ASD Diagnosis in Adults: Phenotype and Genotype Findings from a Clinically-derived Cohort

AbstractBackgroundThe last decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared to children, little is known about the phenotypic and genetic characteristics of these patients.AimsThis e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically-presenting sample of adults diagnosed with ASD by specialist services.MethodsIndividuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA. 105 eligible individuals were matched to 76 healthy controls. We investigated the demographics, social history, comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores calculated.Results89.5% of individuals with ASD had at least one comorbid psychiatric diagnosis with comorbid depression (62.9%) and anxiety (55.2%) the most common. The ASD group experienced more neurological comorbidities than healthy controls, particularly migraine headache. They were less likely to have married or be in work and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared to controls, but there was no difference in the rate of rare CNVs.ConclusionsThis study provides important information about psychiatric comorbidity in adult ASD which may be used to inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within non-intellectually disabled population of adults with ASD.

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Autism spectrum disorder diagnosis in adults: phenotype and genotype findings from a clinically derived cohort

The British Journal of Psychiatry ◽

10.1192/bjp.2019.30 ◽

2019 ◽

Vol 215 (5) ◽

pp. 647-653 ◽

Cited By ~ 6

Author(s):

Jack F. G. Underwood ◽

Kimberley M. Kendall ◽

Jennifer Berrett ◽

Catrin Lewis ◽

Richard Anney ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social History ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Self Report ◽

Risk Scores ◽

Rare Cnvs ◽

Patient Counselling ◽

Genetic Characteristics ◽

Common Genetic Variants

BackgroundThe past decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared with children, little is known about the phenotypic and genetic characteristics of these patients.AimsThis e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically presenting sample of adults diagnosed with ASD by specialist services.MethodIndividuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA; 105 eligible individuals were matched to 76 healthy controls. We investigated demographics, social history and comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores were calculated.ResultsOf individuals with ASD, 89.5% had at least one comorbid psychiatric diagnosis, with depression (62.9%) and anxiety (55.2%) being the most common. The ASD group experienced more neurological comorbidities than controls, particularly migraine headache. They were less likely to have married or be in work, and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared with controls, but there was no difference in the rate of rare CNVs.ConclusionsThis study provides important information about psychiatric comorbidity in adult ASD, which may inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within the non-intellectually disabled population of adults with ASD.Declaration of interestNone.

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Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Nature Communications ◽

10.1038/s41467-019-13380-2 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

L. D’Abate ◽

S. Walker ◽

R. K. C. Yuen ◽

K. Tammimies ◽

J. A. Buchanan ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Copy Number Variations ◽

Recurrence Prediction ◽

Common Genetic Variants ◽

Spectrum Disorders ◽

Atypical Development ◽

Research Consortium

AbstractIdentification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

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Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases

10.1101/406215 ◽

2018 ◽

Author(s):

Alexander W. Charney ◽

Eli A. Stahl ◽

Elaine K. Green ◽

Chia-Yen Chen ◽

Jennifer L. Moran ◽

...

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychiatric Symptoms ◽

Copy Number Variants ◽

Risk Scores ◽

P Value ◽

Bipolar Ii Disorder ◽

Common Genetic Variants ◽

Bipolar Ii ◽

Bipolar Type

AbstractBackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood.MethodsRare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk.ResultsCNV burden did not differ in BD relative to controls when treated as a single diagnostic entity. Burden in SAB was increased compared to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were higher in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 × 10−5). Within BD I, psychosis was associated with higher SCZ PRS (p-value = 0.005) but not with CNV burden.ConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

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Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

10.1101/2021.06.24.21259489 ◽

2021 ◽

Author(s):

Rackeb Tesfaye ◽

Guillaume Huguet ◽

Zoe Schmilovich ◽

Mor Absa Loum ◽

Elise Douard ◽

...

Keyword(s):

Copy Number ◽

Sleep Disturbances ◽

Sleep Problems ◽

Copy Number Variants ◽

Autism Spectrum ◽

Rare Cnvs ◽

Risk Genes ◽

Circadian Genes ◽

Simons Simplex Collection ◽

Generation Scotland

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in a general population are related to ASD risk and common sleep problems like insomnia in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as parent reported sleep disturbances in children diagnosed with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection and MSSNG database, as well as 7463 individuals from two unselected populations (IMAGEN and Generation Scotland). We identified 320 and 626 rare CNVs encompassing circadian genes and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (but not duplications) were also associated with ASD. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Duplications containing circadian genes were associated with shorter sleep duration(22 minutes). Only insomnia risk genes intolerant to haploinsufficiency increased insomnia traits when duplicated. Overall, CNVs encompassing circadian and insomnia risk genes increase ASD risk despite small impacts on sleep disturbances.

