Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75–80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.

注意缺陷多动障碍 (ADHD) 是儿童中最常见的神经发育障碍，遗传因素占表型变异的 75-80%。最近的研究表明，多动症患者可能会出现非典型的中央髓鞘形成，这种情况可能持续到成年期。鉴于鞘脂在髓磷脂形成和维持中的重要作用，我们探索了鞘脂代谢基因的遗传变异与 ADHD 风险的关联。在来自世界不同地区的三个独立队列中对总共 1520 名基因分型受试者进行了全外显子组基因分型。队列 1（MTA（ADHD 儿童多模式治疗研究）样本，371 名受试者）作为发现队列进行分析，而队列 2（Paisa 样本，298 名受试者）和 3（美国样本，851 名受试者）用于复制。根据其在鞘脂代谢中的作用，手动策划了一组 58 个基因。在筛选队列中，对 ADHD 与编码这组基因中常见和罕见的潜在功能等位基因变异的 137 个标记之间的关联进行了有针对性的探索。使用单位点和多位点加性、显性和隐性线性混合效应模型。在发现过程中，我们发现 ADHD 与八个基因（ GALC 、 CERS6 、 SMPD1 、 SMPDL3B 、 CERS2 、 FADS3 、 ELOVL5和CERK ）的变异之间存在统计学显着关联。在两个复制队列中都证明了与GALC 、 SMPD1和CERS6变异关联的成功本地复制。 在发现或复制队列中与 ADHD 相关的变体 rs35785620、rs143078230、rs398607 和 rs1805078 对应于具有预测有害影响的错义突变。表达数量性状位点分析揭示了 rs398607 与小脑中GALC表达增加之间的关联。