Vanessa Hus
University of Michigan
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Featured researches published by Vanessa Hus.
Neuron | 2011
Stephan J. Sanders; A. Gulhan Ercan-Sencicek; Vanessa Hus; Rui Luo; Daniel Moreno-De-Luca; Su H. Chu; Michael P. Moreau; Abha R. Gupta; Susanne Thomson; Christopher E. Mason; Kaya Bilguvar; Patrícia B. S. Celestino-Soper; Murim Choi; Emily L. Crawford; Lea K. Davis; Nicole R. Davis Wright; Rahul M. Dhodapkar; Michael DiCola; Nicholas M. DiLullo; Thomas V. Fernandez; Vikram Fielding-Singh; Daniel O. Fishman; Stephanie Frahm; Rouben Garagaloyan; Gerald Goh; Sindhuja Kammela; Lambertus Klei; Jennifer K. Lowe; Sabata C. Lund; Anna D. McGrew
We 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.
Archives of General Psychiatry | 2012
Catherine Lord; Eva Petkova; Vanessa Hus; Weijin Gan; Feihan Lu; Donna M. Martin; Opal Ousley; Lisa Guy; Raphael Bernier; Jennifer Gerdts; Molly Algermissen; Agnes H. Whitaker; James S. Sutcliffe; Zachary Warren; Ami Klin; Celine Saulnier; Ellen Hanson; Rachel Hundley; Judith Piggot; Eric Fombonne; Mandy Steiman; Judith H. Miles; Stephen M. Kanne; Robin P. Goin-Kochel; Sarika U. Peters; Edwin H. Cook; Stephen J. Guter; Jennifer Tjernagel; Lee Anne Green-Snyder; Somer L. Bishop
CONTEXT Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder-not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. OBJECTIVE To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. DESIGN Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. SETTING Participants were recruited through 12 university-based autism service providers into a genetic study of autism. PARTICIPANTS A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. MAIN OUTCOME MEASURE Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. RESULTS Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. CONCLUSIONS Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.
Molecular Autism | 2012
Lambertus Klei; Stephan J. Sanders; Vanessa Hus; Jennifer K. Lowe; A. Jeremy Willsey; Daniel Moreno-De-Luca; Eric Fombonne; Daniel H. Geschwind; Dorothy E. Grice; David H. Ledbetter; Catherine Lord; Shrikant Mane; Christa Lese Martin; Donna M. Martin; Eric M. Morrow; Christopher A. Walsh; Nadine M. Melhem; Pauline Chaste; James S. Sutcliffe; Matthew W. State; Edwin H. Cook; Kathryn Roeder; Bernie Devlin
BackgroundAutism 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.MethodsBy 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.ResultsBy 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.ConclusionsOur 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.
American Journal of Psychiatry | 2012
Marisela Huerta; Somer L. Bishop; Amie Duncan; Vanessa Hus; Catherine Lord
OBJECTIVE Substantial revisions to the DSM-IV criteria for autism spectrum disorders (ASDs) have been proposed in efforts to increase diagnostic sensitivity and specificity. This study evaluated the proposed DSM-5 criteria for the single diagnostic category of autism spectrum disorder in children with DSM-IV diagnoses of pervasive developmental disorders (PDDs) and non-PDD diagnoses. METHOD Three data sets included 4,453 children with DSM-IV clinical PDD diagnoses and 690 with non-PDD diagnoses (e.g., language disorder). Items from a parent report measure of ASD symptoms (Autism Diagnostic Interview-Revised) and clinical observation instrument (Autism Diagnostic Observation Schedule) were matched to DSM-5 criteria and used to evaluate the sensitivity and specificity of the proposed DSM-5 criteria and current DSM-IV criteria when compared with clinical diagnoses. RESULTS Based on just parent data, the proposed DSM-5 criteria identified 91% of children with clinical DSM-IV PDD diagnoses. Sensitivity remained high in specific subgroups, including girls and children under 4. The specificity of DSM-5 ASD was 0.53 overall, while the specificity of DSM-IV ranged from 0.24, for clinically diagnosed PDD not otherwise specified (PDD-NOS), to 0.53, for autistic disorder. When data were required from both parent and clinical observation, the specificity of the DSM-5 criteria increased to 0.63. CONCLUSIONS These results suggest that most children with DSM-IV PDD diagnoses would remain eligible for an ASD diagnosis under the proposed DSM-5 criteria. Compared with the DSM-IV criteria for Aspergers disorder and PDD-NOS, the DSM-5 ASD criteria have greater specificity, particularly when abnormalities are evident from both parents and clinical observation.
Journal of Autism and Developmental Disorders | 2014
Vanessa Hus; Katherine Gotham; Catherine Lord
Standardized Autism Diagnostic Observation Schedule (ADOS) scores provide a measure of autism severity that is less influenced by child characteristics than raw totals (Gotham et al. in Journal of Autism and Developmental Disorders, 39(5), 693–705 2009). However, these scores combine symptoms from the Social Affect (SA) and Restricted and Repetitive Behaviors (RRB) domains. Separate calibrations of each domain would provide a clearer picture of ASD dimensions. The current study separately calibrated raw totals from the ADOS SA and RRB domains. Standardized domain scores were less influenced by child characteristics than raw domain totals, thereby increasing their utility as indicators of Social-Communication and Repetitive Behavior severity. Calibrated domain scores should facilitate efforts to examine trajectories of ASD symptoms and links between neurobiological and behavioral dimensions.
