Elena L. Grigorenko|Frank Wood|Marianne Meyer|David L. Pauls
Chromosome 6p Influences on Different Dyslexia-Related Cognitive Processes: Further Confirmation
Lomonosov Moscow State University|Moscow State University|Yale University|Wake Forest University|Atrium Health Wake Forest Baptist|Wake Forest University|Atrium Health Wake Forest Baptist|Yale University
summaryin study continuation extension earlier study enrolled two new families n31 recruited individuals previously ascertained families n56 eight multiplex families n171 presented study ascertained sample adult probands whose childhood reading history well documented archival information six phenotypes constructed span range dyslexiarelated cognitive processes phenotypes 1 phonemic awareness spoken words 2 phonological decoding printed nonwords 3 rapid automatized naming colored squares object drawings 4 singleword reading orally printed real words 5 vocabulary 6 spelling dictated words addition diagnosis lifelong dyslexia established clinical means genotyping done nine highly polymorphic markers 6p2236p213 region results two multipoint identitybydescent identitybystate analyses supported importance putative locus d6s464d6s273 region number dyslexiarelated cognitive deficits study continuation extension earlier study enrolled two new families n31 recruited individuals previously ascertained families n56 eight multiplex families n171 presented study ascertained sample adult probands whose childhood reading history well documented archival information six phenotypes constructed span range dyslexiarelated cognitive processes phenotypes 1 phonemic awareness spoken words 2 phonological decoding printed nonwords 3 rapid automatized naming colored squares object drawings 4 singleword reading orally printed real words 5 vocabulary 6 spelling dictated words addition diagnosis lifelong dyslexia established clinical means genotyping done nine highly polymorphic markers 6p2236p213 region results two multipoint identitybydescent identitybystate analyses supported importance putative locus d6s464d6s273 region number dyslexiarelated cognitive deficits recently number research groups followed initial report cardon et al cardon et al 1994cardon le smith sd fulker dw kimberling wj pennington bf defries jc quantitative trait locus reading disability chromosome 6science 1994 266 276279crossref pubmed scopus 471 google scholar cardon et al 1995cardon le smith sd fulker dw kimberling wj pennington bf defries jc quantitative trait locus reading disability correctionscience 1995 268 1553crossref pubmed scopus 95 google scholar suggested putative quantitativetrait locus qtl involved specific reading disability original article reported area interest mapped 6p213 region distal hla complex relatively well characterized physical level feder et al feder et al 1996feder jn gnirke thomas w tsuchihashi z ruddy da basava dormishian f et ala novel mhc class ilike gene mutated patients hereditary haemochromatosisnat genet 1996 13 399408crossref pubmed scopus 3345 google scholar four subsequent searches grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar field kaplan field kaplan 1998field kaplan bj absence linkage phonological coding dyslexia chromosome 6p23p213 large family data setam j hum genet 1998 63 erratum 64334 14481456abstract 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 ala quantitativetrait locus chromosome 6p influences different aspects developmental dyslexiaam j hum genet 1999 64 146156abstract full text full text pdf pubmed scopus 245 google scholar gayn et al gayn et al 1999gayn j smith sd cherny ss cardon lr fulker dw brower olson rk et alquantitativetrait locus specific language reading deficits chromosome 6pam j hum genet 1999 64 157164abstract full text full text pdf pubmed scopus 228 google scholar covered broader regions chromosome 6p differentially bracketing putative chromosomal sector regions narrow 7 cm wide 43 cm grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar using sample six extended families n94 ascertained adult probands evaluated identified children replicated extended initial chromosome 6 findings 1 saturating 20cmwide region panel markers denser original set polymorphic markers 2 dissecting composite phenotype dyslexia hierarchical components ie phonemic awareness phonological decoding rapid naming singleword reading 3 showing differential probabilities linkage region phenotypic components compelling evidence came analyses means phonemicawareness phenotype although linkage results phonologicaldecoding singlewordreading phenotypes also