2A rs6311 -1.22 (0.22) 0.38 (0.71) 1.06 (0.29) 0.65 (0.51) 0.21 (0.84) 0.49 (0.62) NA 0.06 (0.96)
rs6313 -0.83 (0.41) 0.29 (0.77) 1.19 (0.23) 0.20 (0.84) -0.04 (.97) 0.56 (0.58) NA 0.01 (0.99)
rs6314 0.14 (0.89) 0.83 (0.41) -0.57 (0.57) -0.80 (0.42) 0.18 (0.85) -1.91 (0.06) NA -1.57 (0.12)
HTR2C rs1414334 -1.90 (0.06) -0.40 (0.69) 0.004 (0.99) 0.21 (0.84) 0.60 (0.55) 0.84 (0.40) NA 1.79 (0.08)
rs3813929 0.35 (0.73) 0.47 (0.64) -0.64 (0.52) -0.64 (0.52) -0.65 (0.52) -0.93 (0.35) NA -0.12 (0.90)
rs6318 0.97 (0.34) -0.23 (0.82) -0.002 (0.99) 0.002 (0.99) 0.001 (0.99) 0.002 (0.99) NA 0.61 (0.55)

NA: Not available.

allelic combinations and response to methylphenidate treatment (P = 0.02) and BMI (P = 0.02). Association
was also observed between a HTR2A haplotype and mood alterations (P = 0.04). Finally, a DRD3 allelic
combination was associated with presence of side effects (P = 0.05).

DISCUSSION
We aimed to identify genetic predictors of response to pharmacological treatment by investigating 16 SNPs
and VNTRs within 10 candidate genes and their influence on clinical outcome in a cohort of N = 176
children and adolescents with ASD. Several significant associations were observed that may help to identify
patients with ASD likely to show poor response and/or develop side effects.

Previous evidence indicates that variants in dopaminergic genes are associated with emotional dysregulation
[17]
and ADHD symptoms in patients with ASD and with methylphenidate response in children with
ADHD [6,9,18-21] , although these findings have not been universally replicated [22-24] . We investigated
polymorphisms in several dopaminergic genes including SLC6A3, DRD2 (and the ANKK1 Taq I), DRD3,
and DRD4, and their possible relation to symptom improvement after pharmacological treatment in ASD
children.

We did not find association between the SLC6A3 3’ UTR VNTR variant investigated and treatment
response in the study sample that included subjects treated with a variety of psychotropics. Nevertheless, the
SLC6A3 3’ UTR VNTR variant was associated with somnolence (P = 0.02) in the total cohort and with
response in the subgroup of methylphenidate treated patients. Interestingly, previous studies have reported
association between this variant and response to methylphenidate in children with ADHD [14,20] . The
dopamine transporter is a direct target of methylphenidate, a drug widely used in the ASD population for
the treatment of ADHD co-morbid symptoms. Although suggestive, these results require further
investigation. An association was observed between the ANKK1 rs1800497 polymorphism (alternative
nomenclature: DRD2 Taq I) and presence of side effects in the study cohort (P = 0.03). Interestingly, a