语言障碍与更广泛的行为障碍之间的表型关联：常见和罕见遗传变异的综合研究。
Pleiotropy between language impairment and broader behavioral disorders-an investigation of both common and rare genetic variants.
机构信息
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
出版信息
J Neurodev Disord. 2021 Nov 13;13(1):54. doi: 10.1186/s11689-021-09403-z.
BACKGROUND
Language plays a major role in human behavior. For this reason, neurodevelopmental and psychiatric disorders in which linguistic ability is impaired could have a big impact on the individual's social interaction and general wellbeing. Such disorders tend to have a strong genetic component, but most past studies examined mostly the linguistic overlaps across these disorders; investigations into their genetic overlaps are limited. The aim of this study was to assess the potential genetic overlap between language impairment and broader behavioral disorders employing methods capturing both common and rare genetic variants.
METHODS
We employ polygenic risk scores (PRS) trained on specific language impairment (SLI) to evaluate genetic overlap across several disorders in a large case-cohort sample comprising ~13,000 autism spectrum disorder (ASD) cases, including cases of childhood autism and Asperger's syndrome, ~15,000 attention deficit/hyperactivity disorder (ADHD) cases, ~3000 schizophrenia cases, and ~21,000 population controls. We also examine rare variants in SLI/language-related genes in a subset of the sample that was exome-sequenced using the SKAT-O method.
RESULTS
We find that there is little evidence for genetic overlap between SLI and ADHD, schizophrenia, and ASD, the latter being in line with results of linguistic analyses in past studies. However, we observe a small, significant genetic overlap between SLI and childhood autism specifically, which we do not observe for SLI and Asperger's syndrome. Moreover, we observe that childhood autism cases have significantly higher SLI-trained PRS compared to Asperger's syndrome cases; these results correspond well to the linguistic profiles of both disorders. Our rare variant analyses provide suggestive evidence of association for specific genes with ASD, childhood autism, and schizophrenia.
CONCLUSIONS
Our study provides, for the first time, to our knowledge, genetic evidence for ASD subtypes based on risk variants for language impairment.
背景
语言在人类行为中起着重要作用。因此，语言能力受损的神经发育和精神障碍可能会对个体的社交互动和整体幸福感产生重大影响。这些障碍往往具有很强的遗传成分，但过去的大多数研究大多检查了这些障碍之间的语言重叠；对其遗传重叠的调查有限。本研究旨在评估使用捕捉常见和罕见遗传变异的方法，语言障碍与更广泛的行为障碍之间的潜在遗传重叠。
方法
我们使用针对特定语言障碍（SLI）的多基因风险评分（PRS）来评估包含 13000 例自闭症谱系障碍（ASD）病例（包括儿童自闭症和阿斯伯格综合征病例）、15000 例注意缺陷/多动障碍（ADHD）病例、3000 例精神分裂症病例和21000 例人群对照的大型病例-队列样本中多种疾病的遗传重叠。我们还使用 SKAT-O 方法在使用外显子组测序的样本子集中检查 SLI/语言相关基因中的罕见变体。
结果
我们发现 SLI 与 ADHD、精神分裂症和 ASD 之间几乎没有遗传重叠的证据，这与过去研究中的语言分析结果一致。然而，我们观察到 SLI 与儿童自闭症之间存在很小但显著的遗传重叠，而在 SLI 与阿斯伯格综合征之间则没有观察到这种重叠。此外，我们观察到与阿斯伯格综合征病例相比，儿童自闭症病例的 SLI 训练 PRS 显著更高；这些结果与两种疾病的语言特征非常吻合。我们的罕见变异分析提供了特定基因与 ASD、儿童自闭症和精神分裂症关联的提示性证据。
结论
我们的研究首次提供了基于语言障碍风险变异的 ASD 亚型的遗传证据。
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