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Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees.

Coon H, Villalobos ME, Robison RJ, Camp NJ, Cannon DS, Allen-Brady K, Miller JS, McMahon WM - Mol Autism (2010)

Bottom Line: When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77).The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis.These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Utah Autism Research Project, Department of Psychiatry and Division of Genetic Epidemiology, University of Utah, 650 Komas Drive, Suite 206, Salt Lake City, UT 84108, USA. hilary.coon@hsc.utah.edu.

ABSTRACT

Background: Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.

Methods: We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.

Results: When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.

Conclusions: The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.

No MeSH data available.


Related in: MedlinePlus

Histograms of Social Responsiveness Scale scores for subjects in Utah autism pedigrees.
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Figure 1: Histograms of Social Responsiveness Scale scores for subjects in Utah autism pedigrees.

Mentions: Regression adjustment of the SRS for age and gender effects resulted in parameter estimates of -0.074 for age and 1.6 for gender (males have higher scores). Figure 1 gives the distribution of SRS scores by diagnostic category. SRS scores were significantly different between autism and ASD (t = 3.71, P = 0.0003) and between ASD and other relatives (t = 10.57, P < 0.0001). Among affected subjects, substantial correlations were observed between ADI domain scores and the SRS total score. The highest correlations were observed with the ADI social domain score, with a correlation of 0.60 among ASD subjects and a correlation of 0.46 among subjects with AD. For ASD subjects, 17.1% scored in the normal range on the SRS, 39.0% scored in the spectrum range and 43.9% scored in the affected range. Among subjects with a clinical diagnosis of autism, 5.6% scored in the normal range, 19.1% scored in the spectrum range and 75.4% scored in the affected range. The 95 genotyped spouse pairs showed a significant spouse correlation of 0.33 (P = 0.001) using the square root transformed adjusted scores.


Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees.

Coon H, Villalobos ME, Robison RJ, Camp NJ, Cannon DS, Allen-Brady K, Miller JS, McMahon WM - Mol Autism (2010)

Histograms of Social Responsiveness Scale scores for subjects in Utah autism pedigrees.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913945&req=5

Figure 1: Histograms of Social Responsiveness Scale scores for subjects in Utah autism pedigrees.
Mentions: Regression adjustment of the SRS for age and gender effects resulted in parameter estimates of -0.074 for age and 1.6 for gender (males have higher scores). Figure 1 gives the distribution of SRS scores by diagnostic category. SRS scores were significantly different between autism and ASD (t = 3.71, P = 0.0003) and between ASD and other relatives (t = 10.57, P < 0.0001). Among affected subjects, substantial correlations were observed between ADI domain scores and the SRS total score. The highest correlations were observed with the ADI social domain score, with a correlation of 0.60 among ASD subjects and a correlation of 0.46 among subjects with AD. For ASD subjects, 17.1% scored in the normal range on the SRS, 39.0% scored in the spectrum range and 43.9% scored in the affected range. Among subjects with a clinical diagnosis of autism, 5.6% scored in the normal range, 19.1% scored in the spectrum range and 75.4% scored in the affected range. The 95 genotyped spouse pairs showed a significant spouse correlation of 0.33 (P = 0.001) using the square root transformed adjusted scores.

Bottom Line: When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77).The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis.These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Utah Autism Research Project, Department of Psychiatry and Division of Genetic Epidemiology, University of Utah, 650 Komas Drive, Suite 206, Salt Lake City, UT 84108, USA. hilary.coon@hsc.utah.edu.

ABSTRACT

Background: Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.

Methods: We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.

Results: When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.

Conclusions: The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.

No MeSH data available.


Related in: MedlinePlus