THE POLYGENETIC ARCHITECTURE OF AUTISM

IF 6.1 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1016/j.euroneuro.2024.08.045

Jing Zhang , Jakob Grove , Caitlin Carey , Jack Fu , F. Kyle Satterstrom , Susan Kuo , Ajay Nadig , Swapnil Awasthi , Kaitlin Samocha , Anders Børglum , Elise Robinson

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引用次数: 0

Abstract

Autism is highly heritable and has been associated with multiple classes of genetic variation. Common genetic variation contributes substantially to autism. Previously, with 18,381 autistic individuals and 27,969 non-autistic individuals, five genome-wide significant loci were identified. Now with 38,717 autistic individuals and 232,725 non-autistic individuals, we report an updated genome-wide association study (GWAS) of autism with 12 genome-wide significant loci. We observe a moderate genetic correlation (0.675, SE=0.0434) between Europe-based (Nautistic=22,643; Nnon-autistic=204,389) and United States-based (Nautistic =16,074; Nnon-autistic=28,346) autism cohorts, which contributes to the decline of the estimated single nucleotide polymorphism (SNP) heritability (from 0.118 (SE=0.010) to 0.068 (SE=0.003)). The genetic correlation between autism with intellectual disability (ID) (Nautistic=6,590; Nnon-autistic= 43,071; h2=0.062; SE=0.012) and autism without ID (Nautistic=23,173; Nnon-autistic= 204,679; h2=0.089; SE=0.005) is 0.658 (SE=0.086). In the United States family-based cohorts, the genetic correlation between autism with ID (Nfamily=3,993; h2=0.159; SE=0.033) and autism without ID (Nfamily=4,357; h2=0.171; SE=0.031) is 0.812 (SE=0.157). Autism without ID was positively genetically correlated with educational attainment (0.163; P=4.84 × 10-11) and intelligence (0.233; P=1.95 × 10-11). Autism with ID genetically correlated with neither educational attainment (0.036; P=0.409) nor intelligence (-0.072; P=0.235). As ID alone is negatively genetically correlated with intelligence, the lack of correlation between autism with ID and intelligence strongly suggests that autism with ID is genetically different from ID alone. This difference has implications for both research and clinical nosology. Rare and de novo variants contribute substantially to autism in some individuals. Through rare variant analyses, 72 genes have been associated with autism at a genome-wide significant level to date. While de novo protein truncating variants (PTVs) and copy number deletions have been associated with autism, we report preliminary findings that the burden of inherited PTVs and copy number deletions among autistic individuals was elevated compared to their non-autistic siblings (P=4.00 × 10-5). Integration of multiple genetic factors will help us better understand the etiology of autism.

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自闭症的多基因结构

自闭症具有高度遗传性，与多种基因变异有关。常见的遗传变异对自闭症有很大的影响。此前，我们在 18,381 名自闭症患者和 27,969 名非自闭症患者中发现了五个全基因组重要位点。现在，我们以 38,717 名自闭症患者和 232,725 名非自闭症患者为研究对象，报告了一项最新的自闭症全基因组关联研究（GWAS），其中发现了 12 个具有重要意义的全基因组位点。我们观察到自闭症欧洲队列（Nautistic=22,643；Nnon-autistic=204,389）和美国队列（Nautistic=16,074；Nnon-autistic=28,346）之间存在中等程度的遗传相关性（0.675，SE=0.0434），这导致估计的单核苷酸多态性（SNP）遗传率下降（从 0.118（SE=0.010）降至 0.068（SE=0.003））。有智力障碍的自闭症（Nautistic=6 590；Nnon-autistic=43 071；h2=0.062；SE=0.012）与无智力障碍的自闭症（Nautistic=23 173；Nnon-autistic=204 679；h2=0.089；SE=0.005）之间的遗传相关性为 0.658（SE=0.086）。在美国以家庭为基础的队列中，有 ID 的自闭症（Nfamily=3,993；h2=0.159；SE=0.033）与无 ID 的自闭症（Nfamily=4,357；h2=0.171；SE=0.031）之间的遗传相关性为 0.812（SE=0.157）。无智障自闭症与教育程度（0.163；P=4.84 × 10-11）和智力（0.233；P=1.95 × 10-11）呈正相关。带有智障的自闭症与教育程度（0.036；P=0.409）和智力（-0.072；P=0.235）均无遗传相关性。由于单纯的智障与智力在基因上呈负相关，自闭症伴智障与智力之间缺乏相关性强烈表明，自闭症伴智障在基因上与单纯的智障不同。这种差异对研究和临床命名都有影响。罕见变异和新变异对某些个体的自闭症有重大影响。通过罕见变异分析，迄今已有 72 个基因与自闭症有全基因组意义上的关联。虽然从头蛋白质截断变异（PTVs）和拷贝数缺失与自闭症有关，但我们报告的初步研究结果表明，与非自闭症患者的兄弟姐妹相比，自闭症患者的遗传PTVs和拷贝数缺失的负担更高（P=4.00 × 10-5）。整合多种遗传因素将有助于我们更好地了解自闭症的病因。

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来源期刊

European Neuropsychopharmacology 医学-精神病学

CiteScore

10.30

自引率

5.40%

发文量

730

审稿时长

41 days

期刊介绍： European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.