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The severity of autism spectrum disorder (ASD) shows wide variations, though the reason remains unclear. Vitamin D (VitD) deficiency is considered a risk factor for ASD and its supplementation was reported to reduce symptom severity. Since VitD, either synthesized in the skin or absorbed from the food, is transported to the liver by the vitamin D binding protein (DBP), we have analyzed DBP genetic polymorphisms [rs7041 (A/C), rs4588 (G/T), and rs3755967 (C/T)] affecting DBP function [Case = 411; Control = 397], levels of plasma 25(OH)D and DBP [Case = 25; Control = 26], and DBP mRNA expression [Case = 74; Control = 44] in a group of Indo-Caucasoid ASD probands and neurotypical subjects. ASD probands with rs7041'CC', rs4588 'TT', and rs3755967 'TT' genotypes exhibited higher scores for a few traits. Scores for Imitation and Listening response were also higher in the presence of the "A-T" haplotype (rs7041-rs4588). Plasma 25(OH)D and DBP levels as well as DBP mRNA expressions were significantly lower in the ASD probands as compared to the neurotypical subjects. We infer that DBP deficiency, in the presence of risk genetic variants, could be one of the reasons for the reported 25(OH)D deficiency of the ASD probands., (© 2024. The Author(s).)

Glutamate (Glu) is important for memory and learning. Hence, Glu imbalance is speculated to affect autism spectrum disorder (ASD) pathophysiology. The action of Glu is mediated through receptors and we analyzed four metabotropic Glu receptors (mGluR/GRM) in Indo-Caucasoid families with ASD probands and controls. The trait scores of the ASD probands were assessed using the Childhood Autism Rating Scale2-ST. Peripheral blood was collected, genomic DNA isolated, and GRM5 rs905646, GRM6 rs762724 & rs2067011, and GRM7 rs3792452 were analyzed by PCR/RFLP or Taqman assay. Expression of mGluRs was measured in the peripheral blood by qPCR. Significantly higher frequencies of rs2067011 'A' allele/ AA' genotype were detected in the probands. rs905646 'A 'exhibited significantly higher parental transmission. Genetic variants showed independent as well as interactive effects in the probands. Receptor expression was down-regulated in the probands, especially in the presence of rs905646 'AA', rs762724 'TT', rs2067011 'GG', and rs3792452 'CC'. Trait scores were higher in the presence of rs762724 'T' and rs2067011 'G'. Therefore, in the presence of risk genetic variants, down-regulated mGluR expression may increase autistic trait scores. Since our investigation was confined to the peripheral system, in-depth exploration involving peripheral as well as central nervous systems may validate our observation., (© 2024. The Author(s).)

Background: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders., Methods: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5' flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated., Results: A significantly higher occurrence of rs1800955 "T/TT" was observed in the probands. ASD traits were affected by rs1800955 "T" and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 "6R" and rs27072 "CC" and DRD4 rs4646984 higher repeat allele and rs1800955 "T"., Conclusion: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis., (© 2023. Children's Hospital, Zhejiang University School of Medicine.)

Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABA A -receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 "A," GABRG3 rs897173 "A," and GABRA5 rs140682 "T" showed significant association with ASD. Trait scores were influenced by rs1432007 "AA" and rs140682 "TT." GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Folate has a pivotal role in maintaining different cellular processes including DNA integrity and neurotransmitter levels. Further, folate deficiency was reported in subjects with neuropsychiatric disorders including autism spectrum disorder (ASD)., Methods and Results: We recruited ASD probands following the Diagnostic and Statistical Manual of Mental Disorder-IV/-5. Severity was assessed by the Childhood Autism Rating Scale2-Standard Test (CARS2-ST). Functional SNPs in reduced folate carrier1 (rs1051266), methylenetetrahydrofolate dehydrogenase (rs2236225), methylenetetrahydrofolate methyltransferase (rs1805087), methylenetetrahydrofolate reductase (rs1801133 and rs1801131), cystathionine-beta- synthase (rs5742905), and serine hydroxymethyltransferase (rs1979277) genes were analyzed in the ASD probands (N = 203), their parents and controls (N = 250) by PCR/TaqMan based methods. Plasma homocysteine and vitamin B12 levels were examined by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis revealed higher frequencies of rs1051266 and rs1805087 "A" alleles (P = 8.233e-005 and P = 0.010 respectively) and rs1051266 "AA" genotype (P = 0.02) in the ASD probands. Gender based stratified analysis revealed higher frequency of rs1051266 "AA" in the male probands (P = 0.001) while frequencies of rs1805087 "A" (P = 0.001) and "AA" (P < 0.05), and rs2236225 "CC" (P = 0.03) were higher in the females. The case-control analysis also exhibited a significant difference in the occurrence of biallelic and triallelic haplotypes. rs1051266 "A", rs1979277 "T" and rs5742905 "C" alleles showed biased parental transmission (P = 0.02). CARS2-ST scores were higher in the presence of rs5742905 "T" while scores were lower in the presence of rs1979277 "T" and rs1051266 "A". ASD probands showed vitamin B12 deficiency., Conclusion: Based on these observations, we infer that components needed for proper folate metabolism may influence ASD severity in this population., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Imbalance in dopamine (DA) signaling is proposed to play a potential role in the etiology of Autism spectrum disorder (ASD) since, as a neuromodulator, DA regulates executive function, motor activity, social peering, attention as well as perception and subjects with ASD often exhibit deficit in these traits. Level of DA in the synaptic cleft is maintained by dopamine transporter (DAT) and hence, to identify the role of DAT in ASD, we have analyzed four functional genetic variants, rs28363170, rs3836790, rs2652511, rs27072, in nuclear families with ASD probands. Subjects were diagnosed based on Diagnostic and Statistical Manual for Mental Disorders and trait severity was assessed by Childhood Autism Rating Scale 2-Standard test. Informed written consent was obtained from the parents/care givers before recruitment followed by collection of peripheral blood for genomic DNA isolation. Target sites were investigated by PCR-based methods and data obtained was analyzed by population- as well as family-based statistical methods. Case-control analysis revealed significant higher frequencies of 9 repeat (9R) and 5 repeat (5R) alleles of rs28363170 and rs3836790 respectively in the ASD probands. Family-based analysis showed statistically significant higher paternal transmission of rs28363170 9R and rs2652511 T alleles. In the presence of rs28363170 9R, rs27072 C, rs3836790 6R6R, and rs2652511 CC variants, trait scores were higher. Studied variants showed independent as well as interactive effects, which varied based on gender of the probands. We infer that altered DA availability mediated through DAT may affect autistic traits warranting further in depth investigation in the field., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alteration in gamma aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is speculated to be a potential risk factor for Autism Spectrum Disorder (ASD) due to an altered expression in the brain. Sensory, social, and emotional deficits of subjects with ASD were reported to be caused by an imbalance between excitatory and inhibitory neurotransmission as well as GABAergic dysfunction caused by inadequate receptor function. We for the first time studied association between ASD and a missense coding variant rs3810651 (I478F) in the GABRQ gene, encoding for one of the subunits of GABA A receptors. Stratified analysis on families with ASD probands (N = 251) and ethnically matched control subjects (N = 250) revealed marginally higher frequency of "A" allele and "AA" genotype in female ASD probands as compared to gender matched controls. Female probands demonstrated higher severity for Verbal communication (χ 2  = 5.75, P = 0.01), Activity level (χ 2  = 7.26, P  = 0.007), as well as Level and consistency of intellectual response (χ 2  = 7.83 P = 0.005) in presence of "A/AA" warranting further in-depth investigation on the role of rs3810651 in ASD.

