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• W2000622732 abstract "SummaryIn this study, which is a continuation and an extension of an earlier study, we enrolled two new families (N=31) and recruited more individuals from the previously ascertained families (N=56). The eight multiplex families (N=171) presented in this study were ascertained from a sample of adult probands whose childhood reading history is well documented through archival information. Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were (1) phonemic awareness (of spoken words); (2) phonological decoding (of printed nonwords); (3) rapid automatized naming (of colored squares or object drawings); (4) single-word reading (orally, of printed real words); (5) vocabulary; and (6) spelling (of dictated words). In addition, the diagnosis of lifelong dyslexia was established by clinical means. Genotyping was done with nine highly polymorphic markers from the 6p22.3–6p21.3 region. The results of two- and multipoint identity-by-descent and identity-by-state analyses supported the importance of a putative locus in the D6S464–D6S273 region for a number of dyslexia-related cognitive deficits. In this study, which is a continuation and an extension of an earlier study, we enrolled two new families (N=31) and recruited more individuals from the previously ascertained families (N=56). The eight multiplex families (N=171) presented in this study were ascertained from a sample of adult probands whose childhood reading history is well documented through archival information. Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were (1) phonemic awareness (of spoken words); (2) phonological decoding (of printed nonwords); (3) rapid automatized naming (of colored squares or object drawings); (4) single-word reading (orally, of printed real words); (5) vocabulary; and (6) spelling (of dictated words). In addition, the diagnosis of lifelong dyslexia was established by clinical means. Genotyping was done with nine highly polymorphic markers from the 6p22.3–6p21.3 region. The results of two- and multipoint identity-by-descent and identity-by-state analyses supported the importance of a putative locus in the D6S464–D6S273 region for a number of dyslexia-related cognitive deficits. Recently, a number of research groups have followed up on an initial report by Cardon et al. (Cardon et al., 1994Cardon LE Smith SD Fulker DW Kimberling WJ Pennington BF DeFries JC Quantitative trait locus for reading disability on chromosome 6.Science. 1994; 266: 276-279Crossref PubMed Scopus (471) Google Scholar, Cardon et al., 1995Cardon LE Smith SD Fulker DW Kimberling WJ Pennington BF DeFries JC Quantitative trait locus for reading disability: correction.Science. 1995; 268: 1553Crossref PubMed Scopus (95) Google Scholar) that suggested a putative quantitative-trait locus (QTL) involved in specific reading disability. The original article reported that the area of interest mapped to 6p21.3. This region is just distal to the HLA complex and relatively well characterized at the physical level (Feder et al. Feder et al., 1996Feder JN Gnirke A Thomas W Tsuchihashi Z Ruddy DA Basava A Dormishian F et al.A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.Nat Genet. 1996; 13: 399-408Crossref PubMed Scopus (3345) Google Scholar). The four subsequent searches (Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar; Field and Kaplan Field and Kaplan, 1998Field LL Kaplan BJ Absence of linkage of phonological coding dyslexia to chromosome 6p23-p21.3 in a large family data set.Am J Hum Genet. 1998; 63 (erratum: 64:334): 1448-1456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar; Fisher et al. Fisher et al., 1999Fisher SE Marlow AJ Lamb J Maestrini E Williams DF Richardson AJ Weeks DE et al.A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.Am J Hum Genet. 1999; 64: 146-156Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar; Gayán et al. Gayán et al., 1999Gayán J Smith SD Cherny SS Cardon LR Fulker DW Brower AM Olson RK et al.Quantitative-trait locus for specific language and reading deficits on chromosome 6p.Am J Hum Genet. 