statistically significant fisher et al fisher et al 1999fisher se marlow aj lamb j maestrini e williams df richardson aj weeks de et ala quantitativetrait locus chromosome 6p influences different aspects developmental dyslexiaam j hum genet 1999 64 146156abstract full text full text pdf pubmed scopus 245 google scholar using sample 181 sib pairs 82 british nuclear families selected basis dyslexic proband covered area interest 15 highly polymorphic markers spanning 30 cm 6p256p213 region researchers used five quantitative phenotypes singleword reading iqrelated discrepancy orthographic coding phonological decoding ageadjusted additive indicator last two phenotypes fisher et al fisher et al 1999fisher se marlow aj lamb j maestrini e williams df richardson aj weeks de et ala quantitativetrait locus chromosome 6p influences different aspects developmental dyslexiaam j hum genet 1999 64 146156abstract full text full text pdf pubmed scopus 245 google scholar suggested presence 6p213 qtl influencing several components dyslexia particularly singlewordreading phonological orthographic skills gayn et al gayn et al 1999gayn j smith sd cherny ss cardon lr fulker dw brower olson rk et alquantitativetrait locus specific language reading deficits chromosome 6pam j hum genet 1999 64 157164abstract full text full text pdf pubmed scopus 228 google scholar performed set qtl analyses newly ascertained sample 126 sib pairs area interest study covered eight polymorphic markers spanning distance 147 cm 6p2236p213 researchers defined 10 quantitative phenotypes targeting processes phonemic awareness phonological decoding singleword reading orthographic coding well intelligence gayn et al gayn et al 1999gayn j smith sd cherny ss cardon lr fulker dw brower olson rk et alquantitativetrait locus specific language reading deficits chromosome 6pam j hum genet 1999 64 157164abstract full text full text pdf pubmed scopus 228 google scholar located putative qtl influencing several reading components notably phonological awareness orthographic coding region markers d6s461 d6s306d6s258 reported elsewhere cardon et al cardon et al 1994cardon le smith sd fulker dw kimberling wj pennington bf defries jc quantitative trait locus reading disability chromosome 6science 1994 266 276279crossref pubmed scopus 471 google scholar grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar contrast findings recent report field kaplan field kaplan 1998field kaplan bj absence linkage phonological coding dyslexia chromosome 6p23p213 large family data setam j hum genet 1998 63 erratum 64334 14481456abstract full text full text pdf pubmed scopus 82 google scholar failed replicate linkage 6p236p213 region sample 79 canadian families least two affected siblings typing covered region 43 cm 6p2536p213 seven highly informative markers present study continuation extension earlier study grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar enrolled two new families n31 recruited individuals previously ascertained families n56 efforts enlarged sample size 82 eight multiplex families n171 presented study ascertained sample adult probands whose childhood reading history well documented archival information felton et al felton et al 1990felton rh naylor ce wood fb neuropsychological profile adult dyslexicsbrain lang 1990 39 485497crossref pubmed scopus 221 google scholar probands study constitute subset 115 adults evaluated childhood whose childhood records preserved research purposes june lyday samuel orton collection columbia university libraries detailed description sample administered battery found elsewhere felton et al felton et al 1990felton rh naylor ce wood fb neuropsychological profile adult dyslexicsbrain lang 1990 39 485497crossref pubmed scopus 221 google scholar probands selected basis childhood reading scores placed individuals reading achievement bottom 10 population selection required deficit 10th percentile normal population two tests least one singlewordreading test inclusion criteria eight families present study required probands 1 married children 2 least three first seconddegree relatives documented history specific reading problems exclusion criteria included 1 history significant neurological impairment 2 mental retardation 3 major sensory handicap two families eight selected bilateral family history reading problems suggests assortative mating recent studies question validity globalcompositereading phenotype eg see grigorenko grigorenko 1997grigorenko el 1997 linkage analyses chromosome 1 6 15 paper presented 4th world congress dyslexia september 2426 