In their recent genome-wide association study (GWAS) using UK Biobank, Klimentidis and colleagues  identified nine loci associated with self-reported physical activity (PA). We believe that rather than capturing genetic architecture of habitual PA, genetic variants identified in this GWAS, may at least in part reflect information bias in self-reported data, attributable to participants’ cognitive ability of reporting PA.
One of the strongest signals in this study was for APOE, with its risk allele being paradoxically associated with greater self-reported PA. Given the well-established association of APOE ε4 allele with Alzheimer’s disease , the direction of the association is unexpected. Although this could be attributed to selection bias as discussed by the authors (that is, APOE carriers in the study are enriched for healthy lifestyles), this association was not replicated using accelerometer-based PA. Although accelerometer data is only available for a subsample, the loss of power would be compensated by an even stronger selection bias operating in this subsample and objectively-assessed measures being less ‘noisy’. We believe that the more plausible explanation for this paradoxical association is that participants with lower cognitive function in the study tend to over-report their activity levels. This becomes more apparent in the genetic correlation analyses (which aggregate SNP effects across the genome), where increases in self-reported PA were found to be correlated with decreased intelligence, years of schooling, and lower childhood IQ, but increased risk for various mental-health related traits, including schizophrenia, PGC cross-disorder, Bipolar disorder, and Alzheimer’s disease. In contrast, none of these correlations surfaced in the analyses based on accelerometer-based PA, presumably as the objectively-assessed measures were not subject to the bias caused by participants’ cognitive ability of reporting PA.
To examine our hypothesis that participants with lower cognitive function in the study tend to over-report their activity levels, we tabulated average levels of self-reported PA against two distinct cognitive measures, participants’ age and education, and compared the patterns with those seen for accelerometer-based PA. As expected, participants with lower cognitive function, who were older, and who had lower levels of education reported higher levels of activity, with none or opposite patterns seen for the accelerometer-based data (Table 1). Further, this information bias in self-reported PA by indicators of cognitive function has also been reported in an independent sample , and in people with Schizophrenia within the UK Biobank . In summary, associations with self-reported PA are likely biased by participants’ cognitive reporting ability, which should be considered in the context of these genetic findings, and which may limit their usefulness for subsequent genetic correlation or Mendelian Randomization analyses.