Association between genes regulating neural pathways for quantitative traits of speech and language disorders

Penelope Benchek; Robert P Igo Jr; Heather Voss-Hoynes; Yvonne Wren; Gabrielle Miller; Barbara Truitt; Wen Zhang; Michael Osterman; Lisa Freebairn; Jessica Tag; H Gerry Taylor; E Ricky Chan; Panos Roussos; Barbara Lewis; Catherine M Stein; Sudha K Iyengar

doi:10.1038/s41525-021-00225-5

Association between genes regulating neural pathways for quantitative traits of speech and language disorders

NPJ Genom Med. 2021 Jul 27;6(1):64. doi: 10.1038/s41525-021-00225-5.

Authors

Penelope Benchek^#¹, Robert P Igo Jr^#¹, Heather Voss-Hoynes^#¹, Yvonne Wren², Gabrielle Miller³, Barbara Truitt¹, Wen Zhang⁴, Michael Osterman¹, Lisa Freebairn³, Jessica Tag³, H Gerry Taylor^{5

6}, E Ricky Chan¹, Panos Roussos^{4

7}, Barbara Lewis^#^{3

8}, Catherine M Stein^#⁹, Sudha K Iyengar^#¹⁰

Affiliations

¹ Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
² Bristol Dental School, Faculty of Health Sciences, University of Bristol, and Bristol Speech and Language Therapy Research Unit, North Bristol NHS Trust, Bristol, UK.
³ Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Psychiatry, Friedman Brain Institute, and Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Pediatrics, Case Western Reserve University, and Rainbow Babies & Children's Hospital, University Hospital Case Medical Center, Cleveland, OH, USA.
⁶ Nationwide Children's Hospital Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
⁷ Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA.
⁸ Cleveland Hearing and Speech Center, Cleveland, OH, USA.
⁹ Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. cmj7@case.edu.
¹⁰ Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. ski@case.edu.

^# Contributed equally.

Abstract

Speech sound disorders (SSD) manifest as difficulties in phonological memory and awareness, oral motor function, language, vocabulary, reading, and spelling. Families enriched for SSD are rare, and typically display a cluster of deficits. We conducted a genome-wide association study (GWAS) in 435 children from 148 families in the Cleveland Family Speech and Reading study (CFSRS), examining 16 variables representing 6 domains. Replication was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 18 significant loci (combined p < 10^-8) that we pursued bioinformatically. We prioritized 5 novel gene regions with likely functional repercussions on neural pathways, including those which colocalized with differentially methylated regions in our sample. Polygenic risk scores for receptive language, expressive vocabulary, phonological awareness, phonological memory, spelling, and reading decoding associated with increasing clinical severity. In summary, neural-genetic influence on SSD is primarily multigenic and acts on genomic regulatory elements, similar to other neurodevelopmental disorders.

Abstract

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