halkidiki macedoniagoogle scholar grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar field kaplan field kaplan 1998field kaplan bj absence linkage phonological coding dyslexia chromosome 6p23p213 large family data setam j hum genet 1998 63 erratum 64334 14481456abstract 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 ala quantitativetrait locus chromosome 6p influences different aspects developmental dyslexiaam j hum genet 1999 64 146156abstract full text full text pdf pubmed scopus 245 google scholar gayn et al gayn et al 1999gayn j smith sd cherny ss cardon lr fulker dw brower olson rk et alquantitativetrait locus specific language reading deficits chromosome 6pam j hum genet 1999 64 157164abstract full text full text pdf pubmed scopus 228 google scholar iqreadingperformancediscrepancy phenotype eg see lyon lyon 1995lyon gr toward definition dyslexiaannals dyslexia 1995 35 327google scholar siegel himel siegel himel 1998siegel ls himel n socioeconomic status age classification dyslexics poor readers danger using iq scores definition reading disabilitydyslexia 1998 4 90103crossref google scholar study earlier study grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar used variety readingrelated cognitive processes phenotypes added clinical diagnosis lifelong dyslexia discussed later diagnosis made individuals ever met criteria reading disability even currently reading well adults assessed 1 test auditory analysis skills rosner rosner 1979rosner j test auditory analysis skills academic therapy navato ca1979google scholar measure syllable phoneme segmentation 2 lindamood auditory conceptualization test lindamood lindamood lindamood lindamood 1971lindamood ch lindamood pc lindamood auditory conceptualization test teaching resources boston1971google scholar test phonological awareness including phonemic discrimination analysis skills 3 decoding skills test part ii richardson dibenedetto richardson dibenedetto 1985richardson e dibenedetto b decoding skills western psychological services los angeles1985google scholar measure requiring decoding phonetically regular monosyllabic polysyllabic real nonreal words 4 rapid automatized naming test denckla rudel denckla rudel 1976denckla rudel rg naming object drawing dyslexic learning disabled childrenbrain lang 1976 3 116crossref pubmed scopus 343 google scholar test requiring rapid naming colors objects digits letters 5 woodcockjohnson psychoeducational battery reading cluster woodcock johnson woodcock johnson 1977woodcock rw johnson mb woodcockjohnson psychoeducational battery teaching resources hingham ma1977google scholar achievement test subtests sight word identification word attack passage comprehension 6 wide range achievement testrevised jastak wilkinson jastak wilkinson 1984jastak j wilkinson gs wide range achievement test revised edition jastak wilmington de1984google scholar reading sight word identification dictated spelling subtests 7 peabody picture vocabulary testrevised dunn dunn dunn dunn 1981dunn lm dunn lm peabody picture vocabulary tests reviewed american guidance service circle pines mn1981google scholar 8 wechsler intelligence scale vocabulary subtest wechsler wechsler 1974wechsler manual wechsler intelligence scale children rev psychological corporation new york1974google scholar wechsler 1981wechsler wechsler adult intelligence scale review harvard university press cambridge1981google scholar children age 616 years administered battery adults appropriate age norms six phenotypes constructed span range dyslexiarelated cognitive processes phenotypes 1 phonemic awareness spoken words 2 phonological decoding printed nonwords 3 rapid automatized naming colored squares object drawings 4 singleword reading orally printed real words 5 vocabulary 6 spelling dictated words first five phenotypes two separate tests combined phonemic awareness tests test auditory analysis skills rosner rosner 1979rosner j test auditory analysis skills academic therapy navato ca1979google scholar lindamood auditory conceptualization test lindamood lindamood lindamood lindamood 1971lindamood ch lindamood pc lindamood auditory conceptualization test teaching resources boston1971google scholar phonological decoding woodcock johnson word attack subtest woodcock johnson woodcock johnson 1977woodcock rw johnson mb woodcockjohnson psychoeducational battery teaching resources hingham ma1977google scholar decoding skills test nonword section part 2 richardson dibenedetto richardson dibenedetto 1985richardson e dibenedetto b decoding skills western psychological services los