Kornilov Sergey A, Rakhlin Natalia, Koposov Roman, Lee Maria, Yrigollen Carolyn, Caglayan Ahmet Okay, Magnuson James S, Mane Shrikant, Chang Joseph T, Grigorenko Elena L
Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Psychology, University of Connecticut, Storrs, Connecticut; Haskins Laboratories, New Haven, Connecticut; Department of Psychology, Moscow State University, Moscow, Russia; Department of Psychology, Saint Petersburg State University, Saint Petersburg, Russia;
Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Communication Sciences and Disorders, Wayne State University, Detroit, Michigan;
Pediatrics. 2016 Apr;137(4). doi: 10.1542/peds.2015-2469. Epub 2016 Mar 25.
Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).
DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing. Multifaceted phenotypes, representing major domains of expressive language functioning, were derived from collected speech samples.
Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 × 10(-7)). The analysis of exome variants revealed coding sequence variants in 14 genes, most of which play a role in neural development. Targeted enrichment analysis implicated myocyte enhancer factor-2 (MEF2)-regulated genes in DLD in the AZ population. The main findings were successfully replicated in an independent cohort of children at risk for related disorders (n = 372).
MEF2-regulated pathways were identified as potential candidate pathways in the etiology of DLD. Several genes (including the candidate SETBP1 and other MEF2-related genes) seem to jointly influence certain, but not all, facets of the DLD phenotype. Even when genetic and environmental diversity is reduced, DLD is best conceptualized as etiologically complex. Future research should establish whether the signals detected in the AZ population can be replicated in other samples and languages and provide further characterization of the identified pathway.
发育性语言障碍（DLD）是一种高度流行的神经发育障碍，与不同领域的负面结果相关；DLD的病因尚不清楚。为了研究DLD的遗传基础，我们在一个该疾病患病率显著升高的地理隔离人群（即AZ样本）中进行了全基因组关联研究和全外显子组测序研究。
从359名个体中收集DNA样本用于全基因组关联研究，从12名严重受影响的个体中收集DNA样本用于全外显子组测序。从收集的语音样本中得出代表表达性语言功能主要领域的多方面表型。
基于基因的分析显示SETBP1与语言输出复杂性之间存在显著关联（P = 5.47 × 10⁻⁷）。外显子组变异分析揭示了14个基因中的编码序列变异，其中大多数在神经发育中起作用。靶向富集分析表明肌细胞增强因子2（MEF2）调控的基因与AZ人群的DLD有关。主要研究结果在一个独立的有相关疾病风险的儿童队列（n = 372）中成功得到重复验证。
MEF2调控的通路被确定为DLD病因学中的潜在候选通路。几个基因（包括候选基因SETBP1和其他与MEF2相关的基因）似乎共同影响DLD表型的某些方面，但不是全部。即使遗传和环境多样性降低，DLD在病因学上最好被理解为复杂的。未来的研究应确定在AZ人群中检测到的信号是否能在其他样本和语言中得到重复验证，并进一步表征已确定的通路。
