scholarly journals Genetic Risk of Autism Spectrum Disorder in a Pakistani Population

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1206
Author(s):  
Madiha Khalid ◽  
Hashim Raza ◽  
Terri M. Driessen ◽  
Paul J. Lee ◽  
Leon Tejwani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Association Studies ◽  
Statistical Significance ◽  
Large Population ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Pakistani Population ◽  
Future Studies

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, and genome-wide association studies (GWAS). However, associations between different SNPs and ASD vary from population to population. Four SNPs in genes CNTNAP2, EIF4E, ATP2B2, CACNA1C, and SNP rs4307059 (which is found between CDH9 and CDH10 genes) have been identified and reported as candidate risk factors for ASD. The aim of the present study was, for the first time, to assess the association of SNPs in these genes with ASD in the Pakistani population. PCR-based genotyping was performed using allele-specific primers in 93 ASD and 93 control Pakistani individuals. All genetic associations, genotype frequencies, and allele frequencies were computed as odds’ ratios (ORs) using logistic regression with a threshold of p ≤ 0.01 to determine statistical significance. We found that the homozygous genotypes of mutant T alleles of CNTNAP2 and ATP2B2 were significantly associated with Pakistani ASD patients in unadjusted ORs (p < 0.01), but their significance score was lost in the adjusted model. Other SNPs such as rs4307059, rs17850950 of EIF4E, and rs1006737 of CACNA1C were not statistically significant. Based on this, we conclude that SNPs are not associated with, or are not the main cause of, autism in the Pakistani population, indicating the involvement of additional players, which need to be investigated in future studies in a large population size. One of the limitations of present study is its small sample size. However, this study, being the first on Pakistani ASD patients, may lay the foundations for future studies in larger samples.

scholarly journals Prediction of response to drug therapy in psychiatric disorders

Open Biology ◽  
2018 ◽  
Vol 8 (5) ◽  
pp. 180031 ◽  
Author(s):  
Shani Stern ◽  
Sara Linker ◽  
Krishna C. Vadodaria ◽  
Maria C. Marchetto ◽  
Fred H. Gage
Keyword(s):  
Autism Spectrum Disorder ◽  
Bipolar Disorder ◽  
Major Depression ◽  
Personalized Medicine ◽  
Psychiatric Disorders ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Patient Reported

Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.

scholarly journals An Automated Functional Annotation Pipeline That Rapidly Prioritizes Clinically Relevant Genes for Autism Spectrum Disorder

2020 ◽  
Vol 21 (23) ◽  
pp. 9029
Author(s):  
Olivia J. Veatch ◽  
Merlin G. Butler ◽  
Sarah H. Elsea ◽  
Beth A. Malow ◽  
James S. Sutcliffe ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Functional Annotation ◽  
Association Studies ◽  
Clinical Decision ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Annotation Pipeline ◽  
Personalized Care

Human genetic studies have implicated more than a hundred genes in Autism Spectrum Disorder (ASD). Understanding how variation in implicated genes influence expression of co-occurring conditions and drug response can inform more effective, personalized approaches for treatment of individuals with ASD. Rapidly translating this information into the clinic requires efficient algorithms to sort through the myriad of genes implicated by rare gene-damaging single nucleotide and copy number variants, and common variation detected in genome-wide association studies (GWAS). To pinpoint genes that are more likely to have clinically relevant variants, we developed a functional annotation pipeline. We defined clinical relevance in this project as any ASD associated gene with evidence indicating a patient may have a complex, co-occurring condition that requires direct intervention (e.g., sleep and gastrointestinal disturbances, attention deficit hyperactivity, anxiety, seizures, depression), or is relevant to drug development and/or approaches to maximizing efficacy and minimizing adverse events (i.e., pharmacogenomics). Starting with a list of all candidate genes implicated in all manifestations of ASD (i.e., idiopathic and syndromic), this pipeline uses databases that represent multiple lines of evidence to identify genes: (1) expressed in the human brain, (2) involved in ASD-relevant biological processes and resulting in analogous phenotypes in mice, (3) whose products are targeted by approved pharmaceutical compounds or possessing pharmacogenetic variation and (4) whose products directly interact with those of genes with variants recommended to be tested for by the American College of Medical Genetics (ACMG). Compared with 1000 gene sets, each with a random selection of human protein coding genes, more genes in the ASD set were annotated for each category evaluated (p ≤ 1.99 × 10−2). Of the 956 ASD-implicated genes in the full set, 18 were flagged based on evidence in all categories. Fewer genes from randomly drawn sets were annotated in all categories (x = 8.02, sd = 2.56, p = 7.75 × 10−4). Notably, none of the prioritized genes are represented among the 59 genes compiled by the ACMG, and 78% had a pathogenic or likely pathogenic variant in ClinVar. Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing.

