scholarly journals Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

2019 ◽  
Author(s):  
Ellen Verhoef ◽  
Jakob Grove ◽  
Chin Yang Shapland ◽  
Ditte Demontis ◽  
Stephen Burgess ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Association Patterns ◽  
Hyperactivity Disorder ◽  
Risk Alleles ◽  
Genome Wide ◽  
Genetic Overlap ◽  
Multivariable Regression ◽  
Shared Risk ◽  
Insight Into ◽  
Polygenic Variation

AbstractInsight into shared polygenetic architectures affects our understanding of neurodevelopmental disorders. Here, we investigate evidence for pleiotropic mechanisms that may explain the comorbidity between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). These complex neurodevelopmental conditions often co-occur, but differ in their polygenetic association patterns, especially with educational attainment (EA), showing discordant association effects. Using multivariable regression analyses and existing genome-wide summary statistics based on 10,610 to 766,345 individuals, we demonstrate that EA-related polygenic variation is shared between ASD and ADHD. We show that different combinations of the same ASD and ADHD risk-increasing alleles can simultaneously re-capture known ASD-related positive and ADHD-related negative associations with EA. Such patterns, although to a lesser degree, were also present for combinations of other psychiatric disorders. These findings suggest pleiotropic mechanisms, where the same polygenic sites can encode multiple independent, even discordant, association patterns without involving distinct loci, and have implications for cross-disorder investigations.

scholarly journals Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ellen Verhoef ◽  
Jakob Grove ◽  
Chin Yang Shapland ◽  
Ditte Demontis ◽  
Stephen Burgess ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Genetic Correlations ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Risk Variants ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Multivariable Regression ◽  
Marker Alleles ◽  
Independent Effects

AbstractAutism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610–766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions.

scholarly journals Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

2021 ◽  
Author(s):  
Daniel Roelfs ◽  
Dennis van der Meer ◽  
Dag Alnæs ◽  
Oleksandr Frei ◽  
Robert Loughnan ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Brain Connectivity ◽  
Autism Spectrum ◽  
Genetic Determinants ◽  
Functional Brain ◽  
Hyperactivity Disorder ◽  
Genome Wide ◽  
Genetic Overlap ◽  
The Uk ◽  
Shared Genetic

Psychiatric disorders are complex, heritable, and highly polygenic. Supported by findings of abnormalities in functional magnetic resonance imaging (fMRI) based measures of brain connectivity, current theoretical and empirical accounts have conceptualized them as disorders of brain connectivity and dysfunctional integration of brain signaling, however, the extent to which these findings reflect common genetic factors remains unclear. Here, we performed a multivariate genome-wide association analysis of fMRI-based functional brain connectivity in a sample of 30,701 individuals from the UK Biobank and investigated the shared genetic determinants with seven major psychiatric disorders. The analysis revealed significant genetic overlap between functional brain connectivity and schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety, and major depression, adding further genetic support for the dysconnectivity hypothesis of psychiatric disorders and identifying potential genetic and functional targets for future studies.

scholarly journals An approach to gene-based testing accounting for dependence of tests among nearby genes

2021 ◽  
Author(s):  
Ronald J Yurko ◽  
Kathryn Roeder ◽  
Bernie Devlin ◽  
Max G'Sell
Keyword(s):  
Multiple Testing ◽  
Association Studies ◽  
Autism Spectrum ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Strongly Correlated ◽  
Test Statistics ◽  
Test Statistic ◽  
Genome Wide ◽  
Insight Into

In genome-wide association studies (GWAS), it has become commonplace to test millions of SNPs for phenotypic association. Gene-based testing can improve power to detect weak signal by reducing multiple testing and pooling signal strength. While such tests account for linkage disequilibrium (LD) structure of SNP alleles within each gene, current approaches do not capture LD of SNPs falling in different nearby genes, which can induce correlation of gene-based test statistics. We introduce an algorithm to account for this correlation. When a gene's test statistic is independent of others, it is assessed separately; when test statistics for nearby genes are strongly correlated, their SNPs are agglomerated and tested as a locus. To provide insight into SNPs and genes driving association within loci, we develop an interactive visualization tool to explore localized signal. We demonstrate our approach in the context of weakly powered GWAS for autism spectrum disorder, which is contrasted to more highly powered GWAS for schizophrenia and educational attainment. To increase power for these analyses, especially those for autism, we use adaptive p-value thresholding (AdaPT), guided by high-dimensional metadata modeled with gradient boosted trees, highlighting when and how it can be most useful. Notably our workflow is based on summary statistics.

scholarly journals Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia

2013 ◽  
Vol 203 (2) ◽  
pp. 107-111 ◽  
Author(s):  
Marian L. Hamshere ◽  
Evangelia Stergiakouli ◽  
Kate Langley ◽  
Joanna Martin ◽  
Peter Holmans ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Genetic Susceptibility ◽  
Attention Deficit ◽  
Genome Wide Association Study ◽  
Research Work ◽  
Data Set ◽  
Hyperactivity Disorder ◽  
Risk Alleles ◽  
Genome Wide ◽  
Shared Genetic

BackgroundThere is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.AimsTo determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.MethodWe used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.ResultsSchizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).ConclusionsThis increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.

scholarly journals Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics

2019 ◽  
Vol 86 (4) ◽  
pp. 265-273 ◽  
Author(s):  
Oliver Pain ◽  
Andrew J. Pocklington ◽  
Peter A. Holmans ◽  
Nicholas J. Bray ◽  
Heath E. O’Brien ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association ◽  
Expression Data ◽  
Genome Wide ◽  
Insight Into

scholarly journals Visual search in neurodevelopmental disorders: evidence towards a continuum of impairment

2021 ◽  
Author(s):  
Daniela Canu ◽  
Chara Ioannou ◽  
Katarina Müller ◽  
Berthold Martin ◽  
Christian Fleischhaker ◽  
...  
Keyword(s):  
Visual Search ◽  
Cognitive Impairments ◽  
Autism Spectrum ◽  
Phenotypic Differences ◽  
Hyperactivity Disorder ◽  
Genetic Overlap ◽  
Search Processes ◽  
Neurodevelopmental Impairment ◽  
Highly Correlated ◽  
Developmental Features

AbstractDisorders with neurodevelopmental aetiology such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Schizophrenia share commonalities at many levels of investigation despite phenotypic differences. Evidence of genetic overlap has led to the concept of a continuum of neurodevelopmental impairment along which these disorders can be positioned in aetiological, pathophysiological and developmental features. This concept requires their simultaneous comparison at different levels, which has not been accomplished so far. Given that cognitive impairments are core to the pathophysiology of these disorders, we provide for the first time differentiated head-to-head comparisons in a complex cognitive function, visual search, decomposing the task with eye movement-based process analyses. N = 103 late-adolescents with schizophrenia, ADHD, ASD and healthy controls took a serial visual search task, while their eye movements were recorded. Patients with schizophrenia presented the greatest level of impairment across different phases of search, followed by patients with ADHD, who shared with patients with schizophrenia elevated intra-subject variability in the pre-search stage. ASD was the least impaired group, but similar to schizophrenia in post-search processes and to schizophrenia and ADHD in pre-search processes and fixation duration while scanning the items. Importantly, the profiles of deviancy from controls were highly correlated between all three clinical groups, in line with the continuum idea. Findings suggest the existence of one common neurodevelopmental continuum of performance for the three disorders, while quantitative differences appear in the level of impairment. Given the relevance of cognitive impairments in these three disorders, we argue in favour of overlapping pathophysiological mechanisms.

scholarly journals Genome‐wide analysis reveals genetic overlap between alcohol use behaviors, schizophrenia and bipolar disorder and identifies novel shared risk loci

Addiction ◽  
2021 ◽  
Author(s):  
Erik D. Wiström ◽  
Kevin S. O’Connell ◽  
Naz Karadag ◽  
Shahram Bahrami ◽  
Guy F. L. Hindley ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Alcohol Use ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Genetic Overlap ◽  
Shared Risk

scholarly journals Identifying Loci for the Overlap Between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Using a Genome-wide QTL Linkage Approach

2010 ◽  
Vol 49 (7) ◽  
pp. 675-685 ◽  
Author(s):  
Judith S. Nijmeijer ◽  
Alejandro Arias-Vásquez ◽  
Nanda N.J. Rommelse ◽  
Marieke E. Altink ◽  
Richard J.L. Anney ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Hyperactivity Disorder ◽  
Genome Wide ◽  
A Genome

scholarly journals Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1940 ◽  
Author(s):  
Scott J Myers ◽  
Hongjie Yuan ◽  
Jing-Qiong Kang ◽  
Francis Chee Kuan Tan ◽  
Stephen F Traynelis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Clinical Phenotypes ◽  
Hyperactivity Disorder ◽  
Functional Consequences ◽  
Spectrum Disorders ◽  
Circuit Function ◽  
Available Information ◽  
Insight Into

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

scholarly journals Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

2020 ◽  
Author(s):  
Hugo Peyre ◽  
Tabea Schoeler ◽  
Chaoyu Liu ◽  
Camille Michèle Williams ◽  
Nicolas Hoertel ◽  
...  
Keyword(s):  
Structural Equation ◽  
Association Studies ◽  
Autism Spectrum ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hyperactivity Disorder ◽  
Risk Variants ◽  
Genome Wide ◽  
Summary Data ◽  
Shared Genetic

ABSTRACTBackgroundSeveral lines of evidence point toward the presence of shared genetic factors underlying Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, Genome-Wide Association Studies (GWAS) have yet to identify risk variants (i.e. Single-Nucleotide Polymorphisms, SNPs) shared by ADHD and ASD.MethodsTwo complementary multivariate analyses – genomic structural equation modelling (SEM) and colocalization analysis – were exploited to identify the shared SNPs for ASD and ADHD, using summary data from two independent GWAS of ASD (N=46,350) and ADHD individuals (N=55,374).ResultsGenomic SEM identified 7 novel SNPs shared between ASD and ADHD (pgenome-wide<5e-8), including three SNPs that were not identified in any of the original univariate GWAS of ASD and ADHD (rs227378, rs2391769 and rs325506). We also mapped 4 novel genes (MANBA, DPYD, INSM1, and PAX1) to SNPs shared by ASD and ADHD, as well as 4 genes that had already been mapped to SNPs identified in either ASD or ADHD GWAS (SORCS3, XRN2, PTBP2 and NKX2-4). All the shared genes between ADHD and ASD were more prominently expressed in the brain than the genes mapped to SNPs specific to ASD or ADHD. Colocalization analyses revealed that 44% percent of the SNPs associated with ASD (p<1e-6) colocalized with ADHD SNPs and 26% of the SNPs associated with ADHD (p<1e-6) colocalized with ASD SNPs.ConclusionsUsing multivariate genomic analyses, the present study reveals the shared genetic pathways that underlie ASD and ADHD. Further investigation of these pathways may help identify new targets for treatment of these disorders.

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