Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h²_SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.

自闭症谱系障碍（ASD）具有很高的遗传性，其特征是社交沟通不足，行为受限和重复。对表型亚域的双胞胎研究表明潜在的遗传病因有所不同。研究解释表型变异的遗传变异将有助于识别特定的潜在病理机制。我们调查了包括2500多个个体在内的两个队列对ASD子域的共同变异的影响。基于自闭症诊断访谈修订版（ADI-R），我们确定并确认了六个具有基于SNP的遗传遗传力h ² _SNP的亚域 = 0.2–0.4。亚域非语言交流（NVC），社交互动（SI）和同伴互动（PI）共享遗传风险因素，而重复感觉运动行为（RB）和受限制兴趣（RI）的子域在遗传上彼此独立。作为分类诊断的ASD的多基因风险评分（PRS）解释了SI，关节注意（JA）和PI变异的2.3–3.3％，RI的4.5％，RB的1.2％，但NVC的0.7％。我们报告了8个全基因组重要命中（部分复制了以前的发现）和292个已知和新颖的候选基因。潜在的生物学机制与神经元的传播和发展有关。在SNP和基因水平上，除RB外，所有亚域均显示重叠。但是，在功能级别上没有观察到重叠。综上所述，与社交和交流相关的ADI-R算法派生子域显示出一种共同的遗传病因，与限制性行为和重复行为相反。ASD特定的PRS仅部分重叠，表明特定共同变异在塑造ASD子域的表型表达中的其他作用。