截断变异负担在高功能自闭症和 LRP1 在精神表型中的多效性影响。
Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes.
机构信息
From the Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Spain (Torrico, Vivó-Luque, Fernàndez-Castillo, Cormand, Toma); the Institute of Biomedicine, University of Barcelona, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Institut de Recerca Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand); the Neuroscience Research Australia, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Institute of Science and Technology, Barcelona, Spain (Mosca, Aloy); the Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Spain (Hervás); the Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (Aloy); and the Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain (Bayés).
出版信息
J Psychiatry Neurosci. 2019 Sep 1;44(5):350-359. doi: 10.1503/jpn.180184.
BACKGROUND
Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism.
METHODS
We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100).
RESULTS
We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the β-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders: de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 × E−07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 × E−03); and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 × E−05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls.
LIMITATIONS
We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders.
CONCLUSION
Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.
背景
先前的研究表明，新发性和遗传性截短突变与自闭症谱系障碍有关。我们旨在研究遗传性截短突变的负荷是否同样会导致高功能自闭症，并描述高功能自闭症中存在新生变异的基因。
方法
我们对 20 个高功能自闭症家庭（平均智商为 100）进行了全外显子组测序。
结果
我们没有观察到高功能自闭症中传递的截短等位基因与未传递的截短等位基因数量存在差异（117 个与 130 个，p = 0.78）。高功能自闭症中的传递截短和新生变异并未在基因本体论（GO）或京都基因与基因组百科全书（KEGG）类别，或自闭症相关基因集中富集。然而，在一名高功能自闭症患者中，我们鉴定出 LRP1 一个典型剪接位点的新生变异，LRP1 是一个突触后密度基因，也是脆性 X 智力低下蛋白（FRMP）的靶点。该新生变异导致外显子 29 框内跳跃，从而去除 LRP1 的β-螺旋桨结构域 4 的 6 个叶中的 2 个，具有潜在的功能后果。大量数据集表明 LRP1 与多种精神疾病有关：来自联合测序项目的自闭症谱系障碍（p = 0.039）和精神分裂症（p = 0.008）的新生变异；使用精神疾病基因组学联合会的全基因组关联研究数据集的常见变体显示精神分裂症中的基于基因的关联（p = 6.6×E−07）和 7 种精神疾病的荟萃分析中的关联（p = 2.3×E−03）；使用来自 6135 名精神分裂症患者、1778 名自闭症谱系障碍患者和 7875 名对照者的全外显子组测序，已显示超罕见致病性变异的负担在自闭症谱系障碍中更高（p = 1.2×E−05）。
局限性
我们的高功能自闭症患者样本有限，这与招募认知表现高且无精神疾病家族史的患者有关。
结论
先前的研究和我们的研究表明，截短突变的影响仅限于与智力残疾相关的严重自闭症谱系障碍表型。我们提供了 LRP1 基因在精神疾病表型中常见和罕见变异的多效性证据。
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