Unravelling the genetic basis of stuttering: GWAS meta-analysis highlights link with rare speech disorders
Jackson, V. E.; Shin, J. J.; Horton, S.; Boyce, J. O.; Eising, E.; van Reyk, O.; Parker, R.; Thompson-Lake, D. G. Y.; Evans, M.; Beilby, J.; Below, J. E.; Boomsma, D. I.; Bridges, E.; Corfield, E. C.; Franken, M.-C. J.; Gordon, S. D.; Havdahl, A.; Koenraads, S. P. C.; Kraft, S. J.; Luciano, M.; Moen, G.-H.; Mountford, H. S.; Musial, A.; Pennell, C. E.; Polikowsky, H. G.; Pool, R.; Rebattu, V. A.; Rimfeld, K.; Scartozzi, A. C.; St Pourcain, B.; Szilagyi, I. A.; Valand, S. B.; Viljoen, K. Z.; Wang, C. A.; Whitehouse, A. J. O.; Wren, Y. E.; van Bergen, E.; Gillespie, N. A.; Vogel, A. P.; Scheffer
Show abstract
Background: Developmental stuttering affects up to 11% of children globally, with around one-fifth developing a persistent lifelong stutter. Twin and family studies indicate a strong genetic contribution and comorbidity with other heritable traits. Despite efforts to investigate the common genetic architecture of stuttering, much of variation contributing to clinically ascertained stuttering, persistence and recovery remains uncharacterised. Methods: We performed a genome-wide association study (GWAS) meta-analysis of stuttering across 18 cohorts (6,096 cases, 81,629 controls) of European ancestries, with secondary analyses of stuttering persistence and sex-stratified GWAS. Findings: No variant reached genome-wide significance in the primary meta-analysis, but 24 loci showed suggestive association (p<1x10-5), with SNP-based heritability estimated at h2=0.26. FLAMES-prioritised genes at suggestive loci overlapped with those previously implicated in childhood apraxia of speech, including PTBP2, KIRREL3, CAMTA1, GRIN2A, and SETBP1, with significant enrichment for apraxia-associated genes overall (p=1x10-4). Meta-analysis with an independent self-reported stuttering GWAS identified a genome-wide significant association at MPPED2 and gene-level convergence at CAMTA1 and PTBP2. A polygenic risk score derived from this independent GWAS was associated with stuttering susceptibility and severity within clinically ascertained cases. Partitioned heritability analysis pointed to enrichment in conserved regulatory regions, and integration with imaging data highlighted motor circuitry including decreased pallidum volume and cerebellar and white-matter microstructural differences. Interpretation: Our findings support common variant associations in stuttering converging on genes implicated in speech and neurodevelopmental conditions, pointing to basal ganglia-cerebellar motor circuits as central to speech motor control. Funding: Australian National Health and Medical Research Council.
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