Lauren M. McGrath

A framework for the interpretation of de novo mutation in human disease

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.

Etiology and neuropsychology of comorbidity between RD and ADHD: the case for multiple-deficit models.

INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are complex childhood disorders that frequently co-occur, but the etiology of this comorbidity remains unknown. METHOD Participants were 457 twin pairs from the Colorado Learning Disabilities Research Center (CLDRC) twin study, an ongoing study of the etiology of RD, ADHD, and related disorders. Phenotypic analyses compared groups with and without RD and ADHD on composite measures of six cognitive domains. Twin analyses were then used to test the etiology of the relations between the disorders and any cognitive weaknesses. RESULTS Phenotypic analyses supported the hypothesis that both RD and ADHD arise from multiple cognitive deficits rather than a single primary cognitive deficit. RD was associated independently with weaknesses on measures of phoneme awareness, verbal reasoning, and working memory, whereas ADHD was independently associated with a heritable weakness in inhibitory control. RD and ADHD share a common cognitive deficit in processing speed, and twin analyses indicated that this shared weakness is primarily due to common genetic influences that increase susceptibility to both disorders. CONCLUSIONS Individual differences in processing speed are influenced by genes that also increase risk for RD, ADHD, and their comorbidity. These results suggest that processing speed measures may be useful for future molecular genetic studies of the etiology of comorbidity between RD and ADHD.

A multiple deficit model of Reading Disability and Attention- Deficit/Hyperactivity Disorder: Searching for shared cognitive deficits

BACKGROUND This study tests a multiple cognitive deficit model of reading disability (RD), attention-deficit/hyperactivity disorder (ADHD), and their comorbidity. METHODS A structural equation model (SEM) of multiple cognitive risk factors and symptom outcome variables was constructed. The model included phonological awareness as a unique predictor of RD and response inhibition as a unique predictor of ADHD. Processing speed, naming speed, and verbal working memory were modeled as potential shared cognitive deficits. RESULTS Model fit indices from the SEM indicated satisfactory fit. Closer inspection of the path weights revealed that processing speed was the only cognitive variable with significant unique relationships to RD and ADHD dimensions, particularly inattention. Moreover, the significant correlation between reading and inattention was reduced to non-significance when processing speed was included in the model, suggesting that processing speed primarily accounted for the phenotypic correlation (or comorbidity) between reading and inattention. CONCLUSIONS This study illustrates the power of a multiple deficit approach to complex developmental disorders and psychopathologies, particularly for exploring comorbidities. The theoretical role of processing speed in the developmental pathways of RD and ADHD and directions for future research are discussed.

A Principal Components Analysis of the Autism Diagnostic Interview-Revised

OBJECTIVE To develop factors based on the Autism Diagnostic Interview-Revised (ADI-R) that index separate components of the autism phenotype that are genetically relevant and validated against standard measures of the constructs. METHOD ADIs and ADI-Rs of 292 individuals with autism were subjected to a principal components analysis using VARCLUS. The resulting variable clusters were validated against standard measures. RESULTS Six clusters of variables emerged: spoken language, social intent, compulsions, developmental milestones, savant skills and sensory aversions. Five of the factors were significantly correlated with the validating measures and had good internal consistency, face validity, and discriminant and construct validity. Most intraclass correlations between siblings were adequate for use in genetic studies. CONCLUSION The ADI-R contains correlated clusters of variables that are valid, genetically relevant, and that can be used in a variety of studies.

Gene × Environment Interactions in Reading Disability and Attention-Deficit/Hyperactivity Disorder

This article examines Gene x Environment (G x E) interactions in two comorbid developmental disorders--reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD)--as a window on broader issues on G x E interactions in developmental psychology. The authors first briefly review types of G x E interactions, methods for detecting them, and challenges researchers confront in interpreting such interactions. They then review previous evidence for G x E interactions in RD and ADHD, the directions of which are opposite to each other: bioecological for RD and diathesis stress for ADHD. Given these results, the authors formulate and test predictions about G x E interactions that would be expected at the favorable end of each symptom dimension (e.g., above-average reading or attention). Consistent with their prediction, the authors found initial evidence for a resilience interaction for above-average reading: higher heritability in the presence of lower parental education. However, they did not find a G x E interaction at the favorable end of the ADHD symptom dimension. The authors conclude with implications for future research.

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Significance Autism spectrum disorder (ASD) research is complicated by heterogeneity. There are several types of genetic risk factors for ASDs, and that diversity may be reflected in case presentation. This study presents evidence for systematic variation in the genetic architecture of ASDs in which higher functioning cases, defined through cognitive and behavioral assessments, are more likely to manifest familial influences. This finding suggests that genetic and neurobiological research into ASDs and other neuropsychiatric disorders may be pursued more efficiently through greater phenotypic characterization. Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

BACKGROUND Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. METHODS We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. RESULTS Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). CONCLUSIONS Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.

Bringing a developmental perspective to anxiety genetics.

Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.

Gene × Environment interactions in speech sound disorder predict language and preliteracy outcomes

Few studies have investigated the role of gene x environment interactions (G x E) in speech, language, and literacy disorders. Currently, there are two theoretical models, the diathesis-stress model and the bioecological model, that make opposite predictions about the expected direction of G x E, because environmental risk factors may either strengthen or weaken the effect of genes on phenotypes. The purpose of the current study was to test for G x E at two speech sound disorder and reading disability linkage peaks using a sib-pair linkage design and continuous measures of socioeconomic status, home language/literacy environment, and number of ear infections. The interactions were tested using composite speech, language, and preliteracy phenotypes and previously identified linkage peaks on 6p22 and 15q21. Results showed five G x E at both the 6p22 and 15q21 locations across several phenotypes and environmental measures. Four of the five interactions were consistent with the bioecological model of G x E. Each of these four interactions involved environmental measures of the home language/literacy environment. The only interaction that was consistent with the diathesis-stress model was one involving the number of ear infections as the environmental risk variable. The direction of these interactions and possible interpretations are explored in the discussion.