Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

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Price, Kaitlyn M, Wigg, Karen G, Eising, Else, Feng, Yu, Blokland, Kirsten, Wilkinson, Margaret, Kerr, Elizabeth N, Guger, Sharon L, Abbondanza, Filippo, Allegrini, Andrea G et al (show 80 more authors) , Andlauer, Till FM, Bates, Timothy C, Bernard, Manon, Bonte, Milene, Boomsma, Dorret I, Bourgeron, Thomas, Brandeis, Daniel, Carreiras, Manuel, Ceroni, Fabiola, Csepe, Valeria, Dale, Philip S, DeFries, John C, de Jong, Peter F, Demonet, 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, Hernandez-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, Mueller-Myhsok, Bertram ORCID: 0000-0002-0719-101X, Newbury, Dianne F, Noethen, 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-Korne, 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 JO, Willcutt, Erik G, Wright, Margaret J, Zhu, Gu, Fisher, Simon E, Lovett, Maureen W, Strug, Lisa J and Barr, Cathy L (2022) Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities. TRANSLATIONAL PSYCHIATRY, 12 (1). 495-.

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	Quantitative Trait Working Group of the GenLang Consortium, Humans, Dyslexia, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Autism Spectrum Disorder
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health
Depositing User:	Symplectic Admin
Date Deposited:	19 Jan 2023 16:47
Last Modified:	01 Mar 2024 16:42
DOI:	10.1038/s41398-022-02250-z
Open Access URL:	https://doi.org/10.1038/s41398-022-02250-z
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3167168