1999; 64: 157-164Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) covered broader regions of chromosome 6p, differentially bracketing the putative chromosomal sector by regions as narrow as 7 cM or as wide as 43 cM. Grigorenko et al. (Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar), using a sample of six extended families (N=94) that were ascertained through adult probands who had been evaluated and identified as children, replicated and extended the initial chromosome 6 findings by (1) saturating the ∼20-cM–wide region with a panel of markers that was denser than the original set of polymorphic markers, (2) dissecting the composite phenotype of dyslexia into some of its hierarchical components (i.e., phonemic awareness, phonological decoding, rapid naming, and single-word reading), and (3) showing differential probabilities of linkage in the region to some of these phenotypic components (the most compelling evidence came from analyses by means of the phonemic-awareness phenotype, although linkage results with the phonological-decoding and single-word-reading phenotypes were also statistically significant). Fisher et al. (Fisher et al., 1999Fisher SE Marlow AJ Lamb J Maestrini E Williams DF Richardson AJ Weeks DE et al.A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.Am J Hum Genet. 1999; 64: 146-156Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar), using a sample of 181 sib pairs from 82 British nuclear families selected on the basis of a dyslexic proband, covered the area of interest with 15 highly polymorphic markers, spanning ∼30 cM in the 6p25–6p21.3 region. The researchers used five quantitative phenotypes (single-word reading, IQ-related discrepancy, orthographic coding, phonological decoding, and an age-adjusted additive indicator of the last two phenotypes). Fisher et al. (Fisher et al., 1999Fisher SE Marlow AJ Lamb J Maestrini E Williams DF Richardson AJ Weeks DE et al.A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.Am J Hum Genet. 1999; 64: 146-156Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar) suggested the presence, in 6p21.3, of a QTL influencing several components of dyslexia, particularly in single-word-reading, phonological, and orthographic skills. Gayán et al. (Gayán et al., 1999Gayán J Smith SD Cherny SS Cardon LR Fulker DW Brower AM Olson RK et al.Quantitative-trait locus for specific language and reading deficits on chromosome 6p.Am J Hum Genet. 1999; 64: 157-164Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) performed a set of QTL analyses with a newly ascertained sample of 126 sib pairs. The area of interest in that study was covered by eight polymorphic markers spanning distance of 14.7 cM (6p22.3–6p21.3). These researchers defined 10 quantitative phenotypes, targeting the processes of phonemic awareness, phonological decoding, single-word reading, and orthographic coding, as well as intelligence. Gayán et al. (Gayán et al., 1999Gayán J Smith SD Cherny SS Cardon LR Fulker DW Brower AM Olson RK et al.Quantitative-trait locus for specific language and reading deficits on chromosome 6p.Am J Hum Genet. 1999; 64: 157-164Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) located the putative QTL influencing several reading components (most notably, phonological awareness and orthographic coding), in a region, between markers D6S461 and D6S306/D6S258, reported elsewhere (Cardon et al. Cardon et al., 1994Cardon LE Smith SD Fulker DW Kimberling WJ Pennington BF DeFries JC Quantitative trait locus for reading disability on chromosome 6.Science. 1994; 266: 276-279Crossref PubMed Scopus (471) Google Scholar; Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar). In contrast with these findings, a recent report by Field and Kaplan (Field and Kaplan, 1998Field LL Kaplan BJ Absence of linkage of phonological coding dyslexia to chromosome 6p23-p21.3 in a large family data set.Am J Hum Genet. 1998; 63 (erratum: 64:334): 1448-1456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) failed to replicate linkage to the 6p23–6p21.3 region in a sample of 79 Canadian families with at least two affected siblings. Their typing covered a region of 43 cM (6p25.3–6p21.3) with seven highly informative markers. In the present study, which is a continuation and an extension of our earlier study (Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar), we enrolled two new families (N=31) and recruited more individuals from the previously ascertained families (N=56). These efforts enlarged the sample size by 82%. The eight multiplex families (N=171) presented in this study were ascertained from a sample of adult probands whose childhood reading history is well documented through archival information (Felton et al. Felton et al., 1990Felton RH Naylor CE Wood FB Neuropsychological profile of adult dyslexics.Brain Lang. 1990; 39: 485-497Crossref PubMed Scopus (221) Google Scholar). The probands in this study constitute a subset of 115 adults who were evaluated during childhood and whose childhood records were preserved for research purposes in the June Lyday and Samuel T. Orton Collection of the Columbia University Libraries. A detailed description of the