Memory – Learning from data

Memory is a fascinating topic. I recently had a bike accident where I don’t recall any of the events that led up to the event or after the event. That entire series of events (~30 minutes) was completely wiped from my brain.

I do recall taking a picture of a rose (memory formed prior to accident). Next, I’m in an ambulance with a huge bruise on my face, fractured arms, and pain all over my skull.

This started the process of thinking about what drives memory formation. Alzheimer’s disease is a phenotype that we typically think of when we consider memory loss. Another phenotype is Chronic traumatic encephalopathy, a disorder attributed to repeated concussions.

With my colleague Mark Daly we came across a condition referred to as Transient Global Amnesia, a