Objective

Understanding the role of endophenotypes is essential for process models of psychopathology. This study examined which candidate cognitive endophenotypes statistically mediate common variant genetic risk for attention-deficit/hyperactivity disorder (ADHD).

Method

A case-control design using community-recruited volunteer children 7 to 11 years of age (n = 656, n = 435 ADHD), of whom 514 were of homogenous European ancestry for the primary models (n = 337 ADHD, 177 non-ADHD). Children were assessed with a multi-informant, best-estimate diagnostic procedure and laboratory measures of working memory, response inhibition, executive functioning, arousal/attention, temporal information processing, and processing speed. Latent variables were created for the candidate cognitive measures and for parent- and teacher-rated ADHD dimensions. Polygenic risk scores (PGS) were computed using a discovery sample of 20,183 individuals with ADHD and 35,191 controls from the Psychiatric Genetics Consortium. Cognitive measures that survived multiple testing correction for association with the PGS were evaluated for mediation with ADHD using structural equation models.

Results

Results were essentially identical in the homogeneous European ancestry subgroup (n = 514) and in the full sample (N = 656). For the European population, the PGS was associated with ADHD diagnosis (Nagelkerke R² = 0.045; β = 0.233, SE = 0.053, p = .000011) and multi-indicator dimensional ADHD latent variables by parent report (β = 0.185, SE = 0.043) and teacher report (β = 0.165, SE = 0.042). The PGS effect was statistically mediated by working memory (indirect effect, β = 0.101, SE = 0.029, 95% CI = 0.05, 0.16, p = .00049, 43% of genetic effect accounted for) and arousal/alertness (indirect effect β = 0.115, 95% CI = 0.04, 0.20, SE = 0.041, p = .005, 49% of genetic effect accounted for).

Conclusion

This is the first clear demonstration from molecular genetic data that working memory and arousal regulation are promising cognitive endophenotypes for ADHD with regard to mediating genetic risk from common genetic variants.

中文翻译：

---

工作记忆和警惕性为多态性内表型，与注意力缺乏/多动障碍的常见遗传风险相关

客观的

了解内表型的作用对于心理病理学过程模型至关重要。这项研究检查了哪些候选认知内表型在统计学上介导了注意力缺陷/多动障碍（ADHD）的常见变异遗传风险。

方法

病例对照设计，使用了7至11岁的社区招募志愿儿童（n = 656，n = 435 ADHD），其中有514名欧洲血统的主要模型（n = 337 ADHD，177非ADHD） ）。用多信息，最佳估计的诊断程序对儿童进行评估，并对他们的工作记忆，反应抑制，执行功能，唤醒/注意，时间信息处理和处理速度进行实验室测量。为候选的认知测量以及家长和老师评定的ADHD维度创建了潜在变量。使用来自精神病遗传学协会的20,183名患有ADHD的个体和35,191名对照的发现样本来计算多基因风险评分（PGS）。

结果

在同质的欧洲血统亚组（n = 514）和完整样本（N = 656）中，结果基本相同。对于欧洲人群，PGS与多动症诊断相关（Nagelkerke R ²  = 0.045；β= 0.233，SE = 0.053，p  = .000011）和父报告的多指标维度ADHD潜在变量（β= 0.185，SE = 0.043）和教师报告（β= 0.165，SE = 0.042）。PGS效应通过工作记忆（间接效应，β= 0.101，SE  = 0.029，95 ％CI = 0.05，0.16，p = .00049，占遗传效应的43％）和唤醒/机敏性（间接效应β）进行统计学介导。= 0.115，95％CI = 0.04，0.20，SE = 0.041，p  = .005，占遗传效应的49％。

结论

这是分子遗传学数据的第一个明确证据，表明工作记忆和唤醒调节是ADHD在介导常见遗传变异的遗传风险方面有希望的认知内表型。