sample and the administered battery can be found elsewhere (Felton et al. Felton et al., 1990Felton RH Naylor CE Wood FB Neuropsychological profile of adult dyslexics.Brain Lang. 1990; 39: 485-497Crossref PubMed Scopus (221) Google Scholar). Probands were selected on the basis of childhood reading scores that placed these individuals’ reading achievement in the bottom 10% of the population. Selection required a deficit, below the 10th percentile of the normal population, on two tests, at least one of which was a single-word-reading test. The inclusion criteria for the eight families in the present study required that probands (1) be married and have children and (2) have at least three first- or second-degree relatives with a documented history of specific reading problems. The exclusion criteria included (1) a history of significant neurological impairment, (2) mental retardation, or (3) a major sensory handicap. Two families of the eight selected had a bilateral family history of reading problems, which suggests some assortative mating. Recent studies question the validity of both the global-composite-reading phenotype (e.g., see Grigorenko Grigorenko, 1997Grigorenko EL (1997) Linkage analyses on chromosome 1, 6, and 15. Paper presented at the 4th World Congress on Dyslexia, September 24-26, Halkidiki, MacedoniaGoogle Scholar; Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar; Field and Kaplan Field and Kaplan, 1998Field LL Kaplan BJ Absence of linkage of phonological coding dyslexia to chromosome 6p23-p21.3 in a large family data set.Am J Hum Genet. 1998; 63 (erratum: 64:334): 1448-1456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar; Fisher et al. Fisher et al., 1999Fisher SE Marlow AJ Lamb J Maestrini E Williams DF Richardson AJ Weeks DE et al.A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.Am J Hum Genet. 1999; 64: 146-156Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar; Gayán et al. Gayán et al., 1999Gayán J Smith SD Cherny SS Cardon LR Fulker DW Brower AM Olson RK et al.Quantitative-trait locus for specific language and reading deficits on chromosome 6p.Am J Hum Genet. 1999; 64: 157-164Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) and the IQ/reading-performance-discrepancy phenotype (e.g., see Lyon Lyon, 1995Lyon GR Toward a definition of dyslexia.Annals of Dyslexia. 1995; 35: 3-27Google Scholar; Siegel and Himel Siegel and Himel, 1998Siegel LS Himel N Socioeconomic status, age, and the classification of dyslexics and poor readers: the danger of using IQ scores in the definition of reading disability.Dyslexia. 1998; 4: 90-103Crossref Google Scholar). In this study, as in our earlier study (Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar), we used a variety of reading-related cognitive processes as phenotypes and added a clinical diagnosis of lifelong dyslexia. As discussed later, this diagnosis was made if the individuals ever had met criteria for reading disability, even if they currently were reading well. Adults were assessed with (1) the Test of Auditory Analysis Skills (Rosner Rosner, 1979Rosner J Test of auditory analysis skills. Academic Therapy, Navato, CA1979Google Scholar), a measure of syllable and phoneme segmentation; (2) the Lindamood Auditory Conceptualization Test (Lindamood and Lindamood Lindamood and Lindamood, 1971Lindamood CH Lindamood PC Lindamood auditory conceptualization test. Teaching Resources, Boston1971Google Scholar), a test of phonological awareness including phonemic discrimination and analysis skills; (3) Decoding Skills Test Part II (Richardson and DiBenedetto Richardson and DiBenedetto, 1985Richardson E DiBenedetto B Decoding skills. Western Psychological Services, Los Angeles1985Google Scholar), a measure requiring decoding of phonetically regular monosyllabic and polysyllabic real and nonreal words; (4) the Rapid Automatized Naming Test (Denckla and Rudel Denckla and Rudel, 1976Denckla MA Rudel RG Naming of object drawing by dyslexic and other learning disabled children.Brain Lang. 1976; 3: 1-16Crossref PubMed Scopus (343) Google Scholar), a test requiring rapid naming of colors, objects, digits, and letters; (5) the Woodcock-Johnson Psychoeducational Battery reading cluster (Woodcock and Johnson Woodcock and Johnson, 1977Woodcock RW Johnson MB Woodcock-Johnson psychoeducational battery. Teaching Resources, Hingham, MA1977Google Scholar), an achievement test with subtests for sight word identification, word attack, and passage comprehension; (6) the Wide Range Achievement Test-Revised (Jastak and Wilkinson Jastak and Wilkinson, 1984Jastak J Wilkinson GS Wide range achievement test: revised