scholarly journals Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

2019 ◽  
Author(s):  
Kunling Huang ◽  
Yuchang Wu ◽  
Junha Shin ◽  
Ye Zheng ◽  
Alireza Fotuhi Siahpirani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Transmission Disequilibrium ◽  
Fold Enrichment ◽  
Common Genetic Variants ◽  
Regulated Gene Expression

AbstractRecent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p=2.1e-7), a transcription factor (TF) mainly expressed in developmental brain. TF targets regulated by POU3F2 showed a 2.1-fold enrichment for known ASD genes (p=4.6e-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p=7.1e-5). These results provide a clear example of the connection between ASD genes affected by very rare mutations and an unlinked key regulator affected by common genetic variations.

scholarly journals Deletion Involving the 7q31-32 Band at the CADPS2 Gene Locus in a Patient with Autism Spectrum Disorder and Recurrent Psychotic Syndrome Triggered by Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Paulo André Pera Grabowski ◽  
Alexandre Ferreira Bello ◽  
Diogo Lima Rodrigues ◽  
Murilo José Forbeci ◽  
Vinicius Motter ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gene Locus ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Language Communication ◽  
And Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impairments in social functioning, language, communication, and behavior. Recent genome-wide association studies show some microdeletions on the 7q31-32 region, including the CADPS2 locus in autistic patients. This paper reports the case of a patient with ASD and recurrent psychotic syndrome, in which a deletion on the 7q31-32 band at the CADPS2 gene locus was evidenced, as well as a brief review of the literature on the CADPS2 gene and its association with ASD.

scholarly journals Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009309
Author(s):  
Kunling Huang ◽  
Yuchang Wu ◽  
Junha Shin ◽  
Ye Zheng ◽  
Alireza Fotuhi Siahpirani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Transcription Factor ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Transmission Disequilibrium ◽  
Fold Enrichment ◽  
Common Genetic Variants ◽  
Regulated Gene Expression

Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.

scholarly journals Family-Based Genome-Wide Association Study of Autism Spectrum Disorder in Middle Eastern Families

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 761
Author(s):  
Yasser Al-Sarraj ◽  
Eman Al-Dous ◽  
Rowaida Z. Taha ◽  
Dina Ahram ◽  
Fouad Alshaban ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Genetic Architecture ◽  
Association Studies ◽  
Middle Eastern ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Neurodevelopmental Disease ◽  
Genome Wide

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by abnormalities in language and social communication with substantial clinical heterogeneity. Genetic factors play an important role in ASD with heritability estimated between 70% to 80%. Genome-wide association studies (GWAS) have identified multiple loci associated with ASD. However, most studies were performed on European populations and little is known about the genetic architecture of ASD in Middle Eastern populations. Here, we report the first GWAS of ASD in the Middle eastern population of Qatar. We analyzed 171 families with ASD, using linear mixed models adjusting for relatedness and other confounders. Results showed that common single nucleotide polymorphisms (SNP) in seven loci are associated with ASD (p < 1 × 10−5). Although the identified loci did not reach genome-wide significance, many of the top associated SNPs are located within or near genes that have been implicated in ASD or related neurodevelopmental disorders. These include GORASP2, GABBR2, ANKS6, THSD4, ERCC6L, ARHGEF6, and HDAC8. Additionally, three of the top associated SNPs were significantly associated with gene expression. We also found evidence of association signals in two previously reported ASD-susceptibility loci (rs10099100 and rs4299400). Our results warrant further functional studies and replication to provide further insights into the genetic architecture of ASD.

scholarly journals Can probiotics benefit young people with autism spectrum disorders?