Objectives: Proper metabolism of the folate is crucial for maintaining DNA integrity, chromosome structure, methylation, as well as gene expression, and thus, folate is speculated to contribute to the etiology of different disorders. Since the etiology of autism spectrum disorder (ASD) is believed to be influenced by both genetic and environmental factors, we hypothesized that functional single nucleotide polymorphisms (SNPs) affecting folate metabolic pathway may have a causal role in the etiology of ASD. Methods: We analyzed three SNPs, rs2071010, rs2298444 and rs1801198 (in the folate receptor 1, folate receptor 2 and transcobalamin 2, respectively), in 867 ethnically matched subjects including 206 ASD probands and 286 controls. Plasma vitamin B 6 and folate were measured in age-matched probands and controls. Results: ASD probands showed a higher frequency of rs2298444 'A' allele ( P  = 0.01) and genotypes with 'A' allele ( P  = 0.03) when compared with the controls. rs1801198 'C' allele and 'CG' genotype also showed higher occurrence in the probands ( P  = 0.009 and 0.005, respectively). Gender-based stratified analysis revealed a significant higher frequency of rs2298444 'A' allele ( P  = 0.003), genotypes with rs2298444 'A' allele ( P  = 0.003) and rs1801198 CG ( P  = 0.001) in the male probands. Studied variants also showed statistically significant associations with ASD-associated traits measured by the Childhood Autism Rating Scale. ASD subjects exhibited gross deficiency in vitamin B 6 level when compared with age-matched controls ( P  < 0.001), which correlated with risk genetic variants. Discussion: We infer from this pioneering study on eastern Indian subjects that vitamin B 6 deficiency, along with risk gene variants, may affect ASD-associated symptoms, warranting further investigation in large cohorts.

Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Abstract: Autism spectrum disorders are heritable and behaviorally-defined neurodevelopmental disorders having skewed sex ratio. Serotonin as modulator of behavior and implication of serotonergic dysfunction in ASD etiology corroborates that serotonergic system genes are potential candidates for autism susceptibility. In the current study X-chromosomal gene, MAOA responsible for degradation of serotonin is investigated for possible association with ASD using population-based approach. Study covers analysis of 8 markers in 421 subjects including cases and ethnically-matched controls from West Bengal. MAOA marker, rs6323 and various haplotypes formed between the markers show significant association with the disorder. Stratification on the basis of sex reveals significant genetic effect of rs6323 with low activity T allele posing higher risk in males, but not in females. Haplotypic association results also show differential effect both in males and females. Contrasting linkage disequilibrium pattern between pair of markers involving rs6323 in male cases and controls further supports the sex-bias in genetic association. Bioinformatic analysis shows presence of Y-encoded SRY transcription factor binding sites in the neighborhood of rs1137070. C allele of rs1137070 causes deletion of GATA-2 binding site and GATA-2 is known to interact with SRY. This is the first study highlighting male-specific effect of rs6323 marker and its haplotypes in ASD etiology and it suggests sexual dimorphic effect of MAOA in this disorder. Overall results of this study identify MAOA as a possible ASD susceptibility locus and the differential genetic effect in males and females might contribute to the sex ratio differences and molecular pathology of the disorder. [Copyright &y& Elsevier]