Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.
Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China.
Proc Natl Acad Sci U S A. 2022 Nov 15;119(46):e2203491119. doi: 10.1073/pnas.2203491119. Epub 2022 Nov 9.
Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance ( < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense ( = 41) or truncating ( = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (, , , and . This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.
大多数遗传研究将自闭症谱系障碍 (ASD) 和发育障碍 (DD) 分开考虑，尽管它们的共病率很高，且具有共同的遗传病因。在这里，我们分别分析了 15560 例 ASD (来自 SPARK 的 6557 例) 和 31052 例 DD 三核苷酸组中的新生变异 (DNVs)，并使用三种模型将其合并为更广泛的神经发育障碍 (NDD)。我们确定了 615 个 NDD 候选基因 (错误发现率 [FDR] < 0.05)，这些基因得到了至少一个模型的支持，其中 138 个基因在所有模型中达到了 Bonferroni 全基因组显著性 ( < 3.64e-7)。这些基因根据单细胞核转录组数据分为五个功能网络，与不同的脑发育谱系相关。与 DD 显著富集的 18 个基因相比，我们没有发现 ASD 特异性基因的证据。有 53 个基因显示出突变偏向性，包括错义 ( = 41) 或截断 ( = 12) 的 DNV 富集。我们还发现了 10 个具有男性或女性偏向性富集证据的基因，其中包括 4 个 X 染色体基因，具有显著的女性负担 ( 、 、 、和 。这项大规模的综合分析确定了 NDD 候选基因和功能亚群。
Zotero 插件
