Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

The Crowdsourced Replication Initiative: Investigating Immigration and Social Policy Preferences. Executive Report.

In an era of mass migration, social scientists, populist parties and social movements raise concerns over the future of immigration-destination societies. What impacts does this have on policy and social solidarity? Comparative cross-national research, relying mostly on secondary data, has findings in different directions. There is a threat of selective model reporting and lack of replicability. The heterogeneity of countries obscures attempts to clearly define data-generating models. P-hacking and HARKing lurk among standard research practices in this area.This project employs crowdsourcing to address these issues. It draws on replication, deliberation, meta-analysis and harnessing the power of many minds at once. The Crowdsourced Replication Initiative carries two main goals, (a) to better investigate the linkage between immigration and social policy preferences across countries, and (b) to develop crowdsourcing as a social science method. The Executive Report provides short reviews of the area of social policy preferences and immigration, and the methods and impetus behind crowdsourcing plus a description of the entire project. Three main areas of findings will appear in three papers, that are registered as PAPs or in process

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Panel Regression Models for Causal Analysis in Structural Equation Modeling: Recent Developments and Applications

Establishing causal relationships is arguably the most important task of the social sciences. While the relationship between the social sciences and the concept of causality has been rocky, the randomized experiment gives us a concrete definition of a causal effect as the difference in outcomes due to the researcher's intervention. However, many interesting questions cannot be easily examined using experiments. Feasibility and ethics limit the use of randomized experiments in some situations and retrospective questions, i.e., working from the observed outcome to uncover the cause, require a different logic. Observational studies in which we observe pairs of variables without any intervention lend themselves to such situations but come with many difficulties. That is, it is not immediately clear whether an observed relationship between two variables is due to a true causal effect, or whether the relationship is due to other common causes. Panel data describe repeated observations of the same units over time. They offer a powerful framework for approaching causal questions with observational data. Panel analysis allows us to essentially use each unit as their own control. In an experiment, random assignment to either treatment and control group makes both groups equal on all characteristics. Similarly, if we compare the same individual pre- and post-treatment, then the two are equal at least on the things that do not change over time, such as sex, date of birth, nationality, etc. Structural equation modeling (SEM) is a group of statistical methods for assessing relationships between variables, often at the latent (unobserved) variable level. The use of SEM for panel analysis allows for a great deal of flexibility. Latent variables can be incorporated to account for measurement error and rule out alternative models. This dissertation focuses on the use of panel data in SEM for causal analysis. It comprises an introduction, four main chapters and a conclusion. After a short introduction (Chapter 1) outlining the goals and scope of the dissertation, Chapter 2 provides an overview of the topic of causality in the social sciences. Since the randomized experiment is often not feasible in social research, special emphasis has been placed on non-experimental, i.e., observational data. The chapter outlines some competing views on causality with non-experimental data, then discusses the two currently dominant frameworks for causal analysis, potential outcomes and directed graphs. It goes on to outline empirical methods and notes their compatibility with SEM. Chapter 3 discusses how panel data can be used to deal with unobserved time-invariant heterogeneity, i.e., stable characteristics that might normally confound analyses. It attempts to show in detail how basic panel regression in SEM works. It also discusses some issues that are not normally addressed outside of SEM, e.g., measurement error in observed variables, effects that change over time, model comparisons, etc. This discussion of the more basic panel regression setup provides a sort of basis for the more complex discussion in the following chapters. Chapter 4 compares and contrasts several ways to model dynamic processes, where the outcome at a particular point in time may affect future outcomes or even the presumed cause later on. It shows that popular recently proposed modeling techniques have much do to with their older counterparts. In fact, the newer modeling techniques do not seem to offer benefit with regards to estimating the causal effects of interest. The chapter focuses on arguably common situations in which the newer techniques may have serious drawbacks. Chapter 5 provides an applied example. It looks to better assess the causal effect of environmental attitudes on environmental behaviour (mobility, consumption, willingness to sacrifice). It touches on many of the aspects from the previous chapters, including the use of latent variables for constructs that are not directly observable, unobserved time-invariant confounders, state dependence (feedback from outcome to outcome), and reverse causality (feedback from outcome to cause). It shows that failure to account for time-invariant confounders leads to biased estimates of the effect of attitudes on behaviour. After controlling for these factors, the effects disappear in terms of mobility and consumption behaviour: when a person's attitudes become more positive, their behaviour does not become more environmentally-friendly. There is, however, a fairly robust effect of attitudes on willingness to sacrifice, even after controlling for unobserved time-invariant confounders, state dependence and reverse causality. This suggests changing attitudes do affect willingness to make sacrifices, holding potential time-invariant confounders, outcome to outcome feedback (essentially habits), as well as some time-varying confounders constant. Finally, Chapter 6 summarizes the previous chapters and provides an outlook for future work.:1. Introduction 2. Causal Inference in the Social Sciences 3. A Closer Look at Random and Fixed Effects Panel Regression in Structural Equation Modeling Using lavaan 4. Equivalent Approaches to Dealing with Unobserved Heterogeneity in Cross-Lagged Panel Models? 5. Re-Examining the Effect of Environmental Attitudes on Behaviour in a Panel Setting 6. Conclusio

