Eising E, Mirza-Schreiber N, de Zeeuw EL, Wang CA, Truong DT, Allegrini AG, Shapland CY, Zhu G, Wigg KG, Gerritse ML, Molz B, Alagöz G, Gialluisi A, Abbondanza F, Rimfeld K, van Donkelaar M, Liao Z, Jansen PR, Andlauer TFM, Bates TC, Bernard M, Blokland K, Bonte M, Børglum AD, Bourgeron T, Brandeis D, Ceroni F, Csépe V, Dale PS, de Jong PF, DeFries JC, Démonet JF, Demontis D, Feng Y, Gordon SD, Guger SL, Hayiou-Thomas ME, Hernández-Cabrera JA, Hottenga JJ, Hulme C, Kere J, Kerr EN, Koomar T, Landerl K, Leonard GT, Lovett MW, Lyytinen H, Martin NG, Martinelli A, Maurer U, Michaelson JJ, Moll K, Monaco AP, Morgan AT, Nöthen MM, Pausova Z, Pennell CE, Pennington BF, Price KM, Rajagopal VM, Ramus F, Richer L, Simpson NH, Smith SD, Snowling MJ, Stein J, Strug LJ, Talcott JB, Tiemeier H, van der Schroeff MP, Verhoef E, Watkins KE, Wilkinson M, Wright MJ, Barr CL, Boomsma DI, Carreiras M, Franken MJ, Gruen JR, Luciano M, Müller-Myhsok B, Newbury DF, Olson RK, Paracchini S, Paus T, Plomin R, Reilly S, Schulte-Körne G, Tomblin JB, van Bergen E, Whitehouse AJO, Willcutt EG, St Pourcain B, Francks C, and Fisher SE
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.