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MLPA is a practical and complementary alternative to CMA for diagnostic testing in patients with autism spectrum disorders and identifying new candidate CNVs associated with autism

PeerJ ◽

10.7717/peerj.6183 ◽

2019 ◽

Vol 6 ◽

pp. e6183 ◽

Cited By ~ 1

Author(s):

Pavlina Capkova ◽

Josef Srovnal ◽

Zuzana Capkova ◽

Katerina Staffova ◽

Vera Becvarova ◽

...

Keyword(s):

Clinical Significance ◽

Diagnostic Testing ◽

Copy Number Variants ◽

Ring Chromosome ◽

Autism Spectrum ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Rare Cnvs ◽

Pathogenic Variants ◽

Dependent Probe

Background Autism spectrum disorder (ASD) is a complex heterogeneous developmental disease with a significant genetic background that is frequently caused by rare copy number variants (CNVs). Microarray-based whole-genome approaches for CNV detection are widely accepted. However, the clinical significance of most CNV is poorly understood, so results obtained using such methods are sometimes ambiguous. We therefore evaluated a targeted approach based on multiplex ligation-dependent probe amplification (MLPA) using selected probemixes to detect clinically relevant variants for diagnostic testing of ASD patients. We compare the reliability and efficiency of this test to those of chromosomal microarray analysis (CMA) and other tests available to our laboratory. In addition, we identify new candidate genes for ASD identified in a cohort of ASD-diagnosed patients. Method We describe the use of MLPA, CMA, and karyotyping to detect CNV in 92 ASD patients and evaluate their clinical significance. Result Pathogenic and likely pathogenic mutations were identified by CMA in eight (8.07% of the studied cohort) and 12 (13.04%) ASD patients, respectively, and in eight (8.07%) and four (4.35%) patients, respectively, by MLPA. The detected mutations include the 22q13.3 deletion, which was attributed to ring chromosome 22 formation based on karyotyping. CMA revealed a total of 91 rare CNV in 55 patients: eight pathogenic, 15 designated variants of unknown significance (VOUS)—likely pathogenic, 10 VOUS—uncertain, and 58 VOUS—likely benign or benign. MLPA revealed 18 CNV in 18 individuals: eight pathogenic, four designated as VOUS—likely pathogenic, and six designated as VOUS—likely benign/benign. Rare CNVs were detected in 17 (58.62%) out of 29 females and 38 (60.32%) out of 63 males in the cohort. Two genes, DOCK8 and PARK2, were found to be overlapped by CNV designated pathogenic, VOUS—likely pathogenic, or VOUS—uncertain in multiple patients. Moreover, the studied ASD cohort exhibited significant (p < 0.05) enrichment of duplications encompassing DOCK8. Conclusion Multiplex ligation-dependent probe amplification and CMA yielded concordant results for 12 patients bearing CNV designated pathogenic or VOUS—likely pathogenic. Unambiguous diagnoses were achieved for eight patients (corresponding to 8.7% of the total studied population) by both MLPA and CMA, for one (1.09%) patient by karyotyping, and for one (1.09%) patient by FRAXA testing. MLPA and CMA thus achieved identical reliability with respect to clinically relevant findings. As such, MLPA could be useful as a fast and inexpensive test in patients with syndromic autism. The detection rate of potentially pathogenic variants (VOUS—likely pathogenic) achieved by CMA was higher than that for MLPA (13.04% vs. 4.35%). However, there was no corresponding difference in the rate of unambiguous diagnoses of ASD patients. In addition, the results obtained suggest that DOCK8 may play a role in the etiology of ASD.

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Polygenic risk for ADHD and ASD and their relation with cognitive measures in school children

Psychological Medicine ◽

10.1017/s0033291720003189 ◽

2020 ◽

pp. 1-9

Author(s):

Sofía Aguilar-Lacasaña ◽

Natàlia Vilor-Tejedor ◽

Philip R. Jansen ◽

Mònica López-Vicente ◽

Mariona Bustamante ◽

...