angeles1985google scholar rapid naming color object naming subtests rapid automatized naming ran test denckla rudel denckla rudel 1976denckla rudel rg naming object drawing dyslexic learning disabled childrenbrain lang 1976 3 116crossref pubmed scopus 343 google scholar subtests judged less confounded lifelong exposure print letter number subtests singleword reading woodcock johnson word identification subtest woodcock johnson woodcock johnson 1977woodcock rw johnson mb woodcockjohnson psychoeducational battery teaching resources hingham ma1977google scholar decoding skills test realword section part 2 richardson dibenedetto richardson dibenedetto 1985richardson e dibenedetto b decoding skills western psychological services los angeles1985google scholar vocabulary peabody picture vocabulary test dunn dunn elston 1997elston rc algorithms inferences challenge multifactorial diseasesam j hum genet 1997 60 255262pubmed google scholar vocabulary subtest ageappropriate wechsler intelligence scale wechsler wechsler 1974wechsler manual wechsler intelligence scale children rev psychological corporation new york1974google scholar wechsler 1981wechsler wechsler adult intelligence scale review harvard university press cambridge1981google scholar phenotypes affected status required scoring either normative 10th percentile one tests normative 25th percentile tests test norms developed basis two independent epidemiological samples adults children one spelling test available sample therefore affected status required scoring 15th percentile spelling subtest wide range achievement testrevised jastak wilkinson jastak wilkinson 1984jastak j wilkinson gs wide range achievement test revised edition jastak wilmington de1984google scholar table 1 contains pairwise correlations seven phenotypestable 1pairwise correlations seven phenotypes comparisonphenotypephonemic awarenessdecodingrapid namingsingleword readingvocabularyspellinglifelong diagnosisphonemic awarenessdecoding46 00rapid naming25 0029 00singleword reading37 0048 0037 00vocabulary26 0027 0018 0545 00spelling30 0046 0032 0068 0044 00lifelong diagnosis49 0063 0045 0050 0032 0054 00 open table new tab lifelong diagnosis dyslexia established means clinical information diagnosis made individual either adult child reported difficulty acquiring initial reading skills certified learning disabled reading andor required tutoring special reading classes child 68 judged degree dyslexia 33 classified clearly impaired adults continuing show impairment reading children needing ongoing specialized reading instruction remaining 35 classified borderline adults obtained literacy level least eighth grade tests children longer requiring ongoing reading help affected group composed impaired borderline group individuals classified normal reported history difficulty reading acquisition deficient one aspect reading eg phonological decoding phonemic awareness dna extracted whole blood innercheek tissue blood drawn 94 family members 60 ml blood drawn consenting adult 20 ml collected participant age 18 years childrens consent forms signed parents genomic dna prepared edtapreserved whole blood according standard techniques except salting substituted phenol extraction miller et al miller et al 1988miller sa dykes dd polesky hf simple salting procedure extracting dna human nucleated cellsnucleic acids res 1988 16 1215crossref pubmed scopus 17843 google scholar remaining 77 family members four cytological brushings collected two cheek genomic dna prepared collected tissue biorad biomatrix extraction technique webb personal communication genotyping done nine highly polymorphic markers 6p223d6s2856p2131d6s273 region relative chromosomal location heterozygosity marker shown figure 1 probable order markers intermarker distances derived current linkage physical maps 6p pcr primers labeled 6fam hex tet phosphoramidite pcr reactions done 96 well plates pe biosystems thermocycler products appropriate sizes pooled together run 377 sequencer applied biosystems results analyzed means genescan version 20 genotyper version 11 software two sets markerallele frequencies used 1 published frequencies genome database 2 frequencies obtained counting alleles parents married individuals see field kaplan field kaplan 1998field kaplan bj absence linkage phonological coding dyslexia chromosome 6p23p213 large family data setam j hum genet 1998 63 erratum 64334 14481456abstract full text full text pdf pubmed scopus 82 google scholar analyses done twiceonce published estimates estimates obtained counting alleles raw abi data imported excel