dc.description.abstract | BACKGROUND AND OBJECTIVE: 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). METHODS: 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. RESULTS: Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 x 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 = 37). CONCLUSIONS: 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. | en_US |
dc.description.sponsorship | Supported by National Institute of Health grants R01 DC007665 (Dr Grigorenko, Principal Investigator) and P50 HD052120 (Richard Wagner, Principal Investigator), NIH Centers for Mendelian Genomics (5U54HG006504), National Science Foundation Integrative Graduate Education and Research Traineeship grant 114399 (Dr Magnuson, Principal Investigator), and grant 14.Z50.31.0027 from the Government of the Russian Federation (Dr Grigorenko, Principal Investigator). Funded by the National Institutes of Health (NIH). | en_US |
dc.department-temp | [Kornilov, Sergey A. -- Rakhlin, Natalia -- Lee, Maria -- Caglayan, Ahmet Okay -- Mane, Shrikant -- Chang, Joseph T. -- Grigorenko, Elena L.] Yale Univ, Sch Med, Ctr Child Study, 230 South Frontage Rd, New Haven, CT 06519 USA -- [Kornilov, Sergey A. -- Magnuson, James S.] Univ Connecticut, Dept Psychol, Storrs, CT USA -- [Kornilov, Sergey A. -- Grigorenko, Elena L.] Haskins Labs Inc, 270 Crown St, New Haven, CT 06511 USA -- [Kornilov, Sergey A.] Moscow MV Lomonosov State Univ, Dept Psychol, Moscow, Russia -- [Kornilov, Sergey A. -- Grigorenko, Elena L.] St Petersburg State Univ, Dept Psychol, St Petersburg 199034, Russia -- [Rakhlin, Natalia] Wayne State Univ, Dept Commun Sci & Disorders, Detroit, MI USA -- [Koposov, Roman] UiT Arctic Univ Norway, Reg Ctr Child & Youth Mental Hlth & Child Welf, Tromso, Norway -- [Yrigollen, Carolyn] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA -- [Caglayan, Ahmet Okay] Istanbul Bilim Univ, Dept Med Genet, Istanbul, Turkey -- [Grigorenko, Elena L.] Moscow State Univ Psychol & Educ, Moscow, Russia | en_US |