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Published Online: 1 March 2015

Genetic Investigation of Autism-Related Social Communication Deficits

Autism spectrum disorder includes a deficit in social communication as one of its underlying elements or endophenotypes. Endophenotypes are elements of a disorder that are thought to arise from a specific cause, usually a genetic variation. They are generally more widespread in families than the disorder itself, with many nonaffected members of the families expressing the endophenotype but not reaching criteria for the full clinical diagnosis. An endophenotype that is scored quantitatively in all family members has much more power to show genetic linkage in the family than the diagnosis alone, which occurs in only some of the family members. In this issue of the Journal, Lowe et al. (1) hypothesized that social communication deficits might serve as the endophenotype that would provide sufficient power to identify regions with inherited genetic variants that contribute to autism. Most of the genetic risk for autism is inherited (2, 3), yet DNA sequencing projects have focused mostly on de novo (i.e., not inherited) genetic variants found in individuals with autism (48).
Lowe et al. (1) report significant genetic linkage of two distinct regions of chromosome 8 to an autism endophenotype: the scores for all family members on the Social Responsiveness Scale, which quantitatively measures variation in autism-related social impairments. The Social Responsiveness Scale is an assessment of social interaction competence, scored by either teachers or parents, which provides a quantitative endophenotype for autism (9). In a sample of 590 families, from the Autism Genetic Resource Exchange, with Social Responsiveness Scale scores, Lowe et al. found a novel locus on chromosome 8p21.3 that reached the criterion for genome-wide significant linkage using the combined Social Responsiveness Scale scores reported by parents and teachers (LOD [logarithm of the odds ratio]=4.11). A second locus, independent of the first, was also found at chromosome 8q24.22. The sample combined teacher and parent ratings, which were highly correlated with each other. To eliminate any possible interference from two different kinds of raters, a subset of 536 families with only the parent-reported scores was analyzed. Lowe et al. then found that the 8q24.22 locus also reached the criterion for genome-wide significant linkage (LOD=4.54).
To identify common functional genetic variants that contribute to the social responsiveness phenotype, Lowe et al. expanded the cohort to 1,652 Autism Genetic Resource Exchange families, including parent-child trios that were not informative for linkage analysis. Examination of the chromosome 8p21.3 and 8q24.22 regions failed to identify evidence for association after correction for multiple comparisons. The lack of association within the linkage regions suggests that rare variants may contribute to the autism-related social responsiveness phenotype. A limitation of the study is that the rare variants that contribute to the Social Responsiveness Scale phenotype have not yet been identified. As with most linkage studies in psychiatric disorders, the results indicate a region of a chromosome that is thought to harbor a contributing rare variant. Finding these variants will not be easy. The linked region on chromosome 8p21.3 includes 34 characterized genes; the chromosome 8q24.22 region includes 68 characterized genes. Additional targeted sequencing experiments will be required to identify the inherited rare variants.
Although the specific genes and genetic variants on chromosome 8 have not yet been identified, this type of approach has proven successful for one other genetic locus in autism. Genetic linkage studies using an autism-related quantitative language endophenotype identified CNTNAP2 as an autism candidate gene (10). Subsequent studies provided substantial evidence that variation of CNTNAP2 contributes to autism risk, since both common variants and rare mutations of CNTNAP2 were associated with autism risk (see reference 11). Genetic imaging studies further demonstrated that variations in CNTNAP2 contribute to altered functional connectivity in the human cerebral cortex (12). These data establish that linkage studies of autism-related quantitative endophenotypes can provide important leads to find genetic variants that contribute to the changes in brain development that underlie autism.
The chromosome 8 linkage loci identified in this study join five other genetic loci with genome-wide significant association to autism diagnosis (1317). Two of these loci are also associated with quantitative social communication phenotypes in large general population samples (18, 19), indicating that multiple genes contribute to autism-related endophenotypes. Biological studies have revealed that the functional element at one of these genome-wide significant loci (13, 19) is a gene encoding a regulatory, long noncoding RNA, MSNP1AS, suggesting that we will need to look beyond the exome—the 2% of the human genome that encodes proteins—to identify genetic elements that contribute to autism spectrum disorder risk (20).

References

1.
Lowe JK, Werling DM, Constantino JN, et al: Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8. Am J Psychiatry 2015; 172:266–275
2.
Gaugler T, Klei L, Sanders SJ, et al: Most genetic risk for autism resides with common variation. Nat Genet 2014; 46:881–885
3.
Sandin S, Lichtenstein P, Kuja-Halkola R, et al: The familial risk of autism. JAMA 2014; 311:1770–1777
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Iossifov I, Ronemus M, Levy D, et al: De novo gene disruptions in children on the autistic spectrum. Neuron 2012; 74:285–299
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Neale BM, Kou Y, Liu L, et al: Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485:242–245
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O’Roak BJ, Vives L, Fu W, et al: Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012; 338:1619–1622
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O’Roak BJ, Vives L, Girirajan S, et al: Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485:246–250
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Sanders SJ, Murtha MT, Gupta AR, et al: De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485:237–241
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Duvall JA, Lu A, Cantor RM, et al: A quantitative trait locus analysis of social responsiveness in multiplex autism families. Am J Psychiatry 2007; 164:656–662
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Alarcón M, Abrahams BS, Stone JL, et al: Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 2008; 82:150–159
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Peñagarikano O, Geschwind DH: What does CNTNAP2 reveal about autism spectrum disorder? Trends Mol Med 2012; 18:156–163
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Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, et al: Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci Transl Med 2010; 2:56ra80
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Wang K, Zhang H, Ma D, et al: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009; 459:528–533
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Weiss LA, Arking DE, Daly MJ, et al: Gene Discovery Project of Johns Hopkins and the Autism Consortium: a genome-wide linkage and association scan reveals novel loci for autism. Nature 2009; 461:802–808
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Xia K, Guo H, Hu Z, et al: Common genetic variants on 1p13.2 associate with risk of autism. Mol Psychiatry 2013
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Anney R, Klei L, Pinto D, et al: Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet 2012; 21:4781–4792
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Anney R, Klei L, Pinto D, et al: A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 2010; 19:4072–4082
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Jones RM, Cadby G, Blangero J, et al: MACROD2 gene associated with autistic-like traits in a general population sample. Psychiatr Genet 2014; 24:241–248
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St Pourcain B, Wang K, Glessner JT, et al: Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population. Am J Psychiatry 2010; 167:1364–1372
20.
Kerin T, Ramanathan A, Rivas K, et al: A noncoding RNA antisense to moesin at 5p14.1 in autism. Sci Transl Med 2012; 4:128ra40

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 212 - 213
PubMed: 25727530

History

Accepted: December 2014
Published online: 1 March 2015
Published in print: March 01, 2015

Authors

Details

Daniel B. Campbell, Ph.D.
From the Zilkha Neurogenetic Institute and the Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles.

Notes

Address correspondence to Dr. Campbell ([email protected]).

Funding Information

The author reports no financial relationships with commercial interests.

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