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Articles   |    
A Genome Scan for Loci Shared by Autism Spectrum Disorder and Language Impairment
Christopher W. Bartlett, Ph.D.; Liping Hou, Ph.D.; Judy F. Flax, Ph.D.; Abby Hare, B.S.; Soo Yeon Cheong, Ph.D.; Zena Fermano, M.A.; Barbie Zimmerman-Bier, M.D.; Charles Cartwright, M.D.; Marco A. Azaro, Ph.D.; Steven Buyske, Ph.D.; Linda M. Brzustowicz, M.D.
Am J Psychiatry 2014;171:72-81. doi:10.1176/appi.ajp.2013.12081103
View Author and Article Information

Dr. Brzustowicz serves as a consultant for the Janssen Pharmaceutical Companies of Johnson & Johnson. The remaining authors report no financial relationships with commercial interests.

Supported by NIMH grants R01 MH-070366 and RC1 MH-088288 to Dr. Brzustowicz; by the NIMH Center for Collaborative Genomic Studies on Mental Disorders, funded by U24 MH-068457; and by computing time from Ohio Supercomputer Center grant PCCR0001-2 to Dr. Bartlett.

From the Battelle Center for Mathematical Medicine, Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, Ohio State University, Columbus; the Department of Genetics, the Human Genetics Institute of New Jersey, and the Department of Statistics and Biostatistics, Rutgers University, Piscataway, N.J.; the Department of Pediatrics, Saint Peter's University Hospital, New Brunswick, N.J.; and the Department of Psychiatry, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark (now part of Rutgers University).

Address correspondence to Dr. Brzustowicz (brzustowicz@biology.rutgers.edu).

Copyright © 2014 by the American Psychiatric Association

Received August 23, 2012; Revised March 02, 2013; Revised April 21, 2013; Revised August 06, 2013; Accepted August 06, 2013.

Abstract

Objective  The authors conducted a genetic linkage study of families that have both autism spectrum disorder (ASD) and language-impaired probands to find common communication impairment loci. The hypothesis was that these families have a high genetic loading for impairments in language ability, thus influencing the language and communication deficits of the family members with ASD. Comprehensive behavioral phenotyping of the families also enabled linkage analysis of quantitative measures, including normal, subclinical, and disordered variation in all family members for the three general autism symptom domains: social, communication, and compulsive behaviors.

Method  The primary linkage analysis coded persons with either ASD or specific language impairment as “affected.” The secondary linkage analysis consisted of quantitative metrics of autism-associated behaviors capturing normal to clinically severe variation, measured in all family members.

Results  Linkage to language phenotypes was established at two novel chromosomal loci, 15q23–26 and 16p12. The secondary analysis of normal and disordered quantitative variation in social and compulsive behaviors established linkage to two loci for social behaviors (at 14q and 15q) and one locus for repetitive behaviors (at 13q).

Conclusion  These data indicate shared etiology of ASD and specific language impairment at two novel loci. Additionally, nonlanguage phenotypes based on social aloofness and rigid personality traits showed compelling evidence for linkage in this study group. Further genetic mapping is warranted at these loci.

Abstract Teaser
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FIGURE 1. Genome-Wide Linkage Analysis of Five Language-Related Traits in 70 Families With Both Autism Spectrum Disorder (ASD) and Specific Language Impairmenta

a The PPL is scaled such that values below 0.02 represent evidence against linkage to that location while values higher than 0.02 represent evidence for linkage to that location. A PPL of exactly 0.02 indicates that the data are not informative for linkage. The peaks on chromosomes 15 and 16, which represent the LI* and RI* phenotypes, respectively, clearly stand out from the rest of the genome, and overall the PPL displays a high signal-to-noise ratio for linkage mapping. While the three factor scores lack strong peaks, several regions of potential interest are identified.

b PPL, posterior probability of linkage.

c LI* represents oral language impairment and/or ASD. RI* represents reading impairment and/or ASD.

d The factors were derived from 21 standardized measures of language, as described in the data supplement accompanying the online version of this article. Factor loadings are presented in Table S4 in the data supplement.

FIGURE 2. Follow-Up Association Analysis of SNPs Under Genetic Linkage Peaks for Oral Language and Reading Impairment Phenotypes in 79 Families With Both Autism Spectrum Disorder (ASD) and Specific Language Impairment

a PPL, posterior probability of linkage. cPPLD, combined posterior probability of linkage disequilibrium.

FIGURE 3. Genome-Wide Linkage Analysis of Three Non-Language-Related Traits in 70 Families With Both Autism Spectrum Disorder (ASD) and Specific Language Impairmenta

a The largest signals for the three traits were on chromosomes 13, 14, and 15. No overlap was observed between the analyses of the Social Responsiveness Scale quantitative and dichotomous traits.

b PPL, posterior probability of linkage.

FIGURE 4. Follow-Up Association Analysis of SNPs Under Genetic Linkage Peaks for Three Non-Language-Related Traits in 79 Families With Both Autism Spectrum Disorder (ASD) and Specific Language Impairmenta

a No cPPLD values were observed that could account for the linkage signals with the Yale-Brown Obsessive Compulsive Scale or the Social Responsiveness Scale as a quantitative or dichotomous trait.

b PPL, posterior probability of linkage. cPPLD, combined posterior probability of linkage disequilibrium.

Anchor for Jump
TABLE 1.Large Peaksa in Linkage Analysis of Language Impairment in 70 Families With Autism Spectrum Disorder (ASD) and Specific Language Impairment
Table Footer Note

a A large peak was defined as a posterior probability of linkage (PPL) above 0.35.

Table Footer Note

b Sometimes referred to as a mod score.

Table Footer Note

c For categorical analysis these quantities are penetrances, and for quantitative traits they are genotypic means on a z-score scale.

Table Footer Note

d Estimate of the proportion of families linked to a given locus.

Table Footer Note

e LI* represents oral language impairment and/or ASD. RI* represents reading impairment and/or ASD.

+

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