Keyword(s):

Multiple Testing ◽

Autism Spectrum ◽

Developmental Trajectory ◽

Risk Scores ◽

Cognitive Measures ◽

Multiple Testing Correction ◽

Polygenic Risk ◽

Common Genetic Variants ◽

Attention Performance ◽

Over Time

Abstract Background Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach. Methods A total of 1667 children from a population-based cohort aged 7–11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models. Results Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE. Conclusions Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.

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Differences in Reward and Persistency characterise Behavior in Chronic Pain for the Iowa Gambling Task in a Web-based Lab-in-the-field study (Preprint)

10.2196/preprints.26307 ◽

2020 ◽

Author(s):

Lili Zhang ◽

Himanshu Vashisht ◽

Alekhya Nethra ◽

Brian Slattery ◽

Tomas Ward

Keyword(s):

Decision Making ◽

Social Media ◽

Chronic Pain ◽

Iowa Gambling Task ◽

Learning Curves ◽

Self Report ◽

Healthy Controls ◽

Gambling Task ◽

Convenience Sample ◽

Pain Experiences

BACKGROUND Chronic pain is a significant world-wide health problem. It has been reported that people with chronic pain experience decision-making impairments, but these findings have been based on conventional lab experiments to date. In such experiments researchers have extensive control of conditions and can more precisely eliminate potential confounds. In contrast, there is much less known regarding how chronic pain impacts decision-making captured via lab-in-the-field experiments. Although such settings can introduce more experimental uncertainty, it is believed that collecting data in more ecologically valid contexts can better characterize the real-world impact of chronic pain. OBJECTIVE We aim to quantify decision-making differences between chronic pain individuals and healthy controls in a lab-in-the-field environment through taking advantage of internet technologies and social media. METHODS A cross-sectional design with independent groups was employed. A convenience sample of 45 participants were recruited through social media - 20 participants who self-reported living with chronic pain, and 25 people with no pain or who were living with pain for less than 6 months acting as controls. All participants completed a self-report questionnaire assessing their pain experiences and a neuropsychological task measuring their decision-making, i.e. the Iowa Gambling Task (IGT) in their web browser at a time and location of their choice without supervision. RESULTS Standard behavioral analysis revealed no differences in learning strategies between the two groups although qualitative differences could be observed in learning curves. However, computational modelling revealed that individuals with chronic pain were quicker to update their behavior relative to healthy controls, which reflected their increased learning rate (95% HDI from 0.66 to 0.99) when fitted with the VPP model. This result was further validated and extended on the ORL model because higher differences (95% HDI from 0.16 to 0.47) between the reward and punishment learning rates were observed when fitted on this model, indicating that chronic pain individuals were more sensitive to rewards. It was also found that they were less persistent in their choices during the IGT compared to controls, a fact reflected by their decreased outcome perseverance (95% HDI from -4.38 to -0.21) when fitted using the ORL model. Moreover, correlation analysis revealed that the estimated parameters had predictive value for the self-reported pain experiences, suggesting that the altered cognitive parameters could be potential candidates for inclusion in chronic pain assessments. CONCLUSIONS We found that individuals with chronic pain were more driven by rewards and less consistent when making decisions in our lab-in-the-field experiment. In this case study, it was demonstrated that compared to standard statistical summaries of behavioral performance, computational approaches offered superior ability to resolve, understand and explain the differences in decision- making behavior in the context of chronic pain outside the lab.

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Genetic architecture of schizophrenia: a review of major advancements

Psychological Medicine ◽

10.1017/s0033291720005334 ◽

2021 ◽

pp. 1-10

Author(s):

Sophie E. Legge ◽

Marcos L. Santoro ◽

Sathish Periyasamy ◽

Adeniran Okewole ◽

Arsalan Arsalan ◽

...

Keyword(s):

Genetic Architecture ◽

Association Studies ◽

Copy Number Variants ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genetic Loci ◽

Significant Enrichment ◽

High Heritability ◽

Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

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Modified CBT for social anxiety and social functioning in young adults with autism spectrum disorder

Molecular Autism ◽

10.1186/s13229-021-00418-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Emily R. Bemmer ◽

Kelsie A. Boulton ◽

Emma E. Thomas ◽

Ben Larke ◽

Suncica Lah ◽

...

