SLDB

Speech/Language Disorders Database

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Gene / phenotype associations for CMIP

  • Click column headers to sort. Click to expand any row to see more details about the particular assertion of an association between variants of CMIP and a particular phenotypic variable.
  • Click the Pubmed IDs in the last column to link out to the primary research article. Click the links in the last column to download the full Genotype-Phenotype record as JSON or XML formatted text.
Entrez Id Symbol Location Disorder Brief Phenotype Reference Year Download
80790 CMIP 16q23 SLI Nonword repetition Newbury et al 2009 JSON | XML

Additional Phenotype Details: 
Standardized tests for nonword repetition (NWR) include the Children's Test of Nonword Repetition (CNRep, Gathercole et al 1994), the nonword repetition test (NRT, Dollaghan & Campbell 1998), and the Nonword Repetition subtest of the Comprehensive Test of Phonological Processing (Wagner et al. 1999).

References

Gathercole SE, Willis CS, Baddeley AD, Emslie H. The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory 1994;2:103-27.

Dollaghan, C., & Campbell, T. F. (1998). Nonword repetition and child language impairment. Journal of Speech, Language, and Hearing Research, 41, 1136–1146

Wagner, R. K., Torgesen, J. K., & Rashotte, C. A. (1999). Comprehensive test of phonological processing. Austin, TX: PRO-ED.

Basic Study Type:  Association study

Study Cohort: 
Summary:

806 individuals (211 families) for the initial sample (the association screen).
490 individuals for the replication sample.


(1) "The association screen utilized 806 individuals from 211 families ascertained by the SLI Consortium (SLIC). This nuclear-family cohort was collected from five sites across the UK (The Newcomen Centre at Guy’s Hospital, London; the Cambridge Language and Speech Project (CLASP) [13]; the Child Life and Health Department at the University of Edinburgh [14]; the Department of Child Health at the University of Aberdeen; and the Manchester Language Study [15,16]) and included the families in whom the SLI1 linkage was originally identified. . .A more detailed description of these samples and the exclusionary criteria applied to the SLIC collection can be found in previous publications [4,6,7]."

(2) "Our replication sample consisted of 490 cases selected from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [11,12]. This is a general-population sample that follows the development of 14,062 live-born individuals born in the southwest of England. The ALSPAC group periodically performs an assessment of the development of consenting individuals, and these measurements include tests of language ability. . .Of these individuals, 490 had completed a 12-item nonword repetition test."

The authors also performed association analysis "across the entire unselected ALSPAC population (n = 3612)."

Genotyping Methods: 
"Genotyping for the association screen was performed in two phases with a combination of Sequenom and Illumina technologies. We performed an initial high-density screen involving 1906 SNPs to tag all 58 genes (including introns, exons, and 5 Kb 5' and 2 Kb 3' of coding sequences) mapped to the 10.29 Mb SLI1 region of linkage (D16S3138–D16S413. Chromosome 16 position 76.16 Mb–86.45 Mb [B35]). Haplotype blocks were built within Haploview [17] via the Gabriel method. [18] Any between-block gap that was more than 15 Kb in size was tagged with the Tagger algorithm. Two genes that mapped to the region (CDH13 [MIM #601364] and WWOX [MIM #605131]) were found to be larger than 1 Mb in size. For these two genes, blocks were built to cover the exonic regions only. Any region containing a SNP that met our predefined significance threshold (p < 0.001 in any one analysis or p < 0.01 across both analyses) was then supplemented with additional markers in a follow-up panel that included 138 SNPs, eight of which had previously been genotyped. Both phases of genotyping were completed prior to the replication study and were subjected to consistent quality-control procedures. The total genotype mismatch rate was 0.73% for duplicated SNPs and 0.76% for duplicated samples. Across both phases, 261 (12.7%) of SNPs were excluded at the quality-control stage. These included SNPs with a genotype rate of <80%, a minor-allele frequency of <2.5%, SNPs with unusual Beadstudio cluster patterns (Illumina) or atypical peaks in MassArray TyperAnalyser (Sequenom), SNPs with a GenTrain score of <0.5 (Illumina), and markers that showed consistent bad inheritances (>10 errors after data clean up). Across the entire region, the merged data set consisted of, on average, one SNP every 6.4 Kb. Across the known genes, there was on average one SNP every 4.5 Kb, and the largest remaining gap between blocks was 19,579 bp. Details of SNP coverage can be found in Table S1."

Analysis Methods: 
For the initial sample of 211 families:

"Our principal analysis involved the variance-components modeling of 28-item nonword repetition scores [8] within 211 SLIC families (ao option) as a quantitative trait and was performed within QTDT [19]. In addition, we performed a categorical case-control allelic test of association within PLINK [20]."

