The genetics of episodic memory
The latest issue of Science has a really impressive article by Papassotiropoulos et al. probing the genetic basis of episodic memory. In it, the authors identify for the first time a link between a polymorphism in a gene called Kibra and individual variability in performance on delayed episodic memory tasks.
In brief, Papassotiropoulos and colleagues conducted a whole-genome scan on 500,000 distinct single nucleotide polymorphism (SNPs) in a large Swiss sample, and identified a correlation with episodic memory performance in two genes. They subsequently replicated the association between one of the genes (Kibra) and memory performance in two independent samples. What’s striking isn’t just the presence of two successful replications (almost unheard of in a paper that’s first to identify a gene-behavior relationship—many effects of this sort fail to replicate at all in subsequent studies), but also the size of the effect. In the initial sample, T allele non-carriers (i.e., subjects who had 2 C alleles of the Kibra SNP) performed 24% better on a free recall task after a 5 minute delay. You often hear people write off the molecular genetic approach to studying cognitive differences on the grounds that individual genes account for only a fraction of the variance and it’d take dozens or hundreds of genes to form a meaningful account. What the Kibra effect and other similar studies suggest is that, at least for some traits, a handful of genes may actually account for a considerable portion of the variance.
While the discovery and replication of the Kibra-episodic memory association alone would be a high-impact finding, Papassotiropoulos et al. didn’t stop there. They then went on to conduct brain imaging analyses in both humans and mice, demonstrating that a truncated version of Kibra is densely expressed in the medial temporal lobe (a region heavily implicated in episodic memory formation), but not in other areas such as the frontal lobes. They suggest that Kibra may exert its effect on memory via modulation of hippocampal function, though the precise locus and mechanism of effect is currently unknown.
But wait! There’s more! The authors then went on to conduct an fMRI study, in which they imaged 15 T allele carriers and 15 non-carriers during performance of an encoding task (a face-profession association task). They observed selective increases in the medial temporal lobes in non-carriers (the group with poorer performance in the genetic samples) relative to carriers, and no regions showing the converse effect. Because the two groups were matched for delayed memory performance, the relative increase in the group with poorer performance likely reflects less efficient processing, requiring greater activation to achieve the same level of memory performance.
As if all this wasn’t enough, Papassotiropolous et al. also conducted structural imaging analyses using both automated whole-brain and manual tracing approaches. These analyses didn’t turn up any significant findings, but given the amount of effort and breadth of expertise required for all of these analyses, one can only applaud them for trying.
On the whole, I can’t say enough good things about this paper. Regardless of the implications of the substantive finding itself (which, if replicated by other groups, should have important implications both theoretically and practically), it’s remarkable to see such a diversity of approaches and sources of expertise brought to bear on a single problem. Lots of people pay lip service to the notion that inter-disciplinary science is a good thing, but to date there are relatively few demonstrations of the idea on a large scale. The combination of molecular genetics and cognitive neuroimaging seems like a particularly profitable approach, yet few people have applied it thus far (with several notable exceptions, e.g., centers at the NIH and Pittsburgh). If this is the shape of things to come, it’ll be fun to watch over the next few years as this sort of research takes off…