CD38 Gene Polymorphism on Eye-Gaze Ability in Human Social Interaction

Background: Eye contact provides important social and emotional information in human communication. The direction of an individual’s eye-gaze may indicate to others where his or her attention lies. In autism, this ability is impaired. Social interaction abilities such as eye-gaze communication are heritable and are possibly due to genetic variations. CD38 has been reported to be critical for social processing and behaviour by regulating oxytocin secretion. We hypothesised that CD38 gene polymorphisms could contribute to individual variability in the accuracy of detection of another’s direction of gaze.

Objectives: We tested our hypothesis by examining the association between CD38 gene polymorphisms and a standardized measure of direction of gaze detection, in both children with autism and their family members. Our previous work had standardized the measurement of eye-gaze communication impairment in typical population controls, for both age and sex. We could therefore measure individual differences in accuracy on this task in standard deviation scores, using the same instrument for all subjects.

Methods: 757 participants from 209 families were recruited, including 215 children with clinically diagnosed autism (98.4% Caucasians; mean age=11.3±3.4 years; Full Scale IQ=97.4±18.1; male/female ratio=4.4:1), their parents (mean age=42.9±6.0 years; Full Scale IQ=112.6 ±12.6) and their siblings (mean age=12.1±5.1 years; Full Scale IQ=105.6±20.1). All family members completed the standardized social cognition tests, including the test of Eye-Gaze Detection Accuracy. Autistic traits were measured using the Developmental, Dimensional and Diagnostic Interview (3Di) and the Autism Diagnostic Observation Schedule (ADOS).

Biological samples were collected for DNA extraction. Seven CD38 SNPs were identified for analysis, based on previous reports of an association with social skills in ASD. SNP genotyping was done using Kaspar assays. Genetic associations between genotypes and task were analysed using PLINK. Bonferroni corrections were applied for multiple SNPs and phenotype testing. Transcription factor Affinity Prediction (TRAP) was performed to predict regulatory transcription factor binding at intronic SNPs.

Results: We found that CD38 SNP rs3796867 was significantly associated with the eye-gaze endophenotype (p=0.019; p=0.00014 after Bonferroni correction). The task z-scores (mean ± standard error) were strongly related to genotype: AA [-1.14±0.56]; AG [-0.61±0.13]; GG [-0.33±0.064]. The mean z-score of those with A-allele was -0.60±0.1 compared with those with G-allele only -0.33±0.06 (paired t-test, p<1x10^-4) compiled across family members.

Conclusions: Eye-gaze direction detection was significantly impaired in the participants with the ancestral A-allele of rs3796867. This is an intronic SNP located between CD38 gene exons 1 and 2. TRAP predicted some important transcription factors such as PAX2, FOXD3, FOXA1, HFH8 (FOXf1), ZNF333 and SRY could have differential binding affinities to the G and A alleles of the SNP. Accordingly, the regulation of CD38 gene expression could influence individual differences in ability to detect the direction of another’s eye gaze, hence potentially influencing competence in human social interaction.