Genome-wide 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 L. , 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 , Bonte Milene , Børglum Anders D. , Bourgeron Thomas , Brandeis Daniel , Ceroni Fabiola , Csépe Valéria , Dale Philip S. , de Jong Peter F. , DeFries John C. , Démonet Jean-François , Demontis Ditte , Feng Yu , Gordon Scott D. , Guger Sharon L. , Hayiou-Thomas Marianna E. , Hernández-Cabrera Juan A. , Hottenga Jouke-Jan , Hulme Charles , Kere Juha , Kerr Elizabeth N. , Koomar Tanner , Landerl Karin , Leonard Gabriel T. , Lovett Maureen W. , Lyytinen Heikki , 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 Franck , Richer Louis , Simpson Nuala H. , Smith Shelley D. , Snowling Margaret J. , Stein John , Strug Lisa J. , Talcott Joel B. , Tiemeier Henning , van der Schroeff Marc 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 Tomáš , Plomin Robert , Reilly Sheena , Schulte-Körne Gerd , Tomblin J. Bruce , van Bergen Elsje , Whitehouse Andrew J. O. , Willcutt Erik G. , St Pourcain Beate , Francks Clyde , Fisher Simon E. 
Published: August 2022

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. 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) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009,P= 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.