Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci

Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.Peer reviewe

Reweighting UK Biobank corrects for pervasive selection bias due to volunteering

Background: Biobanks typically rely on volunteer-based sampling. This results in large samples (power) at the cost of representativeness (bias). The problem of volunteer bias is debated. Here, we (i) show that volunteering biases associations in UK Biobank (UKB) and (ii) estimate inverse probability (IP) weights that correct for volunteer bias in UKB. Methods: Drawing on UK Census data, we constructed a subsample representative of UKB’s target population, which consists of all individuals invited to participate. Based on demographic variables shared between the UK Census and UKB, we estimated IP weights (IPWs) for each UKB participant. We compared 21 weighted and unweighted bivariate associations between these demographic variables to assess volunteer bias. Results: Volunteer bias in all associations, as naively estimated in UKB, was substantial—in some cases so severe that unweighted estimates had the opposite sign of the association in the target population. For example, older individuals in UKB reported being in better health, in contrast to evidence from the UK Census. Using IPWs in weighted regressions reduced 87% of volunteer bias on average. Volunteer-based sampling reduced the effective sample size of UKB substantially, to 32% of its original size. Conclusions: Estimates from large-scale biobanks may be misleading due to volunteer bias. We recommend IP weighting to correct for such bias. To aid in the construction of the next generation of biobanks, we provide suggestions on how to best ensure representativeness in a volunteer-based design. For UKB, IPWs have been made available.</p

Investigating Genetic Heterogeneity in Major Depression Through Item-level Genetic Analyses of the PHQ-9

26 Background: Major Depressive Disorder (MDD) is a clinically heterogeneous disorder. Previous 2

Genetic heterogeneity in self-reported depressive symptoms identified through genetic analyses of the PHQ-9

BackgroundDepression is a clinically heterogeneous disorder. Previous large-scale genetic studies of depression have explored genetic risk factors of depression case-control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.MethodsWe analyse data from 148 752 subjects of white British ancestry in the UK Biobank who completed nine items of a self-rated measure of current depressive symptoms: The Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD Score Regression was used to calculate SNP-based heritability (h2SNP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Genomic structural equation modelling was used to test the genetic factor structure across the nine symptoms.ResultsWe identified nine genome-wide significant genomic loci (8 novel), with no overlap in loci across symptoms. h2SNP ranged from 6% (concentration problems) to 9% (appetite changes). Genetic correlations ranged from 0.54 to 0.96 (all p < 1.39 × 10-3) with 30 of 36 correlations being significantly smaller than one. A two-factor model provided the best fit to the genetic covariance matrix, with factors representing 'psychological' and 'somatic' symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.ConclusionsPatterns of SNP associations and genetic correlations differ across the nine symptoms, suggesting that current depressive symptoms are genetically heterogeneous. Our study highlights the value of symptom-level analyses in understanding the genetic architecture of a psychiatric trait. Future studies should investigate whether genetic heterogeneity is recapitulated in clinical symptoms of major depression

El acompañamiento espiritual medio sanador y liberador para el enfermo mental inimputable desde el modelo de espiritualidad de San Juan de Dios

El presente trabajo pretende mostrar la importancia en el acompañamiento espiritual al enfermo mental inimputable, presentado como una pedagogía de la acción misericordiosa de Dios, dibujada al estilo de una espiritualidad de vida dentro de la Iglesia católica como lo es la de la Orden Hospitalaria de san Juan de Dios, comunidad religiosa dedicada al servicio de la evangelización y la humanización, en el medio sanitario. Este compendio está elaborado en tres momentos basado en el método de la teología latinoamericana, ver, juzgar y actuar, que permitió obtener unos elementos importantes para una acción del acompañamiento espiritual con la particularidad de la enfermedad mental en personas inimputables. Estos tres capítulos son la respuesta a una serie de objetivos trazados al inicio de la investigación, que lo que busca es presentar una serie de características para el acompañamiento espiritual

Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits

Epidemiological studies show high comorbidity between different mental health problems, indicating that individuals with a diagnosis of one disorder are more likely to develop other mental health problems. Genetic studies reveal substantial sharing of genetic factors across mental health traits. However, mental health is also genetically correlated with socio-economic status (SES) and it is therefore important to investigate and disentangle the genetic relationship between mental health and SES. We used summary statistics from large genome-wide association studies (average N~160,000) to estimate the genetic overlap across nine psychiatric disorders and seven substance use traits and explored the genetic influence of three different indicators of SES. Using Genomic Structural Equation Modelling, we show significant changes in patterns of genetic correlations after partialling out SES-associated genetic variation. Our approach allows the separation of disease-specific genetic variation and genetic variation shared with SES, thereby improving our understanding of the genetic architecture of mental health

Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci

Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits

Risk and Protective Factors of Lifetime Cocaine-Associated Chest Pain

International audienc