The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank

Pasman, Joëlle A.; Chen, Zeli; Smit, Dirk J. A.; Vink, Jacqueline M.; Oever, Michel C. Van Den; Pattij, Tommy; Vries, T.J. De; Abdellaoui, Abdel; Verweij, Karin J. H.

doi:10.1007/s10519-022-10109-8

Cited by 17 publications

(22 citation statements)

References 29 publications

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“…After excluding significant Q-SNPs (i.e., SNPs which are not mediated by the latent factor) from each of the factor results, we identified 15 genomic risk loci for the SUrelated psychopathology factor, 80 risk loci for the non-SU internalizing factor, and 6 risk loci for the non-SU externalizing factor. Interestingly, the strongest gene-based finding for the SUrelated psychopathology factor was CADM2 (Supplementary Table S9), which has been linked to many different behavioral traits and psychiatric disorders (43). This gene was also mapped to risk loci in the non-SU internalizing factor and the non-SU externalizing factor, consistent with prior studies suggesting that this gene might be a shared risk factor for many related behavioral and psychiatric phenotypes.…”

Section: Discussionsupporting

confidence: 81%

Genetic associations among internalizing and externalizing traits with polysubstance use among young adults

Brick

Benca-Bachman

Johnson

et al. 2023

Preprint

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Though most genetic studies of substance use focus on specific substances in isolation or generalized vulnerability across multiple substances, few studies to date focus on the concurrent use of two or more substances within a specified time frame (i.e., polysubstance use; PSU). We evaluated whether distinct genetic factors underlying internalizing and externalizing traits were associated with past 30-day PSU above variance shared across general psychopathology and substance use (SU). Using Genomic Structural Equation Modeling, we constructed theory-driven, multivariate genetic factors of 16 internalizing, externalizing, and SU traits using genome-wide association studies (GWAS) summary statistics. Next, we fit a model with a higher order SU-related psychopathology factor as well as genetic variance specific to externalizing and internalizing (i.e., residual genetic variance not explained by SU or general psychopathology). GWAS-by-subtraction was used to obtain single nucleotide polymorphism effects on each of these factors. Polygenic scores (PGS) were then created in an independent target sample with data on PSU, the National Longitudinal Study of Adolescent to Adult Health. To evaluate the effect of genetic variance due to internalizing and externalizing traits independent of variance related to SU, we regressed PSU on the PGSs, controlling for sex, age, and genetic principal components. PGSs for SU-related psychopathology and non-SU externalizing traits were associated with higher PSU factor scores, while the non-SU internalizing PGS was not significantly associated with PSU. In total, the three PGSs accounted for an additional 4% of the variance in PSU above and beyond a null model with only age, sex, and genetic principal components as predictors. These findings suggest that there may be unique genetic variance in externalizing traits contributing to liability for PSU that is independent of the genetic variance shared with SU.

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Section: Discussionsupporting

confidence: 81%

Genetic associations among internalizing and externalizing traits with polysubstance use among young adults

Brick

Benca-Bachman

Johnson

et al. 2023

Preprint

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“…• Encodes a member of the synaptic cell adhesion molecule 1 (SynCAM) family involved in synaptic organization and signaling, more abundantly expressed in brain tissue compared to other tissue [69,229].…”

Section: Cadm2mentioning

confidence: 99%

The neurobiology of irritable bowel syndrome

Mayer¹,

Ryu

Bhatt

2023

Mol Psychiatry

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Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

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“…Intriguingly, in the context of this discussion, genes found in the most restrictively defined lists of deserts of introgression in modern human genomes (regions of the genome depleted of introgressed alleles from neanderthals/denisovans) (Reher, 2021 ), such as CADM2 , have been linked to personality traits like risk-taking behavior, impulsivity, addiction (Pasman et al, 2022 ; Sanchez-Roige et al, 2022 ). (Similar signals have been associated with other genes in introgression deserts such as CADPS2 or FOXP2 Sanchez-Roige et al, 2022 ).…”

Section: Signals From Comparative (Paleo)genomicsmentioning

confidence: 99%

What made us “hunter-gatherers of words”

Boeckx

2023

Front. Neurosci.

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This paper makes three interconnected claims: (i) the “human condition” cannot be captured by evolutionary narratives that reduce it to a recent ‘cognitive modernity', nor by narratives that eliminates all cognitive differences between us and out closest extinct relatives, (ii) signals from paleogenomics, especially coming from deserts of introgression but also from signatures of positive selection, point to the importance of mutations that impact neurodevelopment, plausibly leading to temperamental differences, which may impact cultural evolutionary trajectories in specific ways, and (iii) these trajectories are expected to affect the language phenotypes, modifying what is being learned and how it is put to use. In particular, I hypothesize that these different trajectories influence the development of symbolic systems, the flexible ways in which symbols combine, and the size and configurations of the communities in which these systems are put to use.

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The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank

Cited by 17 publications

References 29 publications

Genetic associations among internalizing and externalizing traits with polysubstance use among young adults

Genetic associations among internalizing and externalizing traits with polysubstance use among young adults

The neurobiology of irritable bowel syndrome

What made us “hunter-gatherers of words”

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