Supplementary Material for: A Genome-Wide Test of the Differential Susceptibility Hypothesis Reveals a Genetic Predictor of Differential Response to Psychological Treatments for Child Anxiety Disorders

<b><i>Background:</i></b> The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in children with anxiety disorders. <b><i>Methods:</i></b> We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of environmental sensitivity based on the whole-genome findings and tested the score as a moderator of parenting on emotional problems in 1,406 children and response to individual, group and brief parent-led CBT in 973 children with anxiety disorders. <b><i>Results:</i></b> The polygenic score significantly moderated the effects of parenting on emotional problems and the effects of treatment. Individuals with a high score responded significantly better to individual CBT than group CBT or brief parent-led CBT (remission rates: 70.9, 55.5 and 41.6%, respectively). <b><i>Conclusions:</i></b> Pending successful replication, our results should be considered exploratory. Nevertheless, if replicated, they suggest that individuals with the greatest environmental sensitivity may be more likely to develop emotional problems in adverse environments but also benefit more from the most intensive types of treatment.

**<i>背景：</i>** 差异易感性假说（differential susceptibility hypothesis）提出，特定遗传变异可调节负性与正性环境对心理健康的影响，因此或可作为心理治疗响应的重要预测因子。然而迄今为止，此类变异的鉴定仅局限于预先筛选的候选基因。本研究将差异易感性假说从候选基因研究拓展至全基因组研究策略，旨在检验环境敏感性多基因评分（polygenic score of environmental sensitivity）能否预测焦虑障碍儿童对认知行为疗法（CBT）的响应效果。**<i>方法：</i>** 本研究采用一种全新方法鉴定与环境敏感性相关的遗传变异：以1026对同卵双生子（monozygotic twin pairs）的情绪问题组内变异为因变量，分析其与双生子基因型的关联。我们基于全基因组分析结果构建了环境敏感性多基因评分，并分别在1406名儿童中检验该评分对养育行为与情绪问题关系的调节作用，以及在973名焦虑障碍儿童中检验其对个体、团体及简短家长主导式认知行为疗法（brief parent-led CBT）响应效果的调节作用。**<i>结果：</i>** 环境敏感性多基因评分可显著调节养育行为对情绪问题的影响，以及治疗的整体效果。高评分个体对个体认知行为疗法的响应效果显著优于团体认知行为疗法或简短家长主导式认知行为疗法（缓解率分别为70.9%、55.5%与41.6%）。**<i>结论：</i>** 在获得成功重复验证之前，本研究结果仅可视为探索性发现。但若后续研究可重复本结果，则提示环境敏感性最高的个体在不良环境中更易出现情绪问题，但同时也可从强度最高的治疗类型中获益最多。