Causal Inference with Genetic Data: Past, Present, and Future

Pingault, Jean‐Baptiste; Richmond, Rebecca C; Smith, George Davey

doi:10.1101/cshperspect.a041271

Cited by 20 publications

(10 citation statements)

References 87 publications

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“…For example, in the adoption design, the association between ADHD traits in the adoptive mother and child may be partly due to reverse causation. As such, triangulation of findings between studies that employ genetically informed designs with different underlying assumptions and limitations is essential [29,30].…”

Section: Introductionmentioning

confidence: 99%

Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study

et al. 2022

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Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of parents in shaping their children’s outcomes. We investigated whether genetic transmission and genetic nurture (environmentally mediated effects) underlie associations between polygenic scores indexing parental risk and protective factors and their offspring’s ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children’s ADHD traits (n = 9,454 children) using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders. We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score (pΔβ = 9.95 × 10−17 for maternal and pΔβ = 1.48 × 10−14 for paternal estimates), suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children’s ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects.

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Section: Introductionmentioning

confidence: 99%

Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study

et al. 2022

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“…This may result from a cautious attitude of researchers in psychology and psychiatry toward causal inference (Grosz et al, 2020; Rutter, 2007), potentially coupled with a lack of statistical training in such methods. It has been argued that causal relations are often implicitly assumed by researchers but not explicitly expressed; however, the expression of such assumptions is essential to choose adequate methods and to address their specific biases (Goetghebeur et al, 2020; Grosz et al, 2020; Pingault, Richmond, & Smith, 2022). As mentioned, applying these designs can also be challenging as appropriate instruments might not be available for certain research questions.…”

Section: Discussionmentioning

confidence: 99%

Causal inference methods for intergenerational research using observational data.

Frach¹,

Jami²,

McAdams³

et al. 2023

Psychological Review

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Identifying early causal factors leading to the development of poor mental health and behavioral outcomes is essential to design efficient preventive interventions. The substantial associations observed between parental risk factors (e.g., maternal stress in pregnancy, parental education, parental psychopathology, parent-child relationship) and child outcomes point toward the importance of parents in shaping child outcomes. However, such associations may also reflect confounding, including genetic transmission-that is, the child inherits genetic risk common to the parental risk factor and the child outcome. This can generate associations in the absence of a causal effect. As randomized trials and experiments are often not feasible or ethical, observational studies can help to infer causality under specific assumptions. This review aims to provide a comprehensive summary of current causal inference methods using observational data in intergenerational settings. We present the rich causal inference toolbox currently available to researchers, including genetically informed and analytical methods, and discuss their application to child mental health and related outcomes. We outline promising research areas and discuss how existing approaches can be combined or extended to probe the causal nature of intergenerational effects.

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“…The absence of genetic relatedness precludes genetic confounding. Beyond polygenic scores, methods using genetic variants to better understand causality such as intergenerational Mendelian randomisation can also be implemented (Hwang, Davies, Warrington, & Evans, 2021 ; Pingault, Richmond, et al., 2021 ; Richmond et al., 2017 ; Zhang et al., 2015 ).…”

Section: Additional Biases Arise From Jointly Modelling Environmental...mentioning

confidence: 99%

“…The direct effect of a SNP on a phenotype can be conceived as a causal effect in the sense that a change in the SNP, for example by gene editing, should theoretically lead to a change in the phenotype (Lynch, 2021 ; Pingault, Richmond, Richmond, & Smith, 2021 ). Additive heritability captures the addition of all such direct genetic effects.…”

Section: Introductionmentioning

confidence: 99%

Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes

Pingault

Allegrini

Odigie

et al. 2022

Child Psychology Psychiatry

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Background: Genetic influences are ubiquitous as virtually all phenotypes and most exposures typically classified as environmental have been found to be heritable. A polygenic score summarises the associations between millions of genetic variants and an outcome in a single value for each individual. Ever lowering costs have enabled the genotyping of many samples relevant to child psychology and psychiatry research, including cohort studies, leading to the proliferation of polygenic score studies. It is tempting to assume that associations detected between polygenic scores and phenotypes in those studies only reflect genetic effects. However, such associations can reflect many pathways (e.g. via environmental mediation) and biases. Methods: Here, we provide a comprehensive overview of the many reasons why associations between polygenic scores, environmental exposures, and phenotypes exist. We include formal representations of common analyses in polygenic score studies using structural equation modelling. We derive biases, provide illustrative empirical examples and, when possible, mention steps that can be taken to alleviate those biases. Results: Structural equation models and derivations show the many complexities arising from jointly modelling polygenic scores with environmental exposures and phenotypes. Counter-intuitive examples include that: (a) associations between polygenic scores and phenotypes may exist even in the absence of direct genetic effects; (b) associations between child polygenic scores and environmental exposures can exist in the absence of evocative/active gene-environment correlations; and (c) adjusting an exposure-outcome association for a polygenic score can increase rather than decrease bias. Conclusions: Strikingly, using polygenic scores may, in some cases, lead to more bias than not using them. Appropriately conducting and interpreting polygenic score studies thus requires researchers in child psychology and psychiatry and beyond to be versed in both epidemiological and genetic methods or build on interdisciplinary collaborations.

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Causal Inference with Genetic Data: Past, Present, and Future

Cited by 20 publications

References 87 publications

Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study

Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study

Causal inference methods for intergenerational research using observational data.

Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes

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