Replication of Standardized ADOS Domain Scores in the Simons Simplex Collection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115929/1/aur1474.pd

Toward a Better Understanding and Improved Validity of Autism Symptom Measures Across the Lifespan.

Autism Spectrum Disorders (ASDs) are defined by impairments in social- communication skills and restricted, repetitive and stereotyped patterns of behaviors and interests. The presentation of symptoms is affected by a variety of factors not specific to ASD, such as developmental characteristics (e.g., age, language level, and cognitive ability) and co-occurring dimensions of behavior (e.g., internalizing and externalizing behaviors). With the shift toward a dimensional diagnostic system put forth by the DSM- 5, research is needed to explore the influence of non-ASD-specific factors on scores from widely-used ASD diagnostic instruments. This research will inform the development of new measures that take into account the interaction between ASD symptoms and non- ASD-specific dimensions of behavior in order to provide more appropriate quantitative measures of ASD symptoms. This three-study dissertation seeks to expand the valid use of pre-existing ASD diagnostic measures with individuals across a range of ages. Study One provides a systematic look at the influences of developmental characteristics and non-ASD-specific dimensions of behavior on interpretation of scores from the Social Responsiveness Scale (SRS), a parent questionnaire widely used as an index of ASD severity. The second two studies focus on the Autism Diagnostic Observation Schedule (ADOS). Study Two standardizes Social Affect and Restricted, Repetitive Behavior domain scores to provide separate measures of social-communication and repetitive behavior severity that are less influenced by developmental level. Study Three revises the diagnostic algorithm and calibrates scores for ADOS Module 4, used with verbally fluent older adolescents and adults. This increases Module 4’s comparability to other modules used with younger or more language impaired individuals. Overall, the results of these studies provide a more in-depth understanding of how ASD diagnostic measures are influenced by developmental characteristics and non-ASD- specific dimensions of behavior. This knowledge can inform use of these measures as quantitative indices of ASD symptom severity. In clinical settings they may be used to monitor treatment progress. Application in the research domain may facilitate exploration of links between biological mechanisms and behavior and predictors of adult functioning, which will hopefully inform development of targeted interventions to promote positive outcomes for individuals with ASD.PHDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107055/1/vhus_1.pd

Factors influencing scores on the social responsiveness scale

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96433/1/j.1469-7610.2012.02589.x.pd

Commentary: Advancing measurement of ASD severity and social competence: a reply to Constantino and Frazier (2013)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98257/1/jcpp12065.pd

Common Genetic Variants, Acting Additively, Are a Major Source of Risk for Autism

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Common genetic variants, acting additively, are a major source of risk for autism

Abstract Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.http://deepblue.lib.umich.edu/bitstream/2027.42/112370/1/13229_2012_Article_55.pd

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1