Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities
Journal article
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, Fisher, Simon E., Lovett, Maureen W., Strug, Lisa J., Barr, Cathy L. and Hulme, Charles*. (2022). Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities. Translational Psychiatry. 12(1), p. Article 495. https://doi.org/10.1038/s41398-022-02250-z
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, Fisher, Simon E., Lovett, Maureen W., Strug, Lisa J., Barr, Cathy L. and Hulme, Charles* |
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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. |
Year | 2022 |
Journal | Translational Psychiatry |
Journal citation | 12 (1), p. Article 495 |
Publisher | Springer Nature |
ISSN | 2158-3188 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s41398-022-02250-z |
PubMed ID | 36446759 |
Scopus EID | 2-s2.0-85142921133 |
PubMed Central ID | PMC9709072 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-9 |
Funder | National Health and Medical Research Council (NHMRC) |
Australian Research Council (ARC) | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 29 Nov 2022 |
Publication process dates | |
Accepted | 03 Nov 2022 |
Deposited | 07 Aug 2023 |
ARC Funded Research | This output has been funded, wholly or partially, under the Australian Research Council Act 2001 |
Grant ID | 1105008 |
1195955 | |
1116976 | |
1173896 | |
389891 | |
436958 | |
572613 | |
403981 | |
1059711 | |
A7960034 | |
A79906588 | |
A79801419 | |
DP0212016 | |
DP0343921 | |
Additional information | *Charles Hulme is a member of the Quantitative Trait Working Group of the GenLang Consortium For a full list of funders, please refer to the "Acknowledgements" section of the publication. |
https://acuresearchbank.acu.edu.au/item/8z757/hypothesis-driven-genome-wide-association-studies-provide-novel-insights-into-genetics-of-reading-disabilities
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Publisher's version
OA_Price_2022_Hypothesis_driven_genome_wide_association_studies.pdf | |
License: CC BY 4.0 | |
File access level: Open |
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