Autism spectrum disorders and the volume of the striatum and Amygdala: A Mendelian randomization study.

Backgrounds/aims: A number of studies have documented alterations in the structure and function of the striatum in individuals diagnosed with autism spectrum disorder (ASD). Nevertheless, the precise genetic mechanisms underpinning the relationship between autism spectrum disorder (ASD) and striatum and amygdala volume remain to be elucidated. The objective of this study was to estimate the causal effect of ASD on striatum and amygdala volume.

Methods: Summarized data of genome-wide association studies (GWAS) were separately downloaded from the IEU (Integrative Epidemiology Unit) open GWAS project (22138 participants of Europeans (100%), 18,382 cases of ASD and 27,969 controls, with a total of 33,219 brain imaged samples), the Enhancing Neuroimaging Genetics through Meta-Analysis Consortium (ENIGMA) (15640 participants of Europeans (96.5%) and non-Europeans). The MR-egger intercept test, MR-presso and Cochran's Q statistic was used to examine the pleiotropy and heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted, simple mode, and weighted mode methods were used to evaluate the causal association between striatum and amygdala volume and ASD. Finally, the effect of a single SNP (single nucleotide polymorphism) was used to test the SNP bias.

Results: The increased change rate of the putamen shows a strong and statistically significant association with ASD risk (P = 0.015, P = 0.044), with a large beta value (β(SE) = 8.272(3.401), 95 %CI: 1.605 to 14.939) indicating a substantial effect size. This makes it a potentially important changes caused by ASD. However, the increased change rate of the amygdala shows a positive but not statistically significant association with ASD risk (P = 0.119, P = 0.593). The beta value (2.527) is smaller, and the confidence interval includes zero, suggesting that this result is not reliable as a predictor of ASD risk. The other part of GM (grey matter) of striatum and amygdala volume also showed unsignificant result due to small beta values or unsignificant FDR p values.

Conclusions: The putamen's change rate appears to be a significant change caused by ASD which may be a strong predictive capability for ASD risk, while the amygdala's change rate and GM of striatum and amygdala volume does not show a significant predictive capability in this context. The present study provides evidence of a genetic relationship between ASD and putamen volume. Further investigation is required to elucidate the mechanisms underlying the genetic effect of changes in putamen structure and function on ASD.