Population-based genetic effects for developmental stuttering

Abstract

Summary Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = −5.576, p = 2.46 × 10 −8 ) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10 −6 ). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research.

Discovery of 36 loci significantly associated with stuttering

“…Default auto-phi parameters were used in both the male and female derived models and were not optimized to prevent over tting, with LD reference panels constructed using 1KG phase 3 EUR reference for EA, and AFR for AA. Each model was applied to both the international stuttering project (ISP) sample 31 and Add Health sample, 33 Genetic datasets were scored using PLINK 1v9. 92 Genetic liability scores were z-score normalized.…”

“…29,30 To date, two population studies of stuttering have been published in the literature, reporting two genome-wide signi cant genomic loci that confer stuttering risk at the population-level. 31,32 Together, these prior investigations, leveraging both family data and global outbred populations, demonstrate that stuttering genetic risk factors are complex and involve both familial and population variation. Despite this progress, the biological mechanisms by which these variants impact stuttering are unknown.…”

“…called the International Stuttering Project (ISP) 31 and a cohort of self and parental reported stuttering in The National Longitudinal Study of Adolescent to Adult Health (Add Health). 33 These effects are further leveraged to explore genetic correlations between stuttering and its comorbidities.…”

Test of Prosody via Syllable Emphasis (“TOPsy”): Psychometric Validation of a Brief Scalable Test of Lexical Stress Perception

“…The goal of extending these lines of research to other speech, language, and reading traits highlights the need for coordinated efforts toward collecting and meta-analyzing largescale data in cohorts that have been able to link language-related traits to genotypes. [e.g., GenLang consortium (genlang.org): Eising et al, 2021, BioRXiv, Lancaster et al, in prep.; International Stuttering Project (theinternationalstutteringproject.com): Polikowsky et al, 2021;Shaw et al, 2021].…”

“…[e.g., GenLang consortium ( genlang.org ): Eising et al, 2021 , BioRXiv , Lancaster et al, in prep. ; International Stuttering Project ( theinternationalstutteringproject.com ): Polikowsky et al, 2021 ; Shaw et al, 2021 ].…”