American Journal of Medical Genetics (Neuropsychiatric Genetics) 105:507±517 (2001) Evidence for a Susceptibility Locus on Chromosome 6q In¯uencing Phonological Coding Dyslexia Tracey L. Petryshen, 1 Bonnie J. Kaplan, 2,3 Ming Fu Liu, 1 Norma Schmill de French, 1 Rose Tobias, 1 Martha L. Hughes, 1 and L. Leigh Field 1,4 * 1 Department of Medical Genetics, University of Calgary, Calgary Canada 2 Department of Paediatrics, University of Calgary, Calgary Canada 3 Alberta Children's Hospital, Calgary, Canada 4 Department of Medical Genetics, British Columbia Research Institute for Women's and Children's Health, Vancouver, Canada A linkage study of 96 dyslexia families containing at least two affected siblings (totaling 877 individuals) has found evi- dence for a dyslexia susceptibility gene on chromosome 6q11.2±q12 (assigned the name DYX4). Using a qualitative phonological coding dyslexia (PCD) phenotype (affected, unaffected, or uncertain diagnoses), two- point parametric analyses found highly suggestive evidence for linkage between PCD and markers D6S254, D6S965, D6S280, and D6S251 (LOD max scores  2.4 to 2.8) across an 11 cM region. Multipoint para- metric analysis supported linkage of PCD to this region (peak HLOD  1.6), as did multi- point nonparametric linkage analysis (P  0.012). Quantitative trait linkage ana- lyses of four reading measures (phonologi- cal awareness, phonological coding, spelling, and rapid automatized naming speed) also provided evidence for a dyslexia susceptibility locus on chromosome 6q. Using a variance-component approach, ana- lysis of phonological coding and spelling measures resulted in peak LOD scores at D6S965 of 2.1 and 3.3, respectively, under 2 degrees of freedom. Furthermore, multi- point nonparametric quantitative trait sib- lingpair analyses suggested linkage between the 6q region and phonological awareness, phonological coding, and spel- ling (P  0.018, 0.017, 0.0005, respectively, for unweighted sibpairs <18 years of age). Although conventional signi®cance thresh- olds were not reached in the linkage ana- lyses, the chromosome 6q11.2±q12 region clearly warrants investigation in other dys- lexia family samples to attempt replication and con®rmation of a dyslexia susceptibility gene in this region. ß 2001 Wiley-Liss, Inc. KEY WORDS: dyslexia/genetics; human; linkage; quantitative trait; qualitative trait INTRODUCTION Developmental dyslexia is de®ned as severe dif®culty in learning to read that is independent of intelligence and educational opportunity. Dyslexia affects 3 ± 10% of school-age children [Lerner, 1989] and is associated with major negative social, educational, emotional, and economic repercussions [Spreen, 1998]. Cognitive stu- dies demonstrate that most people with dyslexia have dif®culty processing the basic phoneme (sound) units of language, i.e., they display a de®cit in some aspect of phonological processing [Van Orden and Goldinger, 1996]. This dif®culty persists throughout life, although many dyslexic adults are able to read, presumably using visual memory skills and other compensatory strategies. Familial aggregation of dyslexia is well documented [Hallgren, 1950; Zahalkova et al., 1972; Gilger et al., 1991]. Family and twin studies have shown that there is a signi®cant genetic contribution to dyslexia, with heritability estimates for various reading phenotypes ranging from 0.51 to 0.93 [Bakwin, 1973; DeFries et al., 1987; Stevenson et al., 1987; Olson et al., 1989]. Despite the data indicating a genetic basis for reading dis- ability, the mode of inheritance is unclear, with auto- somal dominant, recessive, and polygenic inheritance and genetic heterogeneity suggested [Hallgren, 1950; Finucci et al., 1976; Lewitter et al., 1980; Pennington et al., 1991]. Genetic linkage and linkage disequilibrium studies of families with dyslexic members have found evidence for several loci in¯uencing reading disability, thus con- *Correspondence to: Dr. L. Leigh Field, Department of Medical Genetics, British Columbia Research Institute for Women's and Children's Health, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada. E-mail: ll®eld@interchange.ubc.ca Received 2 October 2000; Accepted 16 April 2001 ß 2001 Wiley-Liss, Inc.