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A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

ABSTRACT: 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.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.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.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.

SUBMITTER: Chaste P

PROVIDER: S-EPMC4379124 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Chaste Pauline P Klei Lambertus L Sanders Stephan J SJ Hus Vanessa V Murtha Michael T MT Lowe Jennifer K JK Willsey A Jeremy AJ Moreno-De-Luca Daniel D Yu Timothy W TW Fombonne Eric E Geschwind Daniel D Grice Dorothy E DE Ledbetter David H DH Mane Shrikant M SM Martin Donna M DM Morrow Eric M EM Walsh Christopher A CA Sutcliffe James S JS Lese Martin Christa C Beaudet Arthur L AL Lord Catherine C State Matthew W MW Cook Edwin H EH Devlin Bernie B

Biological psychiatry 20140930 9

<h4>Background</h4>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) ...[more]

PMID: 25534755

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Project description:BackgroundHeterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder.MethodsThree hundred thirty-two children and adults with ASD between the ages of 6 and 30 years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model.ResultsThe 'three-subgroup/seven-factor' FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety.LimitationsResults were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings.ConclusionSensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD.

Dataset Information

A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Publications

A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

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