Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities
Authors: Price Kaitlyn M. , Wigg Karen G. , Eising Else , Feng Yu , Blokland Kirsten , Wilkinson Margaret , Kerr Elizabeth N. , Guger Sharon L. ,   Quantitative Trait Working Group of the GenLang Consortium, Abbondanza Filippo , Allegrini Andrea G. , Andlauer Till F. M. , Bates Timothy C. , Bernard Manon , Bonte Milene , Boomsma Dorret I. , Bourgeron Thomas , Brandeis Daniel , Carreiras Manuel , Ceroni Fabiola , Csépe Valéria , Dale Philip S. , DeFries John C. , de Jong Peter F. , Démonet Jean Francois , de Zeeuw Eveline L. , Franken Marie-Christine J. , Francks Clyde , Gerritse Margot , Gialluisi Alessandro , Gordon Scott D. , Gruen Jeffrey R. , Hayiou-Thomas Marianna E. , Hernández-Cabrera Juan , Hottenga Jouke-Jan , Hulme Charles , Jansen Philip R. , Kere Juha , Koomar Tanner , Landerl Karin , Leonard Gabriel T. , Liao Zhijie , Luciano Michelle , Lyytinen Heikki , Martin Nicholas G. , Martinelli Angela , Maurer Urs , Michaelson Jacob J. , Mirza-Schreiber Nazanin , Moll Kristina , Monaco Anthony P. , Morgan Angela T. , Müller-Myhsok Bertram , Newbury Dianne F. , Nöthen Markus M. , Olson Richard K. , Paracchini Silvia , Paus Tomas , Pausova Zdenka , Pennell Craig E. , Pennington Bruce F. , Plomin Robert J. , Ramus Franck , Reilly Sheena , Richer Louis , Rimfeld Kaili , Schulte-Körne Gerd , Shapland Chin Yang , Simpson Nuala H. , Smith Shelley D. , Snowling Margaret J. , St Pourcain Beate , Stein John F. , Talcott Joel B. , Tiemeier Henning , Tomblin J. Bruce , Truong Dongnhu T. , van Bergen Elsje , van der Schroeff Marc P. , Van Donkelaar Marjolein , Verhoef Ellen , Wang Carol A. , Watkins Kate E. , Whitehouse Andrew J. O. , Willcutt Erik G. , Wright Margaret J. , Zhu Gu , Fisher Simon E. , Lovett Maureen W. , Strug Lisa J. , Barr Cathy L. 
Published: November 2022

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.