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S282-S282
Author(s):  
Pooja Ramani ◽  
Regina Sala
Keyword(s):  
Autism Spectrum Disorder ◽  
Young People ◽  
Statistical Significance ◽  
Gastrointestinal Symptoms ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Sample Sizes ◽  
Autism Symptoms ◽  
Children With Asd

AimsThe aims are to evaluate the effectiveness of Probiotics on young people with Autism Spectrum Disorder.We hypothesized that there will be an improvement of the comorbid gastrointestinal symptoms that can accompany Autism Spectrum Disorder.We believe that the use of probiotics can exert bidirectional effects on the gut-brain axis which may result in improvements in core Autism symptoms.MethodA literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We used databases including OVID MEDLINE, Pubmed, EMBASE, AMED and the Cochrane register of controlled trials. Studies using Probiotics as a treatment for children with ASD were identified by key search terms; Child*, young person*, adoles*, teenagers, ASD, Autism Spectrum Disorder, Autism, Pervasive developmental disorder, PDD, Probiotics, Supplements, Lactobacillus, and Bifidobacterium. Inclusion criteria: Children of age range 2-18 with a diagnosis of ASD and having at least one gastrointestinal symptom were included. Exclusion criteria: The following were excluded: studies looking at Autism with interventions aside from Probiotics; studies where Probiotics were tested in conjunction with other interventions; studies where there were additional neurodevelopmental disorders.ResultTwelve studies identified all utilized probiotics. This included 7 Randomised Control Trials, 2 Open-Label studies, 1 pre and post-intervention design and 1 Case study. All RCTs gave probiotics or placebo to children.Ten studies showed an improvement in gastrointestinal symptoms. Six studies showed improvements in various behavioral measures. Four studies showed improvements in core autism symptoms. However, the sample sizes in these studies were not large enough to prove statistical significance.ConclusionNo studies showed an adverse reaction which indicates probiotics can be considered a safe treatment.The improvements in a variety of parameters imply probiotics a suitable adjunctive intervention that may help improve ASD core symptoms in young people as well as improving physical and behavioural comorbidities which in some cases was noted by parents.However, due to high dropout rates and generally small sample sizes, larger-scale trials are needed to critically confirm the efficacy of probiotics for children with ASD.

scholarly journals Brief Report: Preferred Processing of Social Stimuli in Autism: A Perception Task

2021 ◽  
Author(s):  
A. Meermeier ◽  
M. Jording ◽  
Y. Alayoubi ◽  
David H. V. Vogel ◽  
K. Vogeley ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Exploratory Analysis ◽  
Spectrum Disorder ◽  
Social Stimuli ◽  
Future Studies ◽  
Perception Task ◽  
Social Images

AbstractIn this study we investigate whether persons with autism spectrum disorder (ASD) perceive social images differently than control participants (CON) in a graded perception task in which stimuli emerged from noise before dissipating into noise again. We presented either social stimuli (humans) or non-social stimuli (objects or animals). ASD were slower to recognize images during their emergence, but as fast as CON when indicating the dissipation of the image irrespective of its content. Social stimuli were recognized faster and remained discernable longer in both diagnostic groups. Thus, ASD participants show a largely intact preference for the processing of social images. An exploratory analysis of response subsets reveals subtle differences between groups that could be investigated in future studies.

scholarly journals Vocal markers of Autism Spectrum Disorder: assessing the generalizability of machine learning models

2021 ◽  
Author(s):  
Astrid Rybner ◽  
Emil Trenckner Jessen ◽  
Marie Damsgaard Mortensen ◽  
Stine Nyhus Larsen ◽  
Ruth Grossman ◽  
...  
Keyword(s):  
Machine Learning ◽  
Autism Spectrum Disorder ◽  
Model Performance ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Future Studies ◽  
Out Of Sample ◽  
Biobehavioral Markers ◽  
Similar Task ◽  
Machine Learning Models

Background: Machine learning (ML) approaches show increasing promise to identify vocal markers of Autism Spectrum Disorder (ASD). Nonetheless, it is unclear to what extent such markers generalize to new speech samples collected in diverse settings such as using a different speech task or a different language. Aim: In this paper, we systematically assess the generalizability of ML findings across a variety of contexts. Methods: We re-train a promising published ML model of vocal markers of ASD on novel cross-linguistic datasets following a rigorous pipeline to minimize overfitting, including cross-validated training and ensemble models. We test the generalizability of the models by testing them on i) different participants from the same study, performing the same task; ii) the same participants, performing a different (but similar) task; iii) a different study with participants speaking a different language, performing the same type of task. Results: While model performance is similar to previously published findings when trained and tested on data from the same study (out-of-sample performance), there is considerable variance between studies. Crucially, the models do not generalize well to new similar tasks and not at all to new languages. The ML pipeline is openly shared. Conclusion: Generalizability of ML models of vocal markers - and more generally biobehavioral markers - of ASD is an issue. We outline three recommendations researchers could take in order to be more explicit about generalizability and improve it in future studies.

Sign in / Sign up

Export Citation Format

Share Document