Keyword(s):

Young Adults ◽

Social Anxiety ◽

Social Functioning ◽

Autism Spectrum ◽

Self Report ◽

Post Intervention ◽

Adults With Autism ◽

Adolescents And Adults ◽

Adults With Asd ◽

Young Adults With Asd

Abstract Background There is a strong research imperative to investigate effective treatment options for adolescents and adults with autism spectrum disorder (ASD). Elevated social anxiety, difficulties with social functioning and poor mental health have all been identified as core treatment targets for this group. While theoretical models posit a strong bidirectionality between social anxiety and ASD social functioning deficits, few interventions have targeted both domains concurrently. Of the two group interventions previously conducted with adolescents and adults with ASD, significant results have only been observed in either social anxiety or social functioning, and have not generalised to changes in overall mood. The aim of this study was to evaluate the potential benefit, tolerability and acceptability of a group cognitive-behaviour therapy (CBT) intervention in young adults with ASD. Primary treatment outcomes were social anxiety symptoms and social functioning difficulties; secondary outcomes were self-reported mood and overall distress. Method Ten groups of participants completed an eight-week, modified group CBT intervention targeting both social anxiety and social functioning, that included social skills training, exposure tasks and behavioural experiment components. Seventy-eight adolescents and young adults with ASD, without intellectual impairment, aged between 16 and 38 (M = 22.77; SD = 5.31), were recruited from the community, Headspace centres and the Autism Clinic for Translational Research at the Brain and Mind Centre, University of Sydney. Outcomes (social anxiety, social functioning and mood) were measured pre- and post-intervention via self-report questionnaires (administered either online or through the return of hard-copy booklets), and participants were invited to provide anonymous feedback on the intervention (at the mid-point and end of the intervention). Results Participants demonstrated statistically significant improvements on all outcome measures in response to the intervention. Specifically, social anxiety symptoms decreased (p < .001), and specific subdomains of social functioning improved post-intervention, particularly in social motivation (p = .032) and restricted interests and repetitive behaviours (p = .025). Self-reported symptom improvements also generalised to mood (depression, anxiety and stress; p < .05). All improvements demonstrated small effect sizes. Participant feedback was positive and indicated strong satisfaction with the program. Limitations The absence of a control group and follow-up measures, reliance on self-report instruments as outcome measures and the exclusion of those with intellectual disability represent significant limitations to this study. Conclusions These findings indicate that a group CBT intervention appears to be a beneficial intervention for self-reported social anxiety, social functioning and overall mental health in adolescents and young adults with ASD. The stand-alone nature of the intervention combined with positive participant feedback indicates it was well tolerated, has potential clinical utility and warrants further study in a randomised-controlled, follow-up design.

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Overcoming limitations of self-report: an assessment of fear of weight gain in anorexia nervosa and healthy controls using implicit association tests

Journal of Eating Disorders ◽

10.1186/s40337-021-00379-8 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Tiana Borgers ◽

Nathalie Krüger ◽

Silja Vocks ◽

Jennifer J. Thomas ◽

Franziska Plessow ◽

...

Keyword(s):

Anorexia Nervosa ◽

Weight Gain ◽

Normal Weight ◽

Self Report ◽

Healthy Controls ◽

Drive For Thinness ◽

Implicit Association ◽

Association Tests ◽

Implicit Assessment ◽

Fear Of Weight Gain

Abstract Background Fear of weight gain is a characteristic feature of anorexia nervosa (AN), and reducing this fear is often a main target of treatment. However, research shows that 20% of individuals with AN do not report fear of weight gain. Studies are needed that evaluate the centrality of fear of weight gain for AN with a method less susceptible to deception than self-report. Methods We approximated implicit fear of weight gain by measuring implicit drive for thinness using implicit association tests (IATs). We asked 64 participants (35 AN, 29 healthy controls [HCs]) to categorize statements as pro-dieting vs. non-dieting and true vs. false in a questionnaire-based IAT, and pictures of underweight vs. normal-weight models and positive vs. negative words in a picture-based IAT using two response keys. We tested for associations between implicit drive for thinness and explicitly reported psychopathology within AN as well as group differences between AN and HC groups. Results Correlation analyses within the AN group showed that higher implicit drive for thinness was associated with more pronounced eating disorder-specific psychopathology. Furthermore, the AN group showed a stronger implicit drive for thinness than HCs in both IATs. Conclusion The results highlight the relevance of considering fear of weight gain as a continuous construct. Our implicit assessment captures various degrees of fear of weight gain in AN, which might allow for more individually tailored interventions in the future.

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