Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis.

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2024-10-15 DOI:10.1186/s13229-024-00624-2
Lukas S Schaffer, Sophie Breunig, Jeremy M Lawrence, Isabelle F Foote, Andrew D Grotzinger
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Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD.

Methods: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD.

Results: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies.

Limitations: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD.

Conclusions: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique.

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通过多层次的生物分析,确定自闭症谱系障碍特有的遗传途径。
背景:自闭症谱系障碍(ASD)是一种神经发育性疾病,其特征是不典型的社会功能模式和重复/受限行为。自闭症谱系障碍通常与多动症(ADHD)并发,尽管两者的临床表现截然不同,但在遗传学上却有相当大的重叠。鉴于二者具有共同的遗传责任,目前尚不清楚哪些遗传途径会增加ASD独立于ADHD的可能性:我们将基因组结构方程模型(SEM)应用于 ASD 和儿童诊断的 ADHD 的 GWAS 统计摘要,将 ASD 的遗传变异分解为 ASD 独有的遗传变异(uASD)和 ADHD 共有的遗传变异。我们计算了 uASD 与 83 个外部特征之间的遗传相关性,以估计 uASD 与其他临床相关表型之间的遗传重叠。我们接着应用分层基因组 SEM 来确定富含 uASD 的基因类别。最后,我们应用全转录组SEM(T-SEM)来探索与uASD相关的基因表达模式:结果:我们观察到uASD与几种外部特征之间存在正遗传相关性,其中最明显的是与认知/教育结果和内化精神特征相关的特征。分层基因组 SEM 显示,uASD 的遗传性显著富集于参与进化保守过程的基因以及生殖基质中的组蛋白标记。T-SEM发现了83个与uASD相关的独特基因,其中34个是单变量分析中发现的新基因。这些基因在皮肤相关病理中的代表性较高:局限性:我们的研究受限于仅来自欧洲血统个体的汇总统计数据。此外,使用基于一般 ASD 诊断的数据限制了我们了解导致 ASD 临床异质性明显的遗传因素的能力:我们的研究结果在全基因组、功能和基因表达水平的分析中勾勒出了独立于多动症的 ASD 独特遗传基础。此外,我们还发现了以前被其对多动症截然不同的影响所掩盖的新关联。总之,这些结果让我们深入了解了 ASD 独特的生物学过程。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
期刊最新文献
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