整合遗传和甲基化组分析确定自闭症和自闭症特征之间的共同生物学特征。
Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits.
机构信息
1Autism Research Centre, University of Cambridge, Cambridge, UK.
2University of Exeter Medical School, University of Exeter, RILD Building, Level 4, Barrack Rd, Exeter, UK.
出版信息
Mol Autism. 2019 Jul 17;10:31. doi: 10.1186/s13229-019-0279-z. eCollection 2019.
Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits-subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year-olds, by conducting a methylome-wide association study (MWAS). We did not identify significant CpGs associated with SCDC. The most significant CpG site was cg14379490, on chromosome 9 (MWAS beta = - 1.78 ± 0.35, value = 5.34 × 10 ). Using methylation data for autism in peripheral tissues, we did not identify a significant concordance in effect direction of CpGs with value < 10 in the SCDC MWAS (binomial sign test, value > 0.5). In contrast, using methylation data for autism from post-mortem brain tissues, we identify a significant concordance in effect direction of CpGs with a value < 10 in the SCDC MWAS (binomial sign test, value = 0.004). Supporting this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain (one-sided Wilcoxon rank-sum test, value = 6.22 × 10). Finally, integrating genome-wide association study (GWAS) data for autism ( = 46,350) with mQTL maps from cord-blood ( = 771), we demonstrate that mQTLs of CpGs associated with SCDC scores at value thresholds of 0.01 and 0.005 are significantly shifted toward lower values in the GWAS for autism ( < 5 × 10). We provide additional support for this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer's disease. Our results highlight the shared cross-tissue methylation architecture of autism and autistic traits, and demonstrate that mQTLs associated with differences in DNA methylation associated with childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits.
先前的研究已经确定了自闭症个体与神经典型个体之间的 DNA 甲基化差异。然而，目前尚不清楚这是否会扩展到自闭症特征的亚临床表现，即自闭症特征在普通人群中的表现。在这里，我们通过进行全基因组甲基化关联研究（MWAS），研究了 701 名 8 岁儿童出生时（脐带血）的 DNA 甲基化与自闭症社交和沟通障碍检查表（SCDC）评分之间的关联，SCDC 是自闭症特征的一种衡量标准。我们没有发现与 SCDC 显著相关的 CpG。最显著的 CpG 位点是 9 号染色体上的 cg14379490（MWAS 贝塔值=−1.78±0.35， 值=5.34×10 ）。使用外周组织的自闭症甲基化数据，我们没有发现 SCDC MWAS 中 值<10 的 CpG 效应方向的一致性（二项式符号检验， 值>0.5）。相比之下，使用来自死后脑组织的自闭症甲基化数据，我们发现 SCDC MWAS 中 值<10 的 CpG 的效应方向存在显著一致性（二项式符号检验， 值=0.004）。支持这一点，我们观察到在死后自闭症大脑中失调的基因富集（单侧 Wilcoxon 秩和检验， 值=6.22×10）。最后，我们将自闭症的全基因组关联研究（GWAS）数据（ =46,350）与脐带血的 mQTL 图谱（ =771）整合，证明了与 SCDC 评分相关的 CpG 的 mQTL 在自闭症的 GWAS 中，在 值阈值为 0.01 和 0.005 时，显著向较低的值偏移（ 值<5×10）。我们使用 SCDC 的 GWAS 提供了额外的支持，并证明了阿尔茨海默病 GWAS 中没有富集。我们的结果强调了自闭症和自闭症特征的跨组织甲基化结构共享，并表明与儿童自闭症特征相关的 DNA 甲基化差异相关的 mQTL 富集了与自闭症和自闭症特征相关的常见遗传变异。
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