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Page 283 Hervas et al. J Transl Genet Genom 2021;5:278-87 https://dx.doi.org/10.20517/jtgg.2021.25

previous study reported this polymorphism associated with insulin-resistance in patients with ASD treated
[25]
with risperidone . We did not find any significant association with the other dopaminergic variants
investigated (DRD2 rs18012028, DRD3 rs167771 & rs6280, and a 48bp repeat in DRD4), although DRD3
haplotype combinations were found nominally associated with shutdowns in the total sample (P = 0.04) and
with side effects in the methylphenidate subgroup (P = 0.05). Previous studies reported association between
[14]
the DRD3 rs6280 polymorphism and methylphenidate response in a group of 64 children with ASD and
risperidone response in a sample of 45 patients with ASD . These findings require further investigation in
[15]
larger samples to confirm the possible contribution of DRD3 variants to treatment response variability in
ASD.

Abnormalities in the serotonergic system have been implicated in several psychiatric disorders. A significant
reduction of serotonin type 1A and 2A (5-HT1A and 5-HT2A) receptor binding densities was observed in
[26]
brain regions of patients with ASD . HTR1A variants, including rs878567, have been associated with
[27]
ADHD risk . HTR2A polymorphisms have also been associated with depression, gastrointestinal disorders,
and risk in patients with ASD [28-32] . Several studies have associated HTR2A and HTR2C polymorphisms with
response to antipsychotic and antidepressant drugs as well as weight gain or increased BMI during
antipsychotic treatment [3,33,34] . HTR1A variants have also been shown to associate with antipsychotic
[36]
[35]
response but not with antidepressant outcomes . In our study, we found significant associations between
the HTR2A rs6314 (His452Tyr) polymorphism and BMI and mood alterations. Carriers of the Tyr452
[37]
variant, with reduced functionality , were more likely to experience mood alterations and somnolence
during treatment but showed less BMI. Haplotype analyses of HTR2A allele combinations showed
significant findings with mood alterations (P = 0.02), somnolence (P = 0.01), and BMI (P = 0.04) in the total
cohort and with mood alterations in the methylphenidate subgroup (P = 0.04). These findings seem to agree
with previous studies that linked HTR2A variants with BMI during pharmacological interventions [33,38] and
[39]
with major depression .
The serotonin 2C (5-HT2C) receptor modulates eating behaviour and has been reported to influence
antipsychotic-induced weight gain and BMI [3,16,40] . Although we did not observe single marker associations,
we found significant associations between HTR2C haplotype combinations and BMI in the study sample (P
= 0.005) and between overall response (P = 0.02), as well as between BMI (P = 0.01) in the subgroup of
methylphenidate patients. Previous studies had also reported association between HTR2C genetic variants
and response to psychotropic treatments . Finally, we did not find any significant association between the
[3]
two HTR1A polymorphisms genotyped, rs6295 and rs878567, and the phenotypes investigated.

BDNF is a protein that modulates stress and mood alterations and several studies link BDNF altered levels
with ASD . It has been reported that methylphenidate treatment increases BDNF serum levels in children
[41]
with ADHD [20,42] . BDNF genetic variants may contribute to ASD pathogenesis and methylphenidate
[43]
response in children with ASD . Our own results showed an association between the BDNF rs6265 variant
[44]
and presence of side effects (P = 0.03 for both the study cohort and the methylphenidate subgroup) during
pharmacological treatment in children with ASD. Additionally, patients carrying the Met66 allele showed
higher levels of somnolence (P = 0.03 in total cohort). However, we were not able to find association
between the rs6265 Vall66 allele and response to methylphenidate (P = 0.26) as previously reported in
Korean children with ADHD . Reports of association between the rs6265 polymorphism and aggression in
[44]
patients with schizophrenia were not confirmed by us and other investigators . Correia et al. found
[15]
[45]
association between the Met66 allele and higher prolactin levels during risperidone treatment of children in
ASD, although no direct association with risperidone response was detected. Insulin resistance during
risperidone treatment was associated with this polymorphism in adolescents with ASD . These results,
[25]