Panel Regression Models for Causal Analysis in Structural Equation Modeling: Recent Developments and Applications

Establishing causal relationships is arguably the most important task of the social sciences. While the relationship between the social sciences and the concept of causality has been rocky, the randomized experiment gives us a concrete definition of a causal effect as the difference in outcomes due to the researcher's intervention. However, many interesting questions cannot be easily examined using experiments. Feasibility and ethics limit the use of randomized experiments in some situations and retrospective questions, i.e., working from the observed outcome to uncover the cause, require a different logic. Observational studies in which we observe pairs of variables without any intervention lend themselves to such situations but come with many difficulties. That is, it is not immediately clear whether an observed relationship between two variables is due to a true causal effect, or whether the relationship is due to other common causes. Panel data describe repeated observations of the same units over time. They offer a powerful framework for approaching causal questions with observational data. Panel analysis allows us to essentially use each unit as their own control. In an experiment, random assignment to either treatment and control group makes both groups equal on all characteristics. Similarly, if we compare the same individual pre- and post-treatment, then the two are equal at least on the things that do not change over time, such as sex, date of birth, nationality, etc. Structural equation modeling (SEM) is a group of statistical methods for assessing relationships between variables, often at the latent (unobserved) variable level. The use of SEM for panel analysis allows for a great deal of flexibility. Latent variables can be incorporated to account for measurement error and rule out alternative models. This dissertation focuses on the use of panel data in SEM for causal analysis. It comprises an introduction, four main chapters and a conclusion. After a short introduction (Chapter 1) outlining the goals and scope of the dissertation, Chapter 2 provides an overview of the topic of causality in the social sciences. Since the randomized experiment is often not feasible in social research, special emphasis has been placed on non-experimental, i.e., observational data. The chapter outlines some competing views on causality with non-experimental data, then discusses the two currently dominant frameworks for causal analysis, potential outcomes and directed graphs. It goes on to outline empirical methods and notes their compatibility with SEM. Chapter 3 discusses how panel data can be used to deal with unobserved time-invariant heterogeneity, i.e., stable characteristics that might normally confound analyses. It attempts to show in detail how basic panel regression in SEM works. It also discusses some issues that are not normally addressed outside of SEM, e.g., measurement error in observed variables, effects that change over time, model comparisons, etc. This discussion of the more basic panel regression setup provides a sort of basis for the more complex discussion in the following chapters. Chapter 4 compares and contrasts several ways to model dynamic processes, where the outcome at a particular point in time may affect future outcomes or even the presumed cause later on. It shows that popular recently proposed modeling techniques have much do to with their older counterparts. In fact, the newer modeling techniques do not seem to offer benefit with regards to estimating the causal effects of interest. The chapter focuses on arguably common situations in which the newer techniques may have serious drawbacks. Chapter 5 provides an applied example. It looks to better assess the causal effect of environmental attitudes on environmental behaviour (mobility, consumption, willingness to sacrifice). It touches on many of the aspects from the previous chapters, including the use of latent variables for constructs that are not directly observable, unobserved time-invariant confounders, state dependence (feedback from outcome to outcome), and reverse causality (feedback from outcome to cause). It shows that failure to account for time-invariant confounders leads to biased estimates of the effect of attitudes on behaviour. After controlling for these factors, the effects disappear in terms of mobility and consumption behaviour: when a person's attitudes become more positive, their behaviour does not become more environmentally-friendly. There is, however, a fairly robust effect of attitudes on willingness to sacrifice, even after controlling for unobserved time-invariant confounders, state dependence and reverse causality. This suggests changing attitudes do affect willingness to make sacrifices, holding potential time-invariant confounders, outcome to outcome feedback (essentially habits), as well as some time-varying confounders constant. Finally, Chapter 6 summarizes the previous chapters and provides an outlook for future work.:1. Introduction 2. Causal Inference in the Social Sciences 3. A Closer Look at Random and Fixed Effects Panel Regression in Structural Equation Modeling Using lavaan 4. Equivalent Approaches to Dealing with Unobserved Heterogeneity in Cross-Lagged Panel Models? 5. Re-Examining the Effect of Environmental Attitudes on Behaviour in a Panel Setting 6. Conclusio