Stergiakouli Evie, Davey Smith George, Martin Joanna, Skuse David H, Viechtbauer Wolfgang, Ring Susan M, Ronald Angelica, Evans David E, Fisher Simon E, Thapar Anita, St Pourcain Beate
MRC Integrative Epidemiology Unit (MRC IEU), University of Bristol, Bristol, UK.
School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
Mol Autism. 2017 Apr 4;8:18. doi: 10.1186/s13229-017-0131-2. eCollection 2017.
Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk.
Social-communication difficulties ( ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms ( ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data.
In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait ≤ 1, 3 × 10) as those between repeated measures of the same trait (within-trait ≤ 0.94, 7 × 10). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (-meta = 6.4 × 10). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder.
In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
已有报道称注意缺陷多动障碍（ADHD）症状与自闭症谱系障碍（ASD）症状之间存在共同的遗传影响。然而，跨性状的遗传关系在发育过程中会发生动态变化。我们调查了儿童期和青少年期一般人群样本中ASD和ADHD症状之间遗传重叠的连续性。我们还研究了与ADHD和ASD遗传风险相关的单维和跨维度性状 - 障碍联系。
在英国一个出生队列（ALSPAC，年龄7至17岁）中反复测量社交沟通困难（≤5551，社交与沟通障碍检查表，SCDC）以及多动冲动/注意力不集中的ADHD联合症状（≤5678，优势与困难问卷，SDQ - ADHD）。精神病基因组学联盟提供了临床ASD（5305例；5305个虚拟对照）和ADHD（4163例；12,040个对照/虚拟对照）的全基因组汇总统计数据。使用全基因组数据估计表型之间的遗传性状方差和遗传重叠。
在一般人群中，SCDC和SDQ - ADHD评分的遗传影响在整个发育过程中是共享的。跨性状的遗传相关性达到了与同一性状的重复测量之间（性状内≤0.94，≤7×10）相似的强度和大小（跨性状≤1，≤3×10）。性状之间共享的遗传影响，尤其是在青春期后期，可能涉及K - RAS信号上调基因中的变异（-meta = 6.4×10）。单维度上，每个基于人群的性状都映射到预期的行为连续体：临床ADHD的风险增加等位基因在整个发育过程中始终与SDQ - ADHD评分相关（边际回归 = 0.084%）。如先前报道所示，儿童期临床ASD与社交沟通困难之间也存在特定年龄的遗传重叠。然而，跨维度上，SCDC和SDQ - ADHD评分均与疾病的遗传风险无关。
在一般人群中，社交沟通困难与ADHD症状之间的遗传病因在儿童和青少年发育过程中是共享的，可能涉及发育过程中共同变化的相似生物学途径。在ASD和ADHD维度内，基于人群的性状也与临床疾病相关，尽管需要更大的临床发现样本才能可靠地检测跨维度性状 - 疾病关系。
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