Kazem Sayeh, Kumar Kuldeep, Jean-Louis Martineau, Huguet Guillaume, Renne Thomas, Saci Zohra, Engchuan Worrawat, Shanta Omar, Thiruvahindrapuram Bhooma, MacDonald Jeffrey R, Greenwood Celia M T, Scherer Stephen W, Almasy Laura, Sebat Jonathan, Glahn David C, Dumas Guillaume, Jacquemont Sébastien
medRxiv. 2025 Feb 26:2025.02.25.25322833. doi: 10.1101/2025.02.25.25322833.
Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage to complex traits remains limited, and whether these functions sensitive to gene dosage are similar to those underlying the effects of rare single nucleotide variants (SNVs) and common variants remains unknown.
We developed FunBurd, a functional burden analysis, to test the association of CNVs aggregated within functional gene sets. We applied this approach in 500,000 individuals from the UK Biobank to associate 43 complex traits with CNVs disrupting 172 gene sets across tissues and cell types. We compared CNV findings with those from common variants and LoF (Loss of Function) SNVs in the same cohort using the same functional gene sets.
All 43 traits showed FDR significant associations with CNVs. Brain tissue and neuronal cell-types showed the highest levels of pleiotropy. Most of the functional gene set associations could, in part, be explained by genetic constraint, except for brain related processes. Shared genetic contributions between pairs of traits were concordant across types of variants, but on average 2-fold higher, for rare CNVs and SNVs compared to common variants.Functional enrichment across traits found limited overlap between CNVs and common variants. Moreover, the effects of deletions and duplications were negatively correlated for most traits.In conclusion, we present new methods to separate the contributions of genetic constraint and gene function to the associations of CNVs with complex traits. Overall, the functional convergence between different types of variants -even between deletions and duplications- remains limited.
Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage to complex traits remains limited.FunBurd (functional burden analysis) was applied in 500,000 individuals from the UKBiobank to associate 43 complex traits with CNVs disrupting 172 tissues/cell type gene sets.All 43 traits showed associations with CNVs. Brain tissue and neuronal cell types showed the highest levels of pleiotropy. Most of the functional gene set associations could, in part, be explained by genetic constraint, except for brain-related processes. Shared genetic contributions between pairs of traits were 2-fold higher for rare compared to common variants. The functional convergence between different types of variants -even between deletions and duplications- was limited. Our findings provide insights to separate the contributions of genetic constraint and gene function to the associations of CNVs with complex traits.
拷贝数变异（CNV）对复杂性状有很大影响，但它们很罕见，研究起来仍然具有挑战性。因此，我们对将基因剂量与复杂性状联系起来的生物学功能的理解仍然有限，而且这些对基因剂量敏感的功能是否与罕见单核苷酸变异（SNV）和常见变异的潜在功能相似仍不清楚。
我们开发了FunBurd，一种功能负担分析方法，以测试功能基因集内聚集的CNV的关联性。我们将这种方法应用于英国生物银行的50万名个体，将43种复杂性状与跨组织和细胞类型破坏172个基因集的CNV进行关联。我们使用相同的功能基因集，将同一队列中CNV的研究结果与常见变异和功能丧失（LoF）SNV的结果进行比较。
所有43种性状均显示与CNV存在FDR显著关联。脑组织和神经元细胞类型显示出最高水平的多效性。除了与大脑相关的过程外，大多数功能基因集关联部分可以由遗传限制来解释。性状对之间的共享遗传贡献在不同类型变异中是一致的，但与常见变异相比，罕见CNV和SNV的平均水平高出2倍。跨性状的功能富集发现CNV和常见变异之间的重叠有限。此外，对于大多数性状，缺失和重复的影响呈负相关。总之，我们提出了新方法来区分遗传限制和基因功能对CNV与复杂性状关联的贡献。总体而言，不同类型变异之间的功能趋同——甚至在缺失和重复之间——仍然有限。
拷贝数变异（CNV）对复杂性状有很大影响，但它们很罕见，研究起来仍然具有挑战性。因此，我们对将基因剂量与复杂性状联系起来的生物学功能的理解仍然有限。FunBurd（功能负担分析）应用于英国生物银行的50万名个体，将43种复杂性状与破坏172个组织/细胞类型基因集的CNV进行关联。所有43种性状均显示与CNV有关联。脑组织和神经元细胞类型显示出最高水平的多效性。除了与大脑相关的过程外，大多数功能基因集关联部分可以由遗传限制来解释。与常见变异相比，罕见变异的性状对之间的共享遗传贡献高出2倍。不同类型变异之间的功能趋同——甚至在缺失和重复之间——是有限的。我们的研究结果为区分遗传限制和基因功能对CNV与复杂性状关联的贡献提供了见解。
