Dazed and confused: A molecular genetic approach to everyday cognitive failure

Highlights

• Cognitive failure susceptibility is a risk factor for physical and mental health.

• We assessed the molecular genetic basis of cognitive failure susceptibility.

• A variant on the dopamine d2 receptor gene constitutes a protective factor.

• This effect was in part mediated by trait impulsiveness.

• Results highlight the importance of the dopaminergic system for cognitive failure.

Abstract

An individual's susceptibility to everyday cognitive failure constitutes a risk factor for physical and mental health. Different factors such as inefficiency of executive functioning and high trait impulsivity have been shown to affect this susceptibility. Furthermore, twin studies indicate a high heritability of failure susceptibility revealing genetic variables as an important biological influence. We tested for a molecular genetic association between variants on the dopamine D2 receptor gene (DRD2), which relate to executive control and impulsivity, and susceptibility to everyday cognitive failure as assessed by the cognitive failure questionnaire (CFQ) in a sample of N = 500 (n = 140 male, n = 360 female, mean age M = 24.62, SD = 7.98) healthy participants of central European descent. Moreover, we assessed whether trait impulsivity as measured by the Barratt impulsiveness scale (BIS-11) qualifies as a mediator between DRD2 variants and CFQ scores. We found a positive association between DRD2 variants and the CFQ. This effect was in part yet not completely mediated by trait impulsivity. The DRD2 C/C variant constitutes a protective factor for the susceptibility to everyday cognitive failure. Results point towards at least two biopsychological pathways that may explain the observed effect.

Introduction

The frequency of every day cognitive failures such as confusing left and right, leaving important letters or emails unanswered for days and forgetting appointments or even people's names varies considerably across people. The Cognitive failure questionnaire (CFQ, [1]) has been developed to measure these individual differences in proneness to slips or errors. The CFQ consists of several brief scenarios that represent perceptual (“Do you fail to notice signposts on the road?”), memory (“Did you forget whether you turned off a light or a fire or locked the door?”) or psychomotor failure (“Did you bump into people?”). Importantly, the scenarios do not aim at failure of ability but at occasional and transient departure from normal functioning. Participants are asked to state on a five-point Likert scale how often the mentioned event happened to them in the past six months.

Validity for the CFQ stems from studies that predict the frequency of every day mishaps and accidents from the CFQ scores. The self-report on the CFQ coincides with the frequency of car accidents [2], [3], injuries from falling [4] and work accidents [2]. Optimized work flow in office jobs is also jeopardized in CFQ-high-scorers as they lose computing work more often because they forget to save it to the hard drive [5]. Furthermore, the CFQ has predictive validity for strain and burden due to occupational stress [6] which highlights the role of cognitive failure susceptibility as a risk factor for aversive conditions at the work place.

Given the relevance of cognitive failure susceptibility for occupational and health related topics, it is of high interest to examine more closely what contributes to individual proneness to cognitive failure. Evidence indicates that cognitive, personality-related and biological variables have an impact on CFQ scores.

Given the proximity of the CFQ's scenarios to situations in which planning skills or focused attention fail, it is not surprising that the CFQ is highly intercorrelated with laboratory measures of executive functioning. People who score low on the CFQ are better at excluding irrelevant distractors from information processing [7], [8], [9], [10] and are more adept at inhibiting preponent yet inappropriate responses [11], [12]. The cognitive deficits associated with high CFQ scores, however, do not extend to general cognitive ability [1], stressing the idea that cognitive failure results from absentmindedness and the failure to deploy attentional resources when appropriate rather than low levels of intellect.

Another source of individual variation is personality. Here, the personality dimension “impulsivity” can predict CFQ scores. Highly impulsive individuals – who tend to react more rapidly or unplanned and with little regard to negative consequences – are more susceptible to cognitive failure [13]. As heightened impulsivity has been linked to various psychopathological conditions, the link with impulsivity might in part account for the role of the CFQ as a clinical assessment tool.

A further perspective on individual differences focuses on biological variables such as genetics. A large family study confirmed a strong genetic influence on the frequency of everyday cognitive failure: additive genetic factors can account for about 50% of the total variance in CFQ scores [14]. This finding is in line with the general notion that executive functioning represents one of the most heritable psychological phenotypes [15].

Given this high heritability, the imperative step in the study of individual differences in proneness to cognitive failures is the identification of genetic variants that impact the CFQ. A promising candidate is the DRD2 gene on the q22-23 strand of chromosome 11 that codes for the dopamine D2 receptor. A common C → T single nucleotide polymorphism (SNP) on this gene is rs6277 (DRD2 c957t). Even though a synonymous nucleotide transition, the functionality of this SNP has been proven by complementary methods in vivo and in vitro [16], [17], [18]. DRD2 rs6277 is in strong linkage disequilibrium with DRD2/ANKK1 Taq Ia (rs1800497), a SNP on the adjacent ANKK1 gene [19]. Literatures have identified rs1800497 as genetic marker for dopamine D2 receptor density [20], [21] but evidence suggests that this association is driven by the mentioned linkage disequilibrium with functional variants on the DRD2 gene such as rs6277 [19], [22]. On the behavioral level, DRD2 rs6277 has been repeatedly associated with measures of executive functioning including working memory [19], [23], [24], [25]. Furthermore, phenotypic associations with impulsivity have been reported [26]. The question which allelic variant is beneficial for cognitive functioning is difficult to answer because directions of reported effects vary, presumably because of interactions with other gene loci [19], [24], [25] or because of different influences on task components [27], [28]. In our work, however, we consistently identified improved cognitive functioning in carriers of the C/C genotype [19], [24], [28]. Given the proof of functionality of DRD2 rs6277 on the cellular and neuronal level and the associations with phenotypes related to the frequency of cognitive failure, it seems plausible to hypothesize an association between the SNP and the CFQ scores as well. Based on our previous findings, we hypothesize reduced failure susceptibility in C/C carriers.

A further issue is the relationship between genetics, personality and cognitive failures. Genes affect the hard-wiring of our brains which represents the biological basis of personality (for review see [29]). It seems plausible that a possible association between DRD2 and the CFQ is mediated by impulsivity: Impulsivity is characterized by aberrations to the mid-brain dopaminergic system resulting in stronger phasic dopamine release in response to novel, rewarding and salient information [30]. Furthermore, trait impulsivity can predict whether an individual's performance in a cognitive control task improves or declines after a pharmacological challenge with dopaminergic agents, indicating that impulsivity reflects an index for base rate dopamine turnaround [31].

Besides from the hypothesis that the rs6277 polymorphism is associated with the CFQ scores we also seek to replicate the observed relationship between DRD2 rs6277 and impulsivity and test whether the relationship between rs6277 and the CFQ is statistically mediated by trait impulsivity.