Methods employed in genome-wide association studies are not feasible ways to explore genotype–phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficit-hyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations.

由于统计能力有限，全基因组关联研究中采用的方法并不是探索罕见疾病基因型-表型关联的可行方法。另一种方法是检查特定单核苷酸多态性 (SNP)、先验选择和行为特征之间的关系。在这里，我们采用这种策略来检查三个 SNP（5-HTTLPR、MAOA、COMT）与特定临床相关行为之间的关系，这些行为是脆性 X 综合征 (FXS) 的表型，但在个体之间的严重程度和频率有所不同。 64 名患有 FXS 的男性参与了当前的研究。对挑战行为（定义为身体攻击、财产破坏、刻板行为和自残）、自闭症症状学、注意力缺陷多动障碍特征、重复行为以及情绪/兴趣和愉悦的标准化知情人测量数据进行了比较SNP 基因型。未观察到行为特征与 5-HTTLPR（血清素）或 MAOA（单胺氧化酶）基因型之间存在关联。然而，与 COMT（多巴胺）AG 和 GG 基因型相比，AA 基因型与对环境的更大兴趣和愉悦感相关，并且与破坏财产、刻板行为和强迫行为的风险降低相关。结果表明，影响大脑多巴胺水平的 COMT 基因型的常见遗传变异可能导致该人群的挑战性和重复性行为以及兴趣和愉悦的变化。 这项研究确定了额外遗传风险在理解导致神经发育障碍表型变异的神经和遗传机制方面的作用，并强调了研究在稀有人群中根据理论基础先验选择的 SNP 的优点。