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 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 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 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 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 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 An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

2018 ◽  
Vol 50 (5) ◽  
pp. 727-736 ◽  
Author(s):  
Donna M. Werling ◽  
Harrison Brand ◽  
Joon-Yong An ◽  
Matthew R. Stone ◽  
Lingxue Zhu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Genome Sequence ◽  
Association Studies ◽  
Analytical Framework ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Whole Genome Sequence ◽  
Whole Genome

scholarly journals The bidirectional causal relationships of insomnia with five major psychiatric disorders: A Mendelian randomization study

2019 ◽  
Vol 60 ◽  
pp. 79-85 ◽  
Author(s):  
Xue Gao ◽  
Ling-Xian Meng ◽  
Kai-Li Ma ◽  
Jie Liang ◽  
Hui Wang ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Bipolar Disorder ◽  
Confidence Interval ◽  
Psychiatric Disorders ◽  
Mendelian Randomization ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Outcome Variable ◽  
Genome Wide Association Studies ◽  
Causal Relationships

AbstractBackground:Several observational studies have investigated the association of insomnia with psychiatric disorders. Such studies yielded mixed results, and whether these associations are causal remains unclear. Thus, we aimed to identify the causal relationships between insomnia and five major psychiatric disorders.Methods:The analysis was implemented with six genome-wide association studies; one for insomnia and five for psychiatric disorders (attention-deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder, schizophrenia, and bipolar disorder). A heterogeneity in dependent instrument (HEIDI) approach was used to remove the pleiotropic instruments, Mendelian randomization (MR)-Egger regression was adopted to test the validity of the screened instruments, and bidirectional generalized summary data-based MR was performed to estimate the causal relationships between insomnia and these major psychiatric disorders.Results:We observed significant causal effects of insomnia on the risk of autism spectrum disorder and bipolar disorder, with odds ratios of 1.739 (95% confidence interval: 1.217–2.486, p = 0.002) and 1.786 (95% confidence interval: 1.396–2.285, p = 4.02 × 10−6), respectively. There was no convincing evidence of reverse causality for insomnia with these two disorders (p = 0.945 and 0.546, respectively). When insomnia was considered as either the exposure or outcome variable, causal estimates for the remaining three psychiatric disorders were not significant.Conclusions:Our results suggest a causal role of insomnia in autism spectrum disorder and bipolar disorder. Future disease models should include insomnia as a factor for these two disorders to develop effective interventions. More detailed mechanism studies may also be inspired by this causal inference.

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

2019 ◽  
Vol 215 (5) ◽  
pp. 647-653 ◽  
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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