edition. Jastak, Wilmington, DE1984Google Scholar), with reading (sight word identification) and dictated spelling subtests; (7) the Peabody Picture Vocabulary Test-Revised (Dunn and Dunn Dunn and Dunn, 1981Dunn LM Dunn LM The Peabody picture vocabulary tests, reviewed. American Guidance Service, Circle Pines, MN1981Google Scholar); and (8) the Wechsler Intelligence Scale vocabulary subtest (Wechsler Wechsler, 1974Wechsler D Manual for the Wechsler intelligence scale for children, rev. The Psychological Corporation, New York1974Google Scholar, Wechsler, 1981Wechsler D Wechsler adult intelligence scale: review. Harvard University Press, Cambridge1981Google Scholar). Children of age 6–16 years were administered the same battery as were the adults, with appropriate age norms. Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were (1) phonemic awareness (of spoken words); (2) phonological decoding (of printed nonwords); (3) rapid automatized naming (of colored squares or object drawings); (4) single-word reading (orally, of printed real words); (5) vocabulary; and (6) spelling (of dictated words). For each of the first five phenotypes, two separate tests were combined: for phonemic awareness, the tests were the Test of Auditory Analysis Skills (Rosner Rosner, 1979Rosner J Test of auditory analysis skills. Academic Therapy, Navato, CA1979Google Scholar) and the Lindamood Auditory Conceptualization Test (Lindamood and Lindamood Lindamood and Lindamood, 1971Lindamood CH Lindamood PC Lindamood auditory conceptualization test. Teaching Resources, Boston1971Google Scholar); for phonological decoding, the Woodcock Johnson Word Attack subtest (Woodcock and Johnson Woodcock and Johnson, 1977Woodcock RW Johnson MB Woodcock-Johnson psychoeducational battery. Teaching Resources, Hingham, MA1977Google Scholar) and the Decoding Skills Test nonword section of Part 2 (Richardson and DiBenedetto Richardson and DiBenedetto, 1985Richardson E DiBenedetto B Decoding skills. Western Psychological Services, Los Angeles1985Google Scholar); for rapid naming, the color and object naming subtests of the rapid automatized naming (RAN) test (Denckla and Rudel Denckla and Rudel, 1976Denckla MA Rudel RG Naming of object drawing by dyslexic and other learning disabled children.Brain Lang. 1976; 3: 1-16Crossref PubMed Scopus (343) Google Scholar; these subtests were judged to be less confounded by lifelong exposure to print than were the letter and number subtests); for single-word reading, the Woodcock Johnson Word Identification subtest (Woodcock and Johnson Woodcock and Johnson, 1977Woodcock RW Johnson MB Woodcock-Johnson psychoeducational battery. Teaching Resources, Hingham, MA1977Google Scholar) and the Decoding Skills Test real-word section of Part 2 (Richardson and DiBenedetto Richardson and DiBenedetto, 1985Richardson E DiBenedetto B Decoding skills. Western Psychological Services, Los Angeles1985Google Scholar); and, for vocabulary, the Peabody Picture Vocabulary Test (Dunn and Dunn Elston, 1997Elston RC Algorithms and inferences: the challenge of multifactorial diseases.Am J Hum Genet. 1997; 60: 255-262PubMed Google Scholar) and the vocabulary subtest of the age-appropriate Wechsler intelligence scale (Wechsler Wechsler, 1974Wechsler D Manual for the Wechsler intelligence scale for children, rev. The Psychological Corporation, New York1974Google Scholar, Wechsler, 1981Wechsler D Wechsler adult intelligence scale: review. Harvard University Press, Cambridge1981Google Scholar). For each of these phenotypes, affected status required scoring either below the normative 10th percentile on one of the tests or below the normative 25th percentile on both tests. The test norms were developed on the basis of two independent epidemiological samples of adults and children. Only one spelling test was available in this sample; therefore, affected status required scoring below the 15th percentile on the spelling subtest of The Wide Range Achievement Test-Revised (Jastak and Wilkinson Jastak and Wilkinson, 1984Jastak J Wilkinson GS Wide range achievement test: revised edition. Jastak, Wilmington, DE1984Google Scholar). Table 1 contains pairwise correlations (ϕ) between the seven phenotypes.Table 1Pairwise Correlations for the Seven Phenotypesϕ for the ComparisonPhenotypePhonemic AwarenessDecodingRapid NamingSingle-Word ReadingVocabularySpellingLifelong DiagnosisPhonemic awarenessDecoding.46 (.00)Rapid naming.25 (.00).29 (.00)Single-word reading.37 (.00).48 (.00).37 (.00)Vocabulary.26 (.00).27 (.00).18 (.05).45 (.00)Spelling.30 (.00).46 (.00).32 (.00).68 (.00).44 (.00)Lifelong diagnosis.49 (.00).63 (.00).45 (.00).50 (.00).32 (.00).54 (.00) Open table in a new tab The lifelong diagnosis of dyslexia was established by means of clinical information. A diagnosis was made if an individual, either adult or child, was reported to have had difficulty acquiring initial reading skills, had been certified as learning disabled in reading, and/or required tutoring or special reading classes as a child. Of the 68 judged to have some degree of dyslexia, 33 were classified as clearly impaired, with adults continuing to show impairment in reading and with children needing ongoing specialized reading instruction; the remaining 35 were classified as “borderline,” with adults having obtained literacy level (at least eighth grade on most tests) and with children no longer requiring ongoing reading help. The affected group was composed of both the impaired and the borderline group. Individuals were classified as “normal” if they had no reported history of difficulty with reading acquisition and if they were deficient in no more than one aspect of reading (e.g., only phonological decoding or only phonemic awareness). DNA was extracted from whole blood and inner-cheek tissue. Blood was drawn from 94 family members; 60 ml of blood were drawn from each consenting adult, but only 20 ml were collected from each participant of age <18 years. Children's consent forms were signed by their parents. Genomic DNA was prepared from EDTA-preserved whole blood, according to standard techniques, except that salting out was substituted for phenol extraction (Miller et al. Miller et al., 1988Miller SA Dykes DD Polesky HF A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17843) Google Scholar). From the remaining 77 family members, four cytological brushings were collected (two from each cheek). Genomic DNA was prepared from the collected tissue, with the BIORAD biomatrix extraction technique (T. Webb, personal communication). Genotyping was done with nine highly polymorphic markers from the 6p22.3(D6S285)–6p21.31(D6S273) region. The relative chromosomal location and heterozygosity of each marker are shown in figure 1. The most probable order of markers and intermarker distances was derived from current linkage and physical maps of 6p. PCR primers were labeled with 6-FAM, HEX, or TET phosphoramidite; PCR reactions were done in 96 well plates on a PE Biosystems thermocycler. Products of appropriate sizes were pooled together and were run on a 377 sequencer (Applied Biosystems), and the results were analyzed by means of GENESCAN (version 2.0) and GENOTYPER (version 1.1) software. Two sets of marker-allele frequencies were used: (1) the published frequencies (Genome Database) and (2) the frequencies obtained by counting alleles in the parents and married individuals (see Field and Kaplan Field and Kaplan, 1998Field LL Kaplan BJ Absence of linkage of phonological coding dyslexia to chromosome 6p23-p21.3 in a large family data set.Am J Hum Genet. 1998; 63 (erratum: 64:334): 1448-1456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Analyses were done twice—once with the published estimates and once with the estimates obtained from counting alleles. The raw ABI data were imported into EXCEL and were processed with SAS and SPSS statistical software macros. Model-based linkage analyses were done with version 5.2 of the LINKAGE program (Lathrop et al. Lathrop et al., 1984Lathrop M Lalouel J Julier C Ott J Strategies for multilocus linkage analysis in humans.Proc Natl Acad Sci USA. 1984; 81: 3443-3446Crossref PubMed Scopus (2254) Google Scholar). Model-free analyses were done by use of the computer programs SIMWALK (Sobel and Lange Sobel and Lange, 1996Sobel E Lange K Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.Am J Hum Genet. 1996; 58: 1323-1337PubMed Google Scholar), SIMIBD (Davis et al. Davis et al., 1996Davis S Schroeder M Goldin LR Weeks DE Nonparametric simulation-based statistics for detecting linkage in general pedigrees.Am J Hum Genet. 1996; 58: 867-880PubMed Google Scholar), and APM (Weeks and Lange Weeks and Lange, 1988Weeks DE Lange K The affected-pedigree-member method of linkage analysis.Am J Hum Genet. 1988; 42: 315-326PubMed Google Scholar). SIMIBD and APM offer three weighting schemes (1, 1/sqr(p), and 1/p), of which the preferred is 1/sqr(p). In this report, only the results obtained with the preferred weighting scheme (1/sqr[p]), recommended by the authors of the software, are presented. Thus, the analyses were done by the methods used in our earlier research (Grigorenko et al. Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar) and by more recent methods developed for large-extended-pedigree analyses. All analyses were conducted for all seven diagnostic schemes. As suggested by Elston (Elston, 1997Elston RC Algorithms and inferences: the challenge of multifactorial diseases.Am J Hum Genet. 1997; 60: 255-262PubMed Google Scholar, Elston, 1998Elston RC Methods of linkage analysis—and the assumptions underlying them.Am J Hum Genet. 1998; 63: 931-934Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar), the precise P values are presented, rather than those adjusted for multiple comparisons. The underlying logic here is that the adjustment assumes that the tests in question were independent; this assumption does not hold in our case because (1) all phenotypes in this study correlate with each other and (2) the genetic markers are located in close proximity to each other. Therefore, a traditional correction for multiple comparisons in our case would have most likely been overly conservative. Parametric linkage analyses were completed by use of three models of transmission (dominant, additive, and recessive; for details, see E. L. Grigorenko, F. B. Wood, M. S. Meyer, J. E. D. Pauls, L. A. Hart, D. L. Pauls, unpublished data). The analyses were done with phenotype-specific sets of parameters obtained from segregation analyses of the patterns of family transmission of corresponding phenotypes. The segregation analyses were conducted with POINTER (Lalouel et al. Lalouel et al., 1983Lalouel JM Rao DC Morton NE Elston RC A unified model for complex segregation analysis.Am J Hum Genet. 1983; 35: 816-826PubMed Google Scholar), with the assumptions of a prevalence of 13% and of a 1:1 male:female ratio. Although there were some weakly positive results (e.g., LOD = .25 for θ=.00 at D6S464, under recessive-model parameters with published allele frequencies for the phenotype of single-word reading), none of the pairwise LOD scores were statistically significant. In general, parametric analyses were uninformative, with the majority of LOD scores between −2 and +1. The results of model-free two-point identity-by-descent (IBD) (done with SIMIBD) and identity-by-state (IBS) (done with APM) analyses are shown in table 2. Field and Kaplan (Field and Kaplan, 1998Field LL Kaplan BJ Absence of linkage of phonological coding dyslexia to chromosome 6p23-p21.3 in a large family data set.Am J Hum Genet. 1998; 63 (erratum: 64:334): 1448-1456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), commenting on the results that Grigorenko et al. (Grigorenko et al., 1997Grigorenko EL Wood FB Meyer MS Hart LA Speed WC Shuster A Pauls DL Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.Am J Hum Genet. 1997; 60: 27-39PubMed Google Scholar) found by using IBS, pointed out that IBS analyses may have a tendency toward false-positive results, because correction for allele frequencies, when done on published data, may sometimes be inadequate. As a consequence, we conducted IBS analyses by using both published and counted allele frequencies. The IBS analyses revealed a consistent pattern of significant P values for all seven phenotypes (both for published and for counted allele frequencies) in the region D6S464–D6S306. The IBD analyses showed a consistent pattern in this region, but for only three phenotypes: single-word reading, vocabulary, and spelling (both for published and counted allele frequencies).Table 2Model-Free Pairwise AnalysesStatistic (P) forPhenotypeD6S285D6S109D6S461D6S299D6S464D6S105D6S306D6S258D6S273IBD: Published: Phonemic awareness39.8 (.25)29.6 (.91)42.1 (.86)41.4 (.84)77.3 (.20)47.8 (.92)36.3 (.75)55.8 (.54)60.9 (.19) Decoding41.2 (.29)31.1 (.72)40.6 (.92)55.2 (.50)78.2 (.44)52.9 (.34)35.3 (.77)55.5 (.21)32.9 (.79) Rapid naming56.4 (.02)29.0 (.89)51.3 (.48)36.9 (.45)70.0 (.32)30.7 (.88)35.6 (.39)33.2 (.50)53.2 (.54) Single-word readingaThe analyses for the single-word-reading phenotype are done on seven of the eight pedigrees. In the eighth pedigree there were only two affected individuals who were unrelated to each other.21.4 (.26)13.7 (.57)22.1 (.22)33.0 (.08)38.7 (.05)42.3 (.01)20.1 (.07)19.3 (.06)28.0 (.60) VocabularybThe analyses for the vocabulary phenotype are done on three of the eight pedigrees. Five smallest pedigrees were eliminated from the analyses because of the absence of nonparent-child pairs of affected relatives.10.7 (.48)12.2 (.43)17.5 (.17)20.7 (.27)20.7 (.30)25.8 (.02)9.0 (.59)20.7 (.07)17.1 (.55) SpellingcThe analyses for the spelling phenotype are perf" @default.
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• W2000622732 title "Chromosome 6p Influences on Different Dyslexia-Related Cognitive Processes: Further Confirmation" @default.
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