美国麻省理工学院和哈佛大学Broad研究所Michael E. Talkowski等团队合作在研究中取得进展。他们的最新研究发现罕见的编码变异有助于深入了解自闭症的遗传结构和表型背景。相关论文于2022年8月18日发表在《自然-遗传学》杂志上。

研究人员通过对63,237名自闭症患者的蛋白质截短变体(PTV)、错义变体和拷贝数变体(CNV)的联合分析，探索了这些变体对基因的破坏。研究发现了72个与自闭症谱系障碍(ASD)相关的基因，其错误发现率(FDR)≤0.001（185个FDR ≤ 0.05）。从头PTV、破坏性错义变异和CNV占关联证据的57.5%、21.1%和8.44%，其中CNV具有最高的相对风险。

对确定发育迟缓(DD) (n = 91,605)队列进行荟萃分析，在FDR≤0.001时发现了373个与ASD/DD相关的基因（在FDR≤0.05时为664个），其中一些基因在ASD和DD之间的相对突变频率有所不同。DD相关基因在祖细胞和未成熟神经元细胞的转录组中富集，而与ASD具有更强相关性的基因在成熟神经元中更丰富，并与精神分裂症相关基因重叠，这表明一些神经精神疾病可能具有共同的风险突变途径。

据悉，一些患有自闭症谱系障碍的人具有普通人群中很少存在的功能突变。

附：英文原文

Title: Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author: Fu, Jack M., Satterstrom, F. Kyle, Peng, Minshi, Brand, Harrison, Collins, Ryan L., Dong, Shan, Wamsley, Brie, Klei, Lambertus, Wang, Lily, Hao, Stephanie P., Stevens, Christine R., Cusick, Caroline, Babadi, Mehrtash, Banks, Eric, Collins, Brett, Dodge, Sheila, Gabriel, Stacey B., Gauthier, Laura, Lee, Samuel K., Liang, Lindsay, Ljungdahl, Alicia, Mahjani, Behrang, Sloofman, Laura, Smirnov, Andrey N., Barbosa, Mafalda, Betancur, Catalina, Brusco, Alfredo, Chung, Brian H. Y., Cook, Edwin H., Cuccaro, Michael L., Domenici, Enrico, Ferrero, Giovanni Battista, Gargus, J. Jay, Herman, Gail E., Hertz-Picciotto, Irva, Maciel, Patricia, Manoach, Dara S., Passos-Bueno, Maria Rita, Persico, Antonio M., Renieri, Alessandra, Sutcliffe, James S., Tassone, Flora, Trabetti, Elisabetta, Campos, Gabriele, Cardaropoli, Simona, Carli, Diana, Chan, Marcus C. Y., Fallerini, Chiara, Giorgio, Elisa, Girardi, Ana Cristina, Hansen-Kiss, Emily, Lee, So Lun, Lintas, Carla, Ludena, Yunin, Nguyen, Rachel, Pavinato, Lisa, Pericak-Vance, Margaret, Pessah, Isaac N., Schmidt, Rebecca J., Smith, Moyra, Costa, Claudia I. S.

Issue&Volume: 2022-08-18

Abstract: Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR)≤0.001 (185 at FDR≤0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n=91,605) yielded 373 genes associated with ASD/DD at FDR≤0.001 (664 at FDR≤0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

DOI: 10.1038/s41588-022-01104-0

Source: https://www.nature.com/articles/s41588-022-01104-0