scholarly journals Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

2021 ◽  
Author(s):  
William R Reay ◽  
Dylan J Kiltschewskij ◽  
Michael P Geaghan ◽  
Joshua R Atkins ◽  
Vaughan J Carr ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Study Data ◽  
Obsessive Compulsive ◽  
Biochemical Traits ◽  
Compulsive Disorder ◽  
Reactive Protein ◽  
Genome Wide ◽  
The Relationship

There is a long-standing interest in exploring the relationship between blood-based biomarkers of biological exposures and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable biochemical traits measured from serum to refine our understanding of causal effect in biochemical-psychiatric trait parings. In accordance with expectation we observed widespread evidence of positive and negative genetic correlation between psychiatric disorders and biochemical traits. We then implemented causal inference to distinguish causation from correlation and found strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders, along with other putatively causal relationships involving urate and glucose. Strikingly, these analyses suggested CRP has a protective effect on three disorders including anorexia nervosa, obsessive-compulsive disorder, and schizophrenia, whilst being a risk factor for major depressive disorder. Multivariable models that conditioned CRP effects on interleukin-6 signalling and body mass index suggested that CRP-schizophrenia relationship was not likely mediated by those factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness, including factors such as CRP that are likely to constitute a causal effect and could be targets for therapeutic intervention and precision medicine.

scholarly journals Significant concordance of genetic variation that increases both the risk for obsessive–compulsive disorder and the volumes of the nucleus accumbens and putamen

2018 ◽  
Vol 213 (1) ◽  
pp. 430-436 ◽  
Author(s):  
Derrek P. Hibar ◽  
Joshua W. Cheung ◽  
Sarah E. Medland ◽  
Mary S. Mufford ◽  
Neda Jahanshad ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Obsessive Compulsive Disorder ◽  
Genome Wide Association Study ◽  
Obsessive Compulsive ◽  
Brain Volumes ◽  
Compulsive Disorder ◽  
Subcortical Brain ◽  
Risk Variants ◽  
Genome Wide ◽  
The Relationship

BackgroundMany studies have identified changes in the brain associated with obsessive–compulsive disorder (OCD), but few have examined the relationship between genetic determinants of OCD and brain variation.AimsWe present the first genome-wide investigation of overlapping genetic risk for OCD and genetic influences on subcortical brain structures.MethodUsing single nucleotide polymorphism effect concordance analysis, we measured genetic overlap between the first genome-wide association study (GWAS) of OCD (1465 participants with OCD, 5557 controls) and recent GWASs of eight subcortical brain volumes (13 171 participants).ResultsWe found evidence of significant positive concordance between OCD risk variants and variants associated with greater nucleus accumbens and putamen volumes. When conditioning OCD risk variants on brain volume, variants influencing putamen, amygdala and thalamus volumes were associated with risk for OCD.ConclusionsThese results are consistent with current OCD neurocircuitry models. Further evidence will clarify the relationship between putamen volume and OCD risk, and the roles of the detected variants in this disorder.Declaration of interestThe authors have declared that no competing interests exist.

scholarly journals Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

2016 ◽  
Vol 47 (5) ◽  
pp. 971-980 ◽  
Author(s):  
S. H. Gage ◽  
H. J. Jones ◽  
S. Burgess ◽  
J. Bowden ◽  
G. Davey Smith ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Control ◽  
Negative Control ◽  
Study Data ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

scholarly journals Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS

2014 ◽  
Vol 20 (3) ◽  
pp. 337-344 ◽  
Author(s):  
M Mattheisen ◽  
J F Samuels ◽  
Y Wang ◽  
B D Greenberg ◽  
A J Fyer ◽  
...  
Keyword(s):  
Association Study ◽  
Obsessive Compulsive Disorder ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Genome Wide

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 Depression and multiple sclerosis: A bidirectional Mendelian randomisation study

2021 ◽  
pp. 135245852199660
Author(s):  
Stefanie Binzer ◽  
Xia Jiang ◽  
Jan Hillert ◽  
Ali Manouchehrinia
Keyword(s):  
Multiple Sclerosis ◽  
Genome Wide Association Study ◽  
Significant Risk ◽  
Underlying Mechanism ◽  
Study Data ◽  
Mendelian Randomisation ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
The Relationship

Depression is common in multiple sclerosis (MS); however, the underlying mechanism for the relationship remains unknown. In this study, we examined a putative causal relationship between depression and MS using a bidirectional Mendelian randomisation (MR) framework. Using the latest genome-wide association study data available, 168 non–major histocompatibility complex (MHC) independent variants associated with MS and 96 independent genetic variants associated with depression susceptibility were used. Maximum likelihood, weighted median, inverse variance weighted method and MR-Egger regression analyses were performed. There was no significant risk for the development of MS in persons carrying variants associated with depression or for risk of depression in individuals who are genetically susceptible to MS.

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 Causal effect of C-reactive protein and vitamin D on human cerebral anatomy observed among genetically correlated biomarkers in blood

2021 ◽  
Author(s):  
Dylan James Kiltschewskij ◽  
William R Reay ◽  
Murray J Cairns
Keyword(s):  
Vitamin D ◽  
Psychiatric Disorders ◽  
Cortical Thickness ◽  
Genetic Architecture ◽  
Causal Effect ◽  
Causal Relationships ◽  
C Reactive Protein ◽  
Biochemical Traits ◽  
Reactive Protein ◽  
Shared Genetic

Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex, which frequently vary with clinically relevant factors including antipsychotic treatment, duration of illness and age of onset. While the underlying variables mediating these structural changes are poorly understood, recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in a number of psychiatric disorders which could be mediated by changes in the cerebral cortex. In the current study, we leveraged publicly available genome-wide association study (GWAS) data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area at both the global and regional levels. Linkage disequilibrium score regression identified a total of 20 significant and 156 suggestive genetically correlated biochemical-cortical trait pairings, of which six exhibited strong evidence for causality in a latent causal variable model. Interestingly, a negative causal relationship was identified between a unit increase in serum C-reactive protein levels and thickness of the lingual and lateral occipital regions that was also supported by Mendelian randomisation, while circulating vitamin D (25-hydroxyvitamin D) levels exhibited a positive causal effect on temporal pole thickness. Taken together, our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical thickness in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.

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