There has been substantial progress in psychiatric genetics in recent years, through collaborative efforts to build large samples sizes for case/control analyses for a number of psychiatric ...disorders. The identification of replicated trait-associated genomic loci represents a large stride forward in a field where little is known about the biological processes involved in disorder. As researchers build on this early foundation, they are beginning to advance the field towards more fine-grained approaches that interrogate the many sources of heterogeneity within psychiatric genetics that can obscure the identification of genotypic influences on disorder. In this review, we provide a brief overview, across a range of psychiatric diagnoses, of recent approaches that have been employed to dissect heterogeneity to give a flavour of the current direction of the field. We group these into three main categories; tackling the heterogeneity in phenotype that is found within the diagnostic categories used within psychiatry, the many different forms of genetic variation that might influence psychiatric traits and then finally, the heterogeneity that is seen across individuals of different ancestries.
Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to ...date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain.
We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism.
We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.
Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations ...can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm.
Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder MDD, attention deficit/hyperactivity disorder ADHD, bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error.
In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.
Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing ...sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10
) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.
Previous studies stratified patients with major depressive disorder (MDD) based on their clinical characteristics. This study used this approach in individuals with lifetime MDD who reported low ...wellbeing, a group of high clinical relevance.
We selected participants in the UK Biobank (UKB) with lifetime MDD and a wellbeing score in the lowest 25 %. A wellbeing score was previously created considering happiness, belief that own life is meaningful, health satisfaction and functioning in relevant areas. In the selected group, we applied latent class analysis using mood-spectrum symptoms and personality traits as input variables, then we compared the clinical-demographic and genetic (polygenic risk scores, PRSs) characteristics of the identified classes.
A total of 13,896 individuals were included and a model with five classes showed the best performance. The most common class (31.25 %) was characterised by periods of irritable mood and trait irritability with high neuroticism. A rarer class (16.49 %) showed depressive-manic mood fluctuations and risk-taking personality, higher percentage of males, atypical depressive symptoms, lower socio-economic status, higher PRS for attention-deficit hyperactivity disorder and lower PRS for education. The second most common class (29.79 %) showed worry as main personality trait with low risk of manic/irritable manifestations. The remaining classes showed an anxious-irritable personality profile and a purely depressive profile (4.92 % and 17.55 %, respectively).
Our results may reflect the characteristics of UKB participants.
Subthreshold manic/irritable mood fluctuations and personality traits irritability and neuroticism may distinguish the most common groups with poor wellbeing in lifetime MDD.
•Low wellbeing in lifetime depression represents a group of high clinical relevance.•We aimed to stratify this group to identify potentially homogeneous classes.•We used latent class analysis with mood symptoms and personality as input variables.•The most common class showed high irritability (state and trait) and neuroticism.•Another class showed distinctive characteristics such as subthreshold manic periods.
BackgroundCardiovascular diseases (CVD) are a major health concern in Africa. Improved identification and treatment of high-risk individuals can reduce adverse health outcomes. Current CVD risk ...calculators are largely unvalidated in African populations and overlook genetic factors. Polygenic scores (PGS) can enhance risk prediction by measuring genetic susceptibility to CVD, but their effectiveness in genetically diverse populations is limited by a European-ancestry bias. To address this, we developed models integrating genetic data and conventional risk factors to assess the risk of developing cardiometabolic outcomes in African populations.MethodsWe used summary statistics from a genome-wide association meta-analysis (n = 14,126) in African populations to derive novel genome-wide PGS for 14 cardiometabolic traits in an independent African target sample (Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen), n = 10,603). Regression analyses assessed relationships between each PGS and corresponding cardiometabolic trait, and seven CVD outcomes (CVD, heart attack, stroke, diabetes mellitus, dyslipidaemia, hypertension, and obesity). The predictive utility of the genetic data was evaluated using elastic net models containing multiple PGS (MultiPGS) and reference-projected principal components of ancestry (PPCs). An integrated risk prediction model incorporating genetic and conventional risk factors was developed. Nested cross-validation was used when deriving elastic net models to enhance generalisability.ResultsOur African-specific PGS displayed significant but variable within- and cross- trait prediction (max.R2 = 6.8%, p = 1.86 × 10−173). Significantly associated PGS with dyslipidaemia included the PGS for total cholesterol (logOR = 0.210, SE = 0.022, p = 2.18 × 10−21) and low-density lipoprotein (logOR = − 0.141, SE = 0.022, p = 1.30 × 10−20); with hypertension, the systolic blood pressure PGS (logOR = 0.150, SE = 0.045, p = 8.34 × 10−4); and multiple PGS associated with obesity: body mass index (max. logOR = 0.131, SE = 0.031, p = 2.22 × 10−5), hip circumference (logOR = 0.122, SE = 0.029, p = 2.28 × 10−5), waist circumference (logOR = 0.013, SE = 0.098, p = 8.13 × 10−4) and weight (logOR = 0.103, SE = 0.029, p = 4.89 × 10−5). Elastic net models incorporating MultiPGS and PPCs significantly improved prediction over MultiPGS alone. Models including genetic data and conventional risk factors were more predictive than conventional risk models alone (dyslipidaemia: R2 increase = 2.6%, p = 4.45 × 10−12; hypertension: R2 increase = 2.6%, p = 2.37 × 10−13; obesity: R2 increase = 5.5%, 1.33 × 10−34).ConclusionsIn African populations, CVD and associated cardiometabolic trait prediction models can be improved by incorporating ancestry-aligned PGS and accounting for ancestry. Combining PGS with conventional risk factors further enhances prediction over traditional models based on conventional factors. Incorporating data from target populations can improve the generalisability of international predictive models for CVD and associated traits in African populations.
Interpreting Genome-Wide Association Studies (GWAS) at a gene level is an important step towards understanding the molecular processes that lead to disease. In order to incorporate prior biological ...knowledge such as pathways and protein interactions in the analysis of GWAS data it is necessary to derive one measure of association for each gene. We compare three different methods to obtain gene-wide test statistics from Single Nucleotide Polymorphism (SNP) based association data: choosing the test statistic from the most significant SNP; the mean test statistics of all SNPs; and the mean of the top quartile of all test statistics. We demonstrate that the gene-wide test statistics can be controlled for the number of SNPs within each gene and show that all three methods perform considerably better than expected by chance at identifying genes with confirmed associations. By applying each method to GWAS data for Crohn's Disease and Type 1 Diabetes we identified new potential disease genes.
There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances ...suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.
In the post-genomic era, genetics has led to limited clinical applications in the diagnosis and treatment of major depressive disorder (MDD). Variants in genes coding for cytochrome enzymes are ...included in guidelines for assisting in antidepressant choice and dosing, but there are no recommendations involving genes responsible for antidepressant pharmacodynamics and no consensus applications for guiding diagnosis or prognosis. However, genetics has contributed to a better understanding of MDD pathogenesis and the mechanisms of antidepressant action, also thanks to recent methodological innovations that overcome the challenges posed by the polygenic architecture of these traits. Polygenic risk scores can be used to estimate the risk of disease at the individual level, which may have clinical relevance in cases with extremely high scores (e.g. top 1%). Genetic studies have also shed light on a wide genetic overlap between MDD and other psychiatric disorders. The relationships between genes/pathways associated with MDD and known drug targets are a promising tool for drug repurposing and identification of new pharmacological targets. Increase in power thanks to larger samples and methods integrating genetic data with gene expression, the integration of common variants and rare variants, are expected to advance our knowledge and assist in personalized psychiatry.
Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, ...TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.
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