Sprache, Kommunikation und soziale Entwicklung

multiple phenotypes which could potentially explain the extensive comorbidity observed across SLI and dyslexia. The large sample sizes make it possible to generate novel hypothesis following sample subgrouping.
Introduction
    Dyslexia and specific language impairment (SLI) are childhood disorders affecting between 5 and 10% school-aged children. Dyslexia is a specific deficit in learning to read whereas SLI is an impairment in the acquisition of oral language (Pennington & Bishop 2009). Both disorders are likely to be the result of multiple interacting factors, many of which have a genetic origin. Family studies have consistently reported that first-degree relatives of affected individuals have a 30 – 50% chance of being affected, which is significantly higher than the population incidence (Fisher & DeFries 2002; Barry et al. 2007). Concordance rate in monozygotic twins has been reported to be as high as 70% (DeFries et al. 1987). Significant comorbidity between RD and SLI has been consistently reported with figures ranging between 40 – 55% (Snowling et al. 2000; McArthur et al. 2000) suggesting that SLI and RD may be manifestations on the spectrum of the same underlying deficit and may share aetiological factors, such as common genetic determinants (Pennington & Bishop 2009). Recently,several genes have been proposed as susceptibility candidates for dyslexia and language disorders (Paracchini et al. 2007; Newbury et al. 2010; Scerri & Schulte-Korne 2010). The dyslexia candidates include the
MRPL19/C2ORF3
locus,
ROBO1
,
KIAA0319
,
DCDC2
and
DYX1C1
. The candidate genes for language include
CMIP
,
ATP2C2
and
CNTNAP2.
Most of these associations have been reported for common single nucleotide polymorphisms (SNPs) which are found at significant frequency (> 5%) in the general population. The validations of such associations and assessment of their statistical significance rely on replication studies. Epidemiological cohorts representing the general population have proved to be a valid alternative for such experiments. In addition to basic replication, they allow further investigation on the phenotypic component (Paracchini et al. 2008; Luciano et al. 2007; Lind et al. 2010). Phenotype definition is crucial when investigating genetics of language and reading disorders in view of reproducibility across studies. Measures of single-word reading and non-word repetition are the most commonly used tests in genetic association studies of dyslexia and SLI respectively. The availability of a large number of cognitive measures, including those used in patient cohorts, in epidemiological samples allows the analysis of multiple traits with the potential of further refining the phenotypic associations. The large sample sizes mean it is possible to stratify the sample in different phenotypic subgroups allowing the generation of novel hypothesis. For example by following up an association between the
PCSK6
gene and handedness in a population cohort it was possible to show that this association has a very specific effect in people with dyslexia (Scerri et al. 2011).
Materials and Methods
    Analysis was performed in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. ALSPAC consists of over 14 000 children from the southwest of England that had expected dates of delivery between 1 st April 1991 and 31 st December 1992 (Golding et al. 2001). From age 7, all children were invited annually for assessments on a wide range of physical, behavioural, and neuropsychological traits, including reading and language-related measures. DNA is available for approximately 11 000 ALSPAC children. Informed written consent was obtained from the parents after receiving a complete description of thestudy at the time of enrolment into the ALSPAC project, with the option for them or their children to withdraw at any time. Ethical approval for the present study was obtained from the ALSPAC Law and Ethics Committee and the Local Research Ethics Committees. We selected a range of quantitative measures which are comparable to the psychometric tests commonly used to ascertain probands and conduct quantitative analysis in genetic studies of dyslexia and SLI (Scerri et al. 2011). As handedness measure we use the peg-board test which assesses quantitatively relative hand skills (Scerri et al. 2011). Cognitive and behavioural phenotypes are available for 3000 – 7000 of children. Genotype data were generated using either Sequenom iPLEX assays