For the replication sample:

"Because the genotyping in the replication sample was restricted to a single individual from each family, we performed a quantitative association analysis within PLINK [20] by using nonword repetition in a linear-regression framework. In addition, we used PLINK[20] to carry out a case-control analysis analogous to that described for SLIC."

Other Details: 
Criteria in quantitative analyses:

For the initial sample, "SLIC families were all selected on the basis of a single proband with receptive and/or expressive language skills more than 1.5 SD below the normative mean for his or her age."

For the replication sample, "we selected individuals from the lower extreme of language-related phenotype distributions (Children’s Communication Checklist (CCC) [24] and Wechsler Objective Language Dimensions (WOLD)[25]) for our replication sample. This included 665 individuals (10.3%) with a CCC pragmatic composite 1–3 SD below the ALSPAC population mean (123 <= x <= 145) or a WOLD listening comprehension score >=2 SD below the ALSPAC population mean (<=3)."

Criteria in case-control analyses:

For the initial sample, "SLIC individuals with low nonword-repetition scores (>2 SD below population mean, n = 79) were chosen as cases, and family members with above-average performance (>0.5 SD above population mean, n = 71) were used as controls. To avoid interdependence, we selected only one case or control from each family unit."

For the replication sample, "cases were selected from the identified replication sample to have nonword repetition scores >= 1 SD below the general-population mean (n = 112), and controls had nonword repetition scores >= 1 SD above the general-population mean (n = 72)."

Associated Markers:
rs6564903 


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80790 CMIP 16q23 SLI Nonword repetition Newbury et al 2011 JSON | XML

Additional Phenotype Details: 
Standardized tests for nonword repetition (NWR) include the Children's Test of Nonword Repetition (CNRep, Gathercole et al 1994), the nonword repetition test (NRT, Dollaghan & Campbell 1998), and the Nonword Repetition subtest of the Comprehensive Test of Phonological Processing (Wagner et al. 1999).

References

Gathercole SE, Willis CS, Baddeley AD, Emslie H. The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory 1994;2:103-27.

Dollaghan, C., & Campbell, T. F. (1998). Nonword repetition and child language impairment. Journal of Speech, Language, and Hearing Research, 41, 1136–1146

Wagner, R. K., Torgesen, J. K., & Rashotte, C. A. (1999). Comprehensive test of phonological processing. Austin, TX: PRO-ED.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs6564903  (P = 0.0007)
rs12927866  (P = 0.0113)
rs3935802  (P = 0.0079)
rs7201632  (P = 0.0157)


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80790 CMIP 16q23 SLI Receptive language skills Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed using the receptive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs6564903  (P = 0.0012)
rs12927866  (P = 0.0027)
rs3935802  (P = 0.0033)
rs7201632  (P = 0.0021)


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80790 CMIP 16q23 SLI Expressive language skills Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed using the expressive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs6564903  (P = 0.0110)
rs12927866  (P = 0.0451)
rs3935802  (P = 0.0285)


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80790 CMIP 16q23 SLI Spelling ability Newbury et al 2011 JSON | XML

Additional Phenotype Details: Possible measures include the spelling subtests of any of a number of intelligence and literacy tests, e.g.:

Peabody Individual Achievement Test (PIAT)
Western Australian Literacy and Numeracy Assessment (WALNA)
Wide Range Achievement Test (WRAT)

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs6564903  (P = 0.0079)
rs12927866  (P = 0.0240)
rs3935802  (P = 0.0277)
rs7201632  (P = 0.0137)


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80790 CMIP 16q23 SLI Single-word reading Newbury et al 2011 JSON | XML

Additional Phenotype Details: Possible measures include the single-word reading subtest of Wechsler Objective Reading Dimensions
(WORD), and the British Ability Scales (BAS) test of single-word reading.


References

Elliot CD, Murray DJ, Pearson LS (1979) The British ability scales. NFER, Slough, UK

Rust J, Golombok S, Trickey G (1993) Wechsler objective reading dimensions. Psychological Corporation, Sidcup.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs6564903  (P = 0.0002)
rs12927866  (P = 0.0046)
rs3935802  (P = 0.0025)
rs7201632  (P = 0.0047)


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80790 CMIP 16q23 Dyslexia Single-word reading Scerri et al 2011 JSON | XML

Additional Phenotype Details: Possible measures include the single-word reading subtest of Wechsler Objective Reading Dimensions
(WORD), and the British Ability Scales (BAS) test of single-word reading.


References

Elliot CD, Murray DJ, Pearson LS (1979) The British ability scales. NFER, Slough, UK

Rust J, Golombok S, Trickey G (1993) Wechsler objective reading dimensions. Psychological Corporation, Sidcup.

Associated Markers:
rs6564903  (P = 0.002)  - significant association in F2 sample (dyslexia with SLI or ADHD comorbidity + unaffected) and F3 sample (pure dyslexia + unaffected)


Comments


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