Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Genet. 2022 Sep;54(9):1320-1331. doi: 10.1038/s41588-022-01104-0. Epub 2022 Aug 18.
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.
一些自闭症谱系障碍（ASD）患者携带在普通人群中很少观察到的功能突变。我们通过对 63237 个人的蛋白质截断变异体（PTV）、错义变异体和拷贝数变异体（CNV）的联合分析，研究了这些变异体所破坏的基因。我们发现了 72 个与 ASD 相关的基因，假发现率（FDR）≤0.001（FDR≤0.05 时有 185 个）。新生 PTV、有害错义变异体和 CNV 分别占关联证据的 57.5%、21.1%和 8.44%，而 CNV 带来的相对风险最大。与为发育迟缓（DD）确定的队列进行荟萃分析（n=91605）产生了 373 个与 ASD/DD 相关的基因，FDR≤0.001（FDR≤0.05 时有 664 个），其中一些基因在 ASD 和 DD 队列之间的突变相对频率不同。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，而在 ASD 中表现出更强证据的基因在成熟神经元中更为丰富，并且与精神分裂症相关基因重叠，这强调了这些神经精神疾病可能具有共同的风险途径。
