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Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects

Abstract

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability—as suggested by shared linkages on 16p, 17q and possibly 10q—but also those that appear to be unique to reading—as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

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Acknowledgements

This work was supported by the National Institute of Health grants: MH58277 (to SLS), MH01969 (to JJM), HD40275 (to SKL) and MH01805 (to JTM); by UC LSI grant L9808 (to SFN); by USPHS National Research Service Award GM07104 (to MNO) and by the Wellcome Trust (support to APM). APM is a Wellcome Trust Principal Research Fellow. SEF is a Royal Society Research Fellow. Thanks are due to all the families who participated in this research; to Elva Rios, Tae Kim, Laura Combs, Leah Pressman, PhD, Melissa Del’Homme, PhD, and Deborah Lynn, MD, for their help in data collection, to Lori Crawford for technical assistance to Rita Cantor, PhD, for statistical consultation; and to Dr Dennis Cantwell, who inspired our work on ADHD.

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Correspondence to S K Loo.

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The accession number and URLs for data presented herein are as follows:ASPEX Linkage Analysis Package, ftp://lahmed.stanford.edu/pub/aspex/index.htmlCenter for Medical Genetics, Marshfield Medical Research Foundation, http://research.marshfieldclinic.org/genetics/Cooperative Human Linkage Centre, http://lpg.nci.nih.gov/ABI/index.htmlGenehunter, http://www.fhcrc.org/labs/kruglyak/Downloads/Genethon, ftp://ftp.genethon.fr/pub/Gmap/Nature-1995/data/Mapmaker/SIBS, http://www-genome.wi.mit.edu/ftp/distribution/software/sibs/Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for ADHD25)RECODE, http://watson.hgen.pitt.edu/registerResearch Genetics, ftp://ftp.resgen.com/pub/mappairs/humanset/

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Loo, S., Fisher, S., Francks, C. et al. Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects. Mol Psychiatry 9, 485–493 (2004). https://doi.org/10.1038/sj.mp.4001450

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