Genome-wide association analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people
Authors: Eising Else , Mirza-Schreiber Nazanin , de Zeeuw Eveline L. , Wang Carol A. , Truong Dongnhu T. , Allegrini Andrea G. , Shapland Chin Yang , Zhu Gu , Wigg Karen G. , Gerritse Margot , Molz Barbara , Alagöz Gökberk , Gialluisi Alessandro , Abbondanza Filippo , Rimfeld Kaili , van Donkelaar Marjolein , Liao Zhijie , Jansen Philip R. , Andlauer Till F. M. , Bates Timothy C. , Bernard Manon , Blokland Kirsten , Børglum Anders D. , Bourgeron Thomas , Brandeis Daniel , Ceroni Fabiola , Dale Philip S. , Landerl Karin , Lyytinen Heikki , de Jong Peter F. , DeFries John C. , Demontis Ditte , Feng Yu , Gordon Scott D. , Guger Sharon L. , Hayiou-Thomas Marianna E. , Hernández-Cabrera Juan A. , Hottenga Jouke-Jan , Hulme Charles , Kerr Elizabeth N. , Koomar Tanner , Lovett Maureen W. , Martin Nicholas G. , Martinelli Angela , Maurer Urs , Michaelson Jacob J. , Moll Kristina , Monaco Anthony P. , Morgan Angela T. , Nöthen Markus M. , Pausova Zdenka , Pennell Craig E. , Pennington Bruce F , Price Kaitlyn M. , Rajagopal Veera M. , Ramus Frank , Richer Louis , Simpson Nuala H. , Smith Shelley , Snowling Margaret J. , Stein John , Strug Lisa J. , Talcott Joel B. , Tiemeier Henning , van de Schroeff Marc M.P. , Verhoef Ellen , Watkins Kate E. , Wilkinson Margaret , Wright Margaret J. , Barr Cathy L. , Boomsma Dorret I. , Carreiras Manuel , Franken Marie-Christine J. , Gruen Jeffrey R. , Luciano Michelle , Müller-Myhsok Bertram , Newbury Dianne F. , Olson Richard K. , Paracchini Silvia , Paus Tomas , Plomin Robert , Schulte-Körne Gerd , Reilly Sheena , Tomblin J. Bruce , van Bergen Elsje , Whitehouse Andrew J.O. , Willcutt Erik G. , Pourcain Beate St , Francks Clyde , Fisher Simon E. 
Published: November 2021

The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, we present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 × 10−8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13–0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.