Biological Psychiatry | 2007
Vanessa Hus; Andrew Pickles; Edwin H. Cook; Susan Risi; Catherine Lord
BACKGROUND Many chromosomal regions for susceptibility to autism spectrum disorders (ASDs) have been identified, but few have reached genomewide significance. In response, researchers have attempted to increase the power of their analyses by stratifying samples to increase phenotypic homogeneity. Although homogeneity has typically been defined by a single variable, resultant groups often differ in other dimensions that may be directly pertinent. Group differences in age, gender, IQ, and measures of autism severity are examined as related to Autism Diagnostic Interview-Revised (ADI-R) domains previously used for subsetting or Quantitative Trait Analysis (QTL). METHODS Participants were research participants and clinic referrals for assessment of possible autism. Assessments included the ADI-R, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, and a developmental or cognitive test. Data were collected for 983 individuals, ages 4 to 52 years, with diagnoses of autism and ASDs. RESULTS Findings suggest that, of several potential grouping variables, only restricted and repetitive behaviors associated with Insistence on Sameness were independent of age, IQ, and autism severity. CONCLUSIONS Results emphasize the potential unintended effects of stratification and the importance of understanding such interrelationships between phenotypic characteristics when defining subgroups or performing QTL.
Biological Psychiatry | 2015
Pauline Chaste; Lambertus Klei; Stephan J. Sanders; Vanessa Hus; Jennifer K. Lowe; A. Jeremy Willsey; Daniel Moreno-De-Luca; Eric Fombonne; Daniel H. Geschwind; Dorothy E. Grice; David H. Ledbetter; Shrikant Mane; Donna M. Martin; Eric M. Morrow; Christopher A. Walsh; James S. Sutcliffe; Christa Lese Martin; Arthur L. Beaudet; Catherine Lord; Matthew W. State; Edwin H. Cook; Bernie Devlin
BACKGROUND Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
Autism Research | 2013
Katherine Gotham; Somer L. Bishop; Vanessa Hus; Marisela Huerta; Sabata C. Lund; Andreas Buja; Abba M. Krieger; Catherine Lord
Elevated anxiety symptoms are one of the most common forms of psychopathology to co‐occur with autism spectrum disorders (ASDs). The purpose of this study was to explore the association between anxiety and ASD symptoms, particularly the degree to which the relationship is explained by insistence on sameness (IS) behaviors and/or cognitive ability. The sample included 1429 individuals aged 5:8–18:0 years who participated in the Simons Simplex Collection, a genetic consortium study of ASD. Child Behavior Checklist Anxiety Problems T‐scores and Autism Diagnostic Interview‐Revised “IS“ item raw totals were treated as both categorical and continuous measures of anxiety and IS, respectively. Chronological age, verbal intelligence quotient (IQ), and a variety of ASD phenotype‐related and other behavioral variables were assessed for potential association with anxiety and IS. Anxiety and IS continuous variables were minimally, although significantly, associated with each other and with chronological age and verbal IQ. Neither anxiety nor IS was associated with other core autism diagnostic scores. Anxiety was associated with a variety of other psychiatric and behavioral symptoms in ASD, including irritability, attention problems, and aggression, while IS was not. Anxiety and IS appear to function as distinct constructs, each with a wide range of expression in children with ASD across age and IQ levels. Thus, both variables could be of use in ASD behavioral research or in dimensional approaches to genetic exploration. Unlike IS, however, anxiety is related to non‐ASD‐specific behavioral symptoms. Autism Res 2012, ●●: ●●–●●.
Biological Psychiatry | 2013
Pauline Chaste; Lambertus Klei; Stephan J. Sanders; Vanessa Hus; Jennifer K. Lowe; A. Jeremy Willsey; Daniel Moreno-De-Luca; Eric Fombonne; Daniel H. Geschwind; Dorothy E. Grice; David H. Ledbetter; Catherine Lord; Shrikant Mane; Christa Lese Martin; Donna M. Martin; Eric M. Morrow; Christopher A. Walsh; James S. Sutcliffe; Matthew W. State; Bernie Devlin; Edwin H. Cook; Soo Jeong Kim
BACKGROUND Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.
Journal of Autism and Developmental Disorders | 2013
Vanessa Hus; Catherine Lord
The Autism Diagnostic Interview-Revised (ADI-R) is commonly used to inform diagnoses of autism spectrum disorders (ASD). Considering the time dedicated to using the ADI-R, it is of interest to expand the ways in which information obtained from this interview is used. The current study examines how algorithm totals reflecting past (ADI-Diagnostic) and current (ADI-Current) behaviors are influenced by child characteristics, such as demographics, behavioral problems and developmental level. Children with less language at the time of the interview had higher ADI-Diagnostic and ADI-Current. ADI-Diagnostic totals were also associated with age; parents of older children reported more severe past behaviors. Recommendations are provided regarding the use of the ADI-R as a measure of ASD severity, taking language and age into account.