<i>DRD2</i>and<i>FOXP2</i>are implicated in the associations between computerized device use and psychiatric disorders

Fr, Wendt; Cm, Carvalho; Gelernter, Joel; Polimanti, Renato

doi:10.1101/497420

Cited by 4 publications

(4 citation statements)

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“…To assess causality among MD, AD, AC-quantity, and AC-frequency, we used GWAS summary association data to conduct two-sample MR analyses (Davey Smith and Hemani, 2014; Burgess et al ., 2015). Since different MR methods have sensitivities to different potential issues, accommodate different scenarios, and vary in their statistical efficiency (Polimanti et al ., 2017, 2018; Ravera et al ., 2018; Wendt et al ., 2018), we considered multiple MR methods (online Supplemental Table S1). These include methods based on median (Bowden et al ., 2017), mean (Bowden et al ., 2016), and mode (Hartwig et al ., 2017), and various adjustments, such as fixed v .…”

Section: Methodsmentioning

confidence: 99%

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

et al. 2019

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BackgroundDespite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.MethodsLinkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).ResultsPositive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation.ConclusionThis study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.

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Section: Methodsmentioning

confidence: 99%

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

et al. 2019

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“…Genetic variants are allocated at conception and do not change throughout life, and they can be used to define reliable genetic instruments that can be applied in a mendelian randomization (MR) analysis. 10,11,12,13,14 The basic principle in MR is that an instrumental variable based on genetic variants associated with a phenotype can be used to represent, or mirror, the disease risk associated with that phenotype without the presence of possible environmental confounders. 15…”

Section: Introductionmentioning

confidence: 99%

Association of Economic Status and Educational Attainment With Posttraumatic Stress Disorder

et al. 2019

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IMPORTANCE There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood. OBJECTIVES To investigate the association of PTSD with traits related to EA. DESIGN, SETTING, AND PARTICIPANTS Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018. MAIN OUTCOMES AND MEASURES Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR. RESULTS Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (r g = −0.26; SE = 0.05; P = 4.60 × 10 −8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (β = −0.23; 95% CI, −0.07 to −0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA

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“…Large scale genome-wide association studies (GWAS) have now identified genetic variants that can be used to define reliable genetic instruments that can be applied for causal inference in a MR analysis. [14][15][16][17][18] The basic principle in MR is that genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor. 19 Previous large-scale GWAS conducted by the Social Science Genetic Association Consortium (SSGAC) investigated traits related to educational attainment (e.g., number of years of schooling and most advanced math course ever successfully completed), identifying a number of loci and biological pathways regulating brain mechanisms at the basis of the human cognitive ability.…”

Section: Introductionmentioning

confidence: 99%

Economic status mediates the relationship between educational attainment and posttraumatic stress disorder: a multivariable Mendelian randomization study

Polimanti

Ratanatharathorn

Maihofer

et al. 2018

Preprint

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Objectives: To investigate the genetic overlap and causal relationship between posttraumatic stress disorder (PTSD) and traits related to educational attainment.Design: Genetic correlation, polygenic risk scoring, and causal inference via multivariable Mendelian randomization (MR).Setting: Psychiatric Genomics Consortium for PTSD, UK Biobank, 23andMe, and Social Science Genetic Association Consortium.Participants: 23,185 PTSD cases and 151,309 controls; up to 1,131,881 individuals assessed for educational attainment and related traits.Main outcome measures: Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and casual effects (beta values) estimated with MR Results: PTSD showed strong negative genetic correlations with educational attainment (EdAtt; rg=-0.26, p=4.6×10 -8 ). PRS based on genome-wide significant variants associated with EdAtt significantly predicted PTSD (p=6.16×10 -4 ), but PRS based on variants associated with PTSD did not predict EdAtt (p>0.05). MR analysis indicated that EdAtt has negative causal effects on PTSD (beta=-0.23, p=0.004). Investigating potential mediators of the EdAtt-PTSD relationship, we observed that propensity for trauma exposure and risk-taking behaviors are risk factors for PTSD independently from EdAtt (beta = 0.36, p = 2.57×10 -5 and beta = 0.76, p = 6.75×10 -4 , respectively), while income fully mediates the causal effect of EdAtt on PSTD (MR: Income -beta = -0.18, p =0.001; EdAtt -beta =-0.23, p=0.004; multivariable MR: Income -beta = -0.32, p = 0.017; EdAtt -beta = -0.04, p = 0.786). ConclusionsWe report novel findings based on large-scale datasets regarding the relationship between educational attainment and PTSD, supporting the role of economic status as the key mediator in the causal relationship observed. What is already known on this topicThere is a well-established negative association of educational attainment and other traits related to cognitive ability with posttraumatic stress disorders (PTSD). However, the findings of these previous studies support various possible causal explanations: 1) individuals with high educational attainment are more resilient with respect to developing PTSD, 2) PTSD negatively impacts cognitive ability, or 3) PTSD and educational attainment share some underlying determinants, including relevant molecular mechanisms.A key obstacle to disentangling the complex association between educational attainment and PTSD is reverse causation, i.e. the situation in which the outcome precedes and causes the exposure instead of the other way around. What this study addsWe conducted a causal-inference investigation based on large-scale information from the investigation of more than one million individuals. Our main assumption is that genetic information can strongly minimize the bias of reverse causation, because genetic variants are determined at conception and do not change throughout life.Our findings indicate 1) the effect of traits related to educational attainment...

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DRD2andFOXP2are implicated in the associations between computerized device use and psychiatric disorders

Cited by 4 publications

References 57 publications

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

Association of Economic Status and Educational Attainment With Posttraumatic Stress Disorder

Economic status mediates the relationship between educational attainment and posttraumatic stress disorder: a multivariable Mendelian randomization study

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