The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains

Abstract

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples – Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) – and then combined results by meta‐analysis. DYX2 markers, specifically those in the 3′ untranslated region of DCDC2 (P = 1.43 × 10−4), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic‐related genes ANKK1 (P = 1.02 × 10−2) and DRD2 (P = 9.22 × 10−3) and nicotinic‐related genes CHRNA3 (P = 2.51 × 10−3) and BDNF (P = 8.14 × 10−3) with case–control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language‐related outcomes remains to be elucidated.

The Use of Machine Learning and Phonetic Endophenotypes to Discover Genetic Variants Associated with Speech Sound Disorder

“…However, the Japanese test only measured general language ability (vocabulary, comprehension, writing) and did not include an articulation test. On the other hand, [11][12][13][14][15] found associations of neurochemical signaling genesparticularly DRD2, a dopamine receptor -with measures of SSD (including GFTA scores) and other language phenotypes, but their studies did not include COMT, a dopamine metabolizer. To our knowledge, this is the first study linking COMT polymorphism with speech sound development in particular.…”

“…A common strategy of SSD studies has been to target genes and loci previously linked to other language disorders [2]. As an example, studies linking neurochemical signaling genes to vocabulary and grammar skills [11,12], language impairment, and reading disorders [13] led to other studies of these genes in relation to SSD [14,15]. They found associations with several genes, particularly DRD2, which encodes a dopamine receptor.…”

“…This is similar to the common concept of an endophenotype [19,20], an objectively defined, measurable behavior used as a proxy for one or multiple cognitive phenotypes. Endophenotype measures are often used in speech studies, such as nonword repetition [21], phonological awareness tests [15], and the test used in our study, the Goldman-Fristoe Test of Articulation ( [22], used in e.g. [1,15]).…”

“…Endophenotype measures are often used in speech studies, such as nonword repetition [21], phonological awareness tests [15], and the test used in our study, the Goldman-Fristoe Test of Articulation ( [22], used in e.g. [1,15]). Here we extend the concept a bit to the use of phonetic classes as distinct measures.…”

The neuronal migration hypothesis of dyslexia: A critical evaluation 30 years on

“…Dyslexia appears to be a complex, multi‐factorial disorder with a strong genetic component in its aetiology, with heritability estimates from twin studies at 40%–70% (Paracchini et al., ). Like other neurodevelopmental disorders, it commonly co‐occurs with conditions including developmental language disorder (DLD; Newbury et al., ; Snowling, ), attention deficit hyperactivity disorder (ADHD; Germano, Gagliano, & Curatolo, ; Gilger, ), and mathematical disability (Davis et al., ; Ritchie & Bates, ), among others (Eicher et al., ; Pennington, ; Richardson & Ross, ).…”