scholarly journals Genetic Association Study of Childhood Aggression across raters, instruments and age

2019 ◽  
Author(s):  
Hill F. Ip ◽  
Camiel M. van der Laan ◽  
Eva M. L. Krapohl ◽  
Isabell Brikell ◽  
Cristina Sánchez-Mora ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Genetic Correlations ◽  
Childhood Aggression ◽  
Age At First Birth ◽  
Nucleotide Polymorphisms ◽  
Obsessive Compulsive ◽  
Psychological Traits ◽  
Compulsive Disorder ◽  
Genome Wide ◽  
Polygenic Scores

AbstractBackgroundHuman aggressive behavior (AGG) has a substantial genetic component. Here we present a large genome-wide association meta-analysis (GWAMA) of childhood AGG.MethodsWe analyzed assessments of AGG for a total of 328,935 observations from 87,485 children (aged 1.5 – 18 years), from multiple assessors, instruments, and ages, while accounting for sample overlap. We performed an overall analysis and meta-analyzed subsets of the data within rater, instrument, and age.ResultsHeritability based on the overall meta-analysis (AGGall) that could be attributed to Single Nucleotide Polymorphisms (SNPs) was 3.31% (SE=0.0038). No single SNP reached genome-wide significance, but gene-based analysis returned three significant genes: ST3GAL3 (P=1.6E-06), PCDH7 (P=2.0E-06) and IPO13 (P=2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children and in retrospectively assessed childhood aggression. We obtained moderate-to-strong genetic correlations (rg‘s) with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19 –.1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg =∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg|: 0.46 – 0.60). Genetic correlations between AGG and psychiatric disorders were strongest for mother- and self-reported AGG.ConclusionsThe current GWAMA of childhood aggression provides a powerful tool to interrogate the genetic etiology of AGG by creating individual polygenic scores and genetic correlations with psychiatric traits.

scholarly journals Genetic association study of childhood aggression across raters, instruments, and age

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hill F. Ip ◽  
Camiel M. van der Laan ◽  
Eva M. L. Krapohl ◽  
Isabell Brikell ◽  
Cristina Sánchez-Mora ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Genetic Correlations ◽  
Teacher Assessment ◽  
Childhood Aggression ◽  
Age At First Birth ◽  
Psychological Traits ◽  
Compulsive Disorder ◽  
Genome Wide ◽  
A Genome ◽  
Variance Explained

AbstractChildhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

scholarly journals Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

2020 ◽  
Author(s):  
Eshim S Jami ◽  
Anke R Hammerschlag ◽  
Hill F Ip ◽  
Andrea G Allegrini ◽  
Beben Benyamin ◽  
...  
Keyword(s):  
Confidence Intervals ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Genetic Effects ◽  
Childhood Aggression ◽  
Genome Wide Association ◽  
Childhood And Adolescence ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Genome Wide

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses showed rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Gene-based analyses showed significant associations with three genes: WNT3 (p=1.13×10-06), CCL26 (p=1.88×10-06), and CENPO (p=2.54×10-06). Of these, WNT3 was previously associated with neuroticism, with which INToverall also shared a strong genetic correlation (rg=0.76). Genetic correlations were also observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Overall, childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could explain both the persistence of internalising symptoms over time, and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

scholarly journals Genetic meta-analysis of obsessive-compulsive disorder and self-report compulsive symptoms

2019 ◽  
Author(s):  
Dirk J.A. Smit ◽  
Danielle Cath ◽  
Nuno R. Zilhão ◽  
Hill F. Ip ◽  
Damiaan Denys ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Genetic Correlations ◽  
Significant Snps ◽  
Population Based ◽  
Case Control ◽  
Reward Processing ◽  
Self Report ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Genome Wide

AbstractWe investigated whether obsessive compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing OCD. We performed a GWAS on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N=8267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case-control GWAS (rG=0.61, p=0.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (rG=–0.02 and rG=0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant SNPs (combined N=17992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, inclusion of dimensional symptom data in genome-wide association on clinical case-control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene-expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

scholarly journals Personality Polygenes, Positive Affect, and Life Satisfaction

2016 ◽  
Vol 19 (5) ◽  
pp. 407-417 ◽  
Author(s):  
Alexander Weiss ◽  
Bart M. L. Baselmans ◽  
Edith Hofer ◽  
Jingyun Yang ◽  
Aysu Okbay ◽  
...  
Keyword(s):  
Life Satisfaction ◽  
Positive Affect ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Genetic Influences ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Neo Five Factor Inventory ◽  
General Wellbeing ◽  
Human Primate

