涉及缺失和序列变异的复合杂合事件对自闭症有什么影响?

IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY European Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1016/j.euroneuro.2024.08.080
Worrawat Engchuan , Brett Trost , Marla Mendes de Aquino , David Mager , Mehdi Zarrei , Rulan Shaath , Rayssa de Melo Wanderley , Faraz Ali , Nickie Safarian , Alex Chan , Shania Wu , Stephen W. Scherer , Elemi Breetvelt , Jacob Vorstman
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引用次数: 0

摘要

当基因组缺失导致单倍体时,大多数人类基因都能保持正常的生物功能。然而,当剩余等位基因受到额外功能变异的影响时,致病性仍然可能产生。在此,我们将介绍一种特定类型复合杂合性的分析策略,即缺失和影响另一个等位基因的序列级变异的共同发生,以下简称缺失复合杂合性(DelCH)。我们分析了来自 MSSNG、Simons Simplex Collection 和 SPARK 队列的全基因组测序数据(共有 11,636 名自闭症患者和 22,962 名家庭成员)。我们开发了多种分析策略来研究罕见(事件发生率为 1%)的 DelCH:1)负担分析使用条件逻辑回归对以下两种情况的 DelCH 发生率进行群体水平的比较:a)将遗传性缺失作为随机效应变量,比较受试者与其缺失传播父母之间的 DelCH 发生率;或 b)将家庭 ID 作为随机效应变量,比较受试者与其家庭成员之间的 DelCH 发生率;2)传播不平衡检验(TDT)比较缺失非传播父母将受缺失影响的基因内的序列水平变异传播给其自闭症后代的比率。如果非同义变异的传递率高于偶然预测的传递率,则表明存在关联。作为额外的对照分析,在未受影响的兄弟姐妹中重复了这一方法。第一种负荷分析(1a)实现了删除序列的完美匹配和变异体的明确分期,但仅限于原核父母配对。第二种负担分析(1b)受益于更大的样本量,但无法区分从头变异和遗传变异。此外,只有在缺失边界内的 SNV 才有可能进行明确的分期。与此相反,虽然 TDT(2)可以包括缺失边界以外的 SNV,从而提高统计能力,但却无法分析从新发生的事件。负担分析的结果表明,DelCH 在 ASD 中的富集程度不高,与应用的变异频率阈值成反比。鉴于其机制由同一位点上的两个罕见事件组成,在人群水平上,DelCH 在 ASD 病因学中的作用可能不大,需要大样本量才能获得足够的统计能力。除了 "雷击两次 "之外,数据准备工作也要求很高,因为每个受试者都有独特的缺失区域,其中另一个等位基因上的序列级变异需要统计。变异选择指标包括等位基因频率阈值、常染色体显性缺失性预测阈值以及与缺失边界相关的变异包含规则。我们的研究结果表明,改变其中任何一个指标都会影响研究结果,因此需要慎重考虑。了解 DelCH 的潜在作用可能有助于建立更全面的 ASD 相关遗传变异库。DelCH可以解释为什么个别ASD患者会出现遗传自非受影响父母的缺失。最后,在遗传分析中研究DelCH可能有助于发现隐性ASD基因,否则这些基因将无法被发现。
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WHAT IS THE IMPACT OF COMPOUND HETEROZYGOUS EVENTS INVOLVING DELETIONS AND SEQUENCE-LEVEL VARIANTS IN AUTISM?
The majority of human genes maintain normal biological function when they become haploid due to a genomic deletion. However, pathogenicity may still arise when the remaining allele is affected by additional functional variation. Here, we describe analytical strategies for examining a specific type of compound heterozygosity, namely the co-occurrence of a deletion and a sequence-level variant affecting the other allele, hereafter referred to as deletion compound heterozygosity (DelCH). We report preliminary results in using these strategies to assess DelCH in Autism Spectrum Disorder (ASD).
We analyzed whole-genome sequencing data from MSSNG, Simons Simplex Collection, and SPARK cohorts (collectively 11,636 autistic individuals and 22,962 family members).
We developed multiple analytical strategies to examine rare (event rate < 1%) DelCH:
  • 1)
    The burden analysis uses conditional logistic regression for group-level comparisons of DelCH rates between a) probands and their deletion-transmitting parents, with inherited deletion as a random effect variable, or b) probands and their family members, with family ID as a random effect variable;
  • 2)
    The transmission disequilibrium test (TDT) compares the rates with which deletion-non-transmitting parents transmit sequence-level variants within genes affected by deletions to their autistic offspring. Association is indicated by transmission of non-synonymous variants at a rate higher than predicted by chance. This approach was repeated in unaffected siblings as an additional control analysis.
Each strategy has different strengths and weaknesses. The first burden analysis (1a) achieves perfect matching of deleted sequence and unambiguous phasing of variants but is restricted to proband-parent pairs. The second burden analysis (1b) benefits from a larger sample size but cannot distinguish between de novo and inherited variation. In addition, unambiguous phasing is possible only for SNVs within deletion boundaries. In contrast, while the TDT (2) can include SNVs outside deletion boundaries, thereby increasing statistical power, de novo events are not analyzed.
Our preliminary findings show variability in results as a function of the analytical strategy. Findings from the burden analysis suggest a modest enrichment of DelCH in ASD which was inversely proportional to the variant frequency thresholds applied.
Given that the mechanism consists of two rare events at the same locus, on the population level the role of DelCH in ASD etiology is likely modest, requiring large samples sizes for sufficient statistical power. In addition to this “lightning striking twice”, data preparation is demanding, as every subject has unique deletion regions in which sequence-level variants on the other allele are tallied. Variant selection metrics include allele frequency thresholds, the threshold for predicted autosomal dominant deleteriousness, and variant inclusion rules with respect to the deletion boundaries. Our findings show that altering any of these metrics affects the results, warranting careful consideration.
Understanding the potential role of DelCH may contribute to a more comprehensive library of ASD-associated genetic variation. DelCHs could explain why individual probands with ASD present with a deletion inherited from a non-affected parent. Lastly, examining DelCH in genetic analyses may help identify recessive ASD genes, which otherwise escape detection.
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来源期刊
European Neuropsychopharmacology
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.
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