processed sas spss statistical software macros modelbased linkage analyses done version 52 linkage program lathrop et al lathrop et al 1984lathrop lalouel j julier c ott j strategies multilocus linkage analysis humansproc natl acad sci usa 1984 81 34433446crossref pubmed scopus 2254 google scholar modelfree analyses done use computer programs simwalk sobel lange sobel lange 1996sobel e lange k descent graphs pedigree analysis applications haplotyping location scores markersharing statisticsam j hum genet 1996 58 13231337pubmed google scholar simibd davis et al davis et al 1996davis schroeder goldin lr weeks de nonparametric simulationbased statistics detecting linkage general pedigreesam j hum genet 1996 58 867880pubmed google scholar apm weeks lange weeks lange 1988weeks de lange k affectedpedigreemember method linkage analysisam j hum genet 1988 42 315326pubmed google scholar simibd apm offer three weighting schemes 1 1sqrp 1p preferred 1sqrp report results obtained preferred weighting scheme 1sqrp recommended authors software presented thus analyses done methods used earlier research grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar recent methods developed largeextendedpedigree analyses analyses conducted seven diagnostic schemes suggested elston elston 1997elston rc algorithms inferences challenge multifactorial diseasesam j hum genet 1997 60 255262pubmed google scholar elston 1998elston rc methods linkage analysisand assumptions underlying themam j hum genet 1998 63 931934abstract full text full text pdf pubmed scopus 47 google scholar precise p values presented rather adjusted multiple comparisons underlying logic adjustment assumes tests question independent assumption hold case 1 phenotypes study correlate 2 genetic markers located close proximity therefore traditional correction multiple comparisons case would likely overly conservative parametric linkage analyses completed use three models transmission dominant additive recessive details see e l grigorenko f b wood meyer j e pauls l hart l pauls unpublished data analyses done phenotypespecific sets parameters obtained segregation analyses patterns family transmission corresponding phenotypes segregation analyses conducted pointer lalouel et al lalouel et al 1983lalouel jm rao dc morton ne elston rc unified model complex segregation analysisam j hum genet 1983 35 816826pubmed google scholar assumptions prevalence 13 11 malefemale ratio although weakly positive results eg lod 25 00 d6s464 recessivemodel parameters published allele frequencies phenotype singleword reading none pairwise lod scores statistically significant general parametric analyses uninformative majority lod scores 2 1 results modelfree twopoint identitybydescent ibd done simibd identitybystate ibs done apm analyses shown table 2 field kaplan field kaplan 1998field kaplan bj absence linkage phonological coding dyslexia chromosome 6p23p213 large family data setam j hum genet 1998 63 erratum 64334 14481456abstract full text full text pdf pubmed scopus 82 google scholar commenting results grigorenko et al grigorenko et al 1997grigorenko el wood fb meyer ms hart la speed wc shuster pauls dl susceptibility loci distinct components developmental dyslexia chromosomes 6 15am j hum genet 1997 60 2739pubmed google scholar found using ibs pointed ibs analyses may tendency toward falsepositive results correction allele frequencies done published data may sometimes inadequate consequence conducted ibs analyses using published counted allele frequencies ibs analyses revealed consistent pattern significant p values seven phenotypes published counted allele frequencies region d6s464d6s306 ibd analyses showed consistent pattern region three phenotypes singleword reading vocabulary spelling published counted allele frequenciestable 2modelfree pairwise analysesstatistic p forphenotyped6s285d6s109d6s461d6s299d6s464d6s105d6s306d6s258d6s273ibd published phonemic awareness398 25296 91421 86414 84773 20478 92363 75558 54609 19 decoding412 29311 72406 92552 50782 44529 34353 77555 21329 79 rapid naming564 02290 89513 48369 45700 32307 88356 39332 50532 54 singleword readingathe analyses singlewordreading phenotype done seven eight pedigrees eighth pedigree two affected individuals unrelated other214 26137 57221 22330 08387 05423 01201 07193 06280 60 vocabularybthe analyses vocabulary phenotype done three eight pedigrees five smallest pedigrees eliminated analyses absence nonparentchild pairs affected relatives107 48122 43175 17207 27207 30258 0290 59207 07171 55 spellingcthe analyses spelling phenotype perf