scholarly journals Investigating genetic links between grapheme–colour synaesthesia and neuropsychiatric traits

2019 ◽  
Vol 374 (1787) ◽  
pp. 20190026 ◽  
Author(s):  
Amanda K. Tilot ◽  
Arianna Vino ◽  
Katerina S. Kucera ◽  
Duncan A. Carmichael ◽  
Loes van den Heuvel ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Autism Spectrum ◽  
Negative Control ◽  
Genomic Variation ◽  
Sensory Sensitivity ◽  
Sensory Experiences ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Prior Literature ◽  
Family Based

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia ( n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R 2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R 2 = 0.00092, empirical p = 0.54) or body mass index ( R 2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue ‘Bridging senses: novel insights from synaesthesia'.

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

scholarly journals Genome-wide Polygenic Scores for Multiple Psychiatric and Common Traits Identify Preadolescent Youth with Risk for Suicide

2021 ◽  
Author(s):  
Yoonjung Yoonie Joo ◽  
Seo-Yoon Moon ◽  
Hee-Hwan Wang ◽  
Hyeonjin Kim ◽  
Eun-Ji Lee ◽  
...  
Keyword(s):  
Machine Learning ◽  
Suicidal Ideation ◽  
Family Environment ◽  
Autism Spectrum ◽  
Cognitive Capacity ◽  
European Ancestry ◽  
Environment Interaction ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Preadolescent Youth

Abstract Importance. Suicide is the second leading cause of death in children worldwide but no available means exist to identify the risk in youth. Objective. To predict the risk of suicide in children and to investigate whether and to what extents genetic factors and a major environmental risk factor, early life stress(ELS), influence youth suicide. Design, Setting and Participants. We analyzed the genotype-phenotype data of 11,869 preadolescent children ages 9- to 10-year-old from the Adolescent Brain and Cognitive Development (ABCD) study. We estimated genome-wide polygenic scores (GPSs) of 25 complex traits to investigate their phenome-wide associations and predictive utility with suicidality (suicidal ideation and attempt) with machine learning approaches. Predictors. GPSs of 25 traits including psychiatric disorders, personality, cognitive capacity, and psychological traits. Parent Child Behavior Checklist to measure ELS in youth and Youth Family Environment Scale to assess family environment. Main outcomes and Measures. Records of suicidal ideation and attempt of the participants were derived from the computerized version of Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Results. We identified three GPSs associated with youth suicidality in multiethnic (n = 7,206) and European-ancestry (n = 5,749) participants: ADHD (P = 3.48x10− 4; odds ratio = 1.13 in multiethnic participants, P = 5.60x10− 5, OR = 1.25 in European-ancestry participants), general happiness (P = 1.43x10− 3; OR = 0.89 in multiethnic, P = 8.61x10− 4, OR = 0.89 in European) and autism spectrum disorder(ASD) (P = 1.81x10− 3; OR = 1.15 in multiethnic, P = 1.26x10− 3, OR = 1.18 in European). We also found a significant GPS-by-environment interaction between the effects of genetic risk factors for ASD and the level of ELS in increasing the risk for suicidal ideation (P = 1.36x10− 2, OR = 1.12 in multiethnic, P = 1.39x10− 3, OR = 1.19 in European). A machine learning model trained on the same data showed moderately accurate prediction of children with overall suicidal ideation with a test ROC-AUC of 0.727 (0.746 in European), and with suicidal attempts with a test ROC-AUC of 0.641 (0.975 in European) in held-out samples. Conclusions and Relevance. This study provides the first quantitative account of polygenic and environmental factors of suicidality in a large, representative population of preadolescent youth. It thus shows the potential utility of the GPSs in identifying a child with high risk for suicidality for early screening, intervention, and prevention.

scholarly journals Polygenic profiles define aspects of clinical heterogeneity in ADHD

2021 ◽  
Author(s):  
Andrew Schork ◽  
Sonja LaBianca ◽  
Isabell Brickell ◽  
Dorte Helenius ◽  
Robert Loughnan ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Clinical Heterogeneity ◽  
Behavioral Traits ◽  
Complex Disorder ◽  
Novel Approach ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Significant Locus ◽  
Unique Approach ◽  
Genetic Contributions

Abstract Attention deficit hyperactivity disorder (ADHD) is a complex disorder with heterogeneous clinical presentations that manifest variability in long-term outcomes. The genetic contributions to this clinical heterogeneity, however, are not well understood. Here, we study 14 084 individuals diagnosed with ADHD to identify several genetic factors underlying clinical heterogeneity. One genome-wide significant locus was specifically associated with an autism spectrum disorder (ASD) diagnosis among individuals diagnosed with ADHD and it was not previously associated with ASD nor ADHD, individually. We used a novel approach to compare profiles of polygenic scores for groups of individuals diagnosed with ADHD and uncovered robust evidence that biology is an important factor in on-going clinical debates. Specifically, individuals diagnosed with ASD and ADHD, substance use disorder (SUD) and ADHD, or first diagnosed with ADHD in adulthood had different profiles of polygenic scores for ADHD and multiple other psychiatric, cognitive, and socio-behavioral traits. A polygene overlap between an ASD diagnosis in ADHD and cognitive performance was replicated in an independent, typically developing cohort. Our unique approach uncovered evidence of genetic heterogeneity in a widely studied complex disorder, allowing for timely contributions to the understanding of ADHD etiology and providing a model for similar studies of other disorders.

scholarly journals Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

2019 ◽  
Vol 28 (13) ◽  
pp. 2201-2211 ◽  
Author(s):  
Chloe C Y Wong ◽  
Rebecca G Smith ◽  
Eilis Hannon ◽  
Gokul Ramaswami ◽  
Neelroop N Parikshak ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Genomic Variation ◽  
Molecular Signatures ◽  
Post Mortem ◽  
Human Brain Tissue ◽  
Genome Wide ◽  
Syndromic Autism

Abstract Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

scholarly journals Polygenic profiles define aspects of clinical heterogeneity in ADHD

2021 ◽  
Author(s):  
Sonja LaBianca ◽  
Isabell Brikell ◽  
Dorte Helenius ◽  
Robert John Loughnan ◽  
Joel Mefford ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Clinical Heterogeneity ◽  
Behavioral Traits ◽  
Complex Disorder ◽  
Novel Approach ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Significant Locus ◽  
Unique Approach ◽  
Genetic Contributions

Attention deficit hyperactivity disorder (ADHD) is a complex disorder with heterogeneous clinical presentations that manifest variability in long-term outcomes. The genetic contributions to this clinical heterogeneity, however, are not well understood. Here, we study 14 084 individuals diagnosed with ADHD to identify several genetic factors underlying clinical heterogeneity. One genome-wide significant locus was specifically associated with an autism spectrum disorder (ASD) diagnosis among individuals diagnosed with ADHD and it was not previously associated with ASD nor ADHD, individually. We used a novel approach to compare profiles of polygenic scores for groups of individuals diagnosed with ADHD and uncovered robust evidence that biology is an important factor in on-going clinical debates. Specifically, individuals diagnosed with ASD and ADHD, substance use disorder (SUD) and ADHD, or first diagnosed with ADHD in adulthood had different profiles of polygenic scores for ADHD and multiple other psychiatric, cognitive, and socio-behavioral traits. A polygene overlap between an ASD diagnosis in ADHD and cognitive performance was replicated in an independent, typically developing cohort. Our unique approach uncovered evidence of genetic heterogeneity in a widely studied complex disorder, allowing for timely contributions to the understanding of ADHD etiology and providing a model for similar studies of other disorders.

scholarly journals Genome-wide association study of suicide death and polygenic prediction of clinical antecedents

2017 ◽  
Author(s):  
Anna R. Docherty ◽  
Andrey A. Shabalin ◽  
Emily DiBlasi ◽  
Eric Monson ◽  
Niamh Mullins ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Case Control ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Behavioral Disinhibition ◽  
Suicide Death ◽  
Polygenic Score ◽  
Death Case ◽  
Genome Wide ◽  
Polygenic Scores

ABSTRACTObjectiveSuicide death is a highly preventable, yet growing, worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizeable suicide death cohorts available for study. To address this limitation, we conducted the first comprehensive genomic analysis of suicide death, using a previously unpublished suicide cohort.MethodsThe analysis sample consisted of 3,413 population-ascertained cases of European ancestry and 14,810 ancestrally matched controls. Analytical methods included principle components analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic relatedness matrix), gene and gene set enrichment testing, polygenic score analyses, as well as SNP heritability and genetic correlation estimation using LD score regression.ResultsGWAS identified two genome-wide significant loci (6 SNPs, p<5×10−8). Gene-based analyses implicated 19 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide heritability was estimated h2 =0.2463, SE = 0.0356 using summary statistics from a multivariate logistic GWAS adjusting for ancestry. Notably, suicide polygenic scores were robustly predictive of out of sample suicide death, as were polygenic scores for several other psychiatric disorders and psychological traits, particularly behavioral disinhibition and major depressive disorder.ConclusionsIn this report, we identify multiple genome-wide significant loci/genes, and demonstrate robust polygenic score prediction of suicide death case-control status, adjusting for ancestry, in independent training and test sets. Additionally, we report that suicide death cases have increased genetic risk for behavioral disinhibition, major depression, autism spectrum disorder, psychosis, and alcohol use disorder relative to controls. Results demonstrate the ability of polygenic scores to robustly, and multidimensionally, predict suicide death case-control status.

scholarly journals Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in post-mortem human brain tissue

2018 ◽  
Author(s):  
Chloe C.Y. Wong ◽  
Rebecca G. Smith ◽  
Eilis Hannon ◽  
Gokul Ramaswami ◽  
Neelroop N. Parikshak ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Genomic Variation ◽  
Molecular Signatures ◽  
Post Mortem ◽  
Human Brain Tissue ◽  
Systematic Analysis ◽  
Genome Wide

AbstractAutism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

scholarly journals Genome-wide Polygenic Scores for Multiple Psychiatric and Common Traits Identify Preadolescent Youth with Risk for Suicide

2020 ◽  
Author(s):  
Yoonjung Yoonie Joo ◽  
Seo-Yoon Moon ◽  
Hee-Hwan Wang ◽  
Hyeonjin Kim ◽  
Eun-Ji Lee ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Life Stress ◽  
Odds Ratio ◽  
Area Under The Curve ◽  
Autism Spectrum ◽  
Environment Interaction ◽  
Early Screening ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Preadolescent Youth

Abstract Suicide is a leading cause of death in youth worldwide, but identifying which youth are at high risk for suicide remains challenging. We constructed genome-wide polygenic scores (GPSs) from 24 psychiatric disorders and common traits from 8,212 US preadolescent children ages 9 to 10 and investigated their associations and predictive utility with suicidality (suicidal ideation and attempt). We identified three GPSs significantly associated with youth suicidality: ADHD (P=2.83x10-4; odds ratio=1.12), general happiness with a belief that life is meaningful (P=1.30x10-3; odds ratio=0.89) and autism spectrum disorder (ASD) (P=1.81x10-3; odds ratio=1.14). We also found a significant gene-by-environment interaction such that the GPS of ASD in the context of early life stress substantially increased suicidal ideation (P=1.39x10-2, odds ratio=1.11). Machine learning models showed, in predicting suicidal ideation, a receiver operators characteristics-area under the curve (ROC-AUC) of 0.72, and, in suicidal attempts, a ROC-AUC of 0.765. By providing the first quantitative account of the polygenic and environmental factors of suicidality in a large, representative population of preadolescent youth, this study shows the potential utility of the GPSs in investigating youth suicidality for early screening, intervention, and prevention.

scholarly journals Association between polygenic propensity for psychiatric disorders and nutrient intake

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Avina K. Hunjan ◽  
Christopher Hübel ◽  
Yuhao Lin ◽  
Thalia C. Eley ◽  
Gerome Breen
Keyword(s):  
Psychiatric Disorders ◽  
Nutrient Intake ◽  
Autism Spectrum ◽  
Dietary Behaviour ◽  
Obsessive Compulsive ◽  
Higher Alcohol ◽  
Polygenic Score ◽  
Compulsive Disorder ◽  
Genome Wide ◽  
Polygenic Scores

AbstractDespite the observed associations between psychiatric disorders and nutrient intake, genetic studies are limited. We examined whether polygenic scores for psychiatric disorders are associated with nutrient intake in UK Biobank (N = 163,619) using linear mixed models. We found polygenic scores for attention-deficit/hyperactivity disorder, bipolar disorder, and schizophrenia showed the highest number of associations, while a polygenic score for autism spectrum disorder showed no association. The relatively weaker obsessive-compulsive disorder polygenic score showed the greatest effect sizes suggesting its association with diet traits may become more apparent with larger genome-wide analyses. A higher alcohol dependence polygenic score was associated with higher alcohol intake and individuals with higher persistent thinness polygenic scores reported their food to weigh less, both independent of socioeconomic status. Our findings suggest that polygenic propensity for a psychiatric disorder is associated with dietary behaviour. Note, nutrient intake was self-reported and findings must therefore be interpreted mindfully.

scholarly journals Analysis of common genetic variation and rare CNVs in the Australian Autism Biobank

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chloe X. Yap ◽  
Gail A. Alvares ◽  
Anjali K. Henders ◽  
Tian Lin ◽  
Leanne Wallace ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Autism Spectrum ◽  
Research Centre ◽  
Summary Statistics ◽  
Uk Biobank ◽  
Common Genetic Variation ◽  
Cooperative Research ◽  
Rare Cnvs ◽  
Genome Wide ◽  
Polygenic Scores

Abstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition whose biological basis is yet to be elucidated. The Australian Autism Biobank (AAB) is an initiative of the Cooperative Research Centre for Living with Autism (Autism CRC) to establish an Australian resource of biospecimens, phenotypes and genomic data for research on autism. Methods Genome-wide single-nucleotide polymorphism genotypes were available for 2,477 individuals (after quality control) from 546 families (436 complete), including 886 participants aged 2 to 17 years with diagnosed (n = 871) or suspected (n = 15) ASD, 218 siblings without ASD, 1,256 parents, and 117 unrelated children without an ASD diagnosis. The genetic data were used to confirm familial relationships and assign ancestry, which was majority European (n = 1,964 European individuals). We generated polygenic scores (PGS) for ASD, IQ, chronotype and height in the subset of Europeans, and in 3,490 unrelated ancestry-matched participants from the UK Biobank. We tested for group differences for each PGS, and performed prediction analyses for related phenotypes in the AAB. We called copy-number variants (CNVs) in all participants, and intersected these with high-confidence ASD- and intellectual disability (ID)-associated CNVs and genes from the public domain. Results The ASD (p = 6.1e−13), sibling (p = 4.9e−3) and unrelated (p = 3.0e−3) groups had significantly higher ASD PGS than UK Biobank controls, whereas this was not the case for height—a control trait. The IQ PGS was a significant predictor of measured IQ in undiagnosed children (r = 0.24, p = 2.1e−3) and parents (r = 0.17, p = 8.0e−7; 4.0% of variance), but not the ASD group. Chronotype PGS predicted sleep disturbances within the ASD group (r = 0.13, p = 1.9e−3; 1.3% of variance). In the CNV analysis, we identified 13 individuals with CNVs overlapping ASD/ID-associated CNVs, and 12 with CNVs overlapping ASD/ID/developmental delay-associated genes identified on the basis of de novo variants. Limitations This dataset is modest in size, and the publicly-available genome-wide-association-study (GWAS) summary statistics used to calculate PGS for ASD and other traits are relatively underpowered. Conclusions We report on common genetic variation and rare CNVs within the AAB. Prediction analyses using currently available GWAS summary statistics are largely consistent with expected relationships based on published studies. As the size of publicly-available GWAS summary statistics grows, the phenotypic depth of the AAB dataset will provide many opportunities for analyses of autism profiles and co-occurring conditions, including when integrated with other omics datasets generated from AAB biospecimens (blood, urine, stool, hair).

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