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximalN= 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.

scholarly journals Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Joey Ward ◽  
Laura M. Lyall ◽  
Richard A. I. Bethlehem ◽  
Amy Ferguson ◽  
Rona J. Strawbridge ◽  
...  
Keyword(s):  
White Matter ◽  
Psychiatric Disorders ◽  
Brain Structure ◽  
Genetic Correlations ◽  
Grey Matter Volume ◽  
Obsessive Compulsive ◽  
Major Depressive ◽  
Compulsive Disorder ◽  
Matter Volume ◽  
Genome Wide

AbstractAnhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson’s Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h2SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson’s Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.

scholarly journals Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure

2019 ◽  
Author(s):  
Joey Ward ◽  
Laura M. Lyall ◽  
Richard A. I. Bethlehem ◽  
Amy Ferguson ◽  
Rona J. Strawbridge ◽  
...  
Keyword(s):  
White Matter ◽  
Psychiatric Disorders ◽  
Brain Structure ◽  
Genetic Correlations ◽  
Grey Matter Volume ◽  
Obsessive Compulsive ◽  
Major Depressive ◽  
Compulsive Disorder ◽  
Matter Volume ◽  
Genome Wide

AbstractAnhedonia is a core feature of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson’s Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h2SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson’s Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including nucleus accumbens, caudate and medial frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this trait as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for anhedonia influences brain structure, particularly in regions associated with reward and pleasure processing.

scholarly journals Genome-wide analyses indirectly implicate miRNA regulatory mechanisms in Obsessive-compulsive Disorder psychopathology

2019 ◽  
Author(s):  
NW McGregor ◽  
KS O’Connell ◽  
L Davis ◽  
CA Mathews ◽  
C Lochner ◽  
...  
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Clinical Manifestation ◽  
Messenger Rna ◽  
Meta Analysis ◽  
Regulatory Mechanisms ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Small Noncoding Rnas ◽  
Genome Wide

ABSTRACTBackgroundMiRNAs are small, noncoding RNAs possessing the potential to modulate gene expression upon binding to their target messenger RNA (mRNA) constructs, and are known to play a role in the pathogenesis of a range of psychiatric disorders. To date, little work has focused on the role of miRNAs in obsessive-compulsive disorder (OCD). The aim of this study was to assess the potential involvement of miRNAs in OCD psychopathology.MethodsThe most significant variants (p ≤ 1×10−4) from the Psychiatric Genomics Consortium (PGC) TS/OCD Workgroup OCD meta-analysis were selected and investigated using miRBASE, TargetScan and SNPnexus to determine whether they influence miRNA- mediated regulation in the clinical manifestation of OCD.ResultsTwo-hundred and forty SNPs were identified from the PGC OCD summarystatistics, of which none were found to directly alter miRNA-related gene regulation using in silico analyses. Enrichment analyses identified several potential indirect miRNA-mediated targets associated with both increased (ITPR3: mir-124A) and decreased risk (GPR109A: mir-520A, and mir-525; CGNL1: mir-98 and mir-219).ConclusionmiRNA-mediated regulation was indirectly implicated in the psychopathology of OCD. Enrichment analyses implicates intracellular calcium and immune dysregulation in the clinical manifestation of the disorder and warrants further investigation of the role the immune system may play in the manifestation of disease.

scholarly journals Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness

2019 ◽  
Vol 28 (22) ◽  
pp. 3853-3865 ◽  
Author(s):  
Abdel Abdellaoui ◽  
Sandra Sanchez-Roige ◽  
Julia Sealock ◽  
Jorien L Treur ◽  
Jessica Dennis ◽  
...  
Keyword(s):  
Genetic Predisposition ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
High Density Lipoproteins ◽  
Physical And Mental Health ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Wide Range ◽  
Genetic Overlap

Abstract Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

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 Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

2019 ◽  
Author(s):  
◽  
Phil H. Lee ◽  
Verneri Anttila ◽  
Hyejung Won ◽  
Yen-Chen A. Feng ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Pleiotropic Effects ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Hyperactivity Disorder ◽  
Genome Wide ◽  
Genomic Relationships ◽  
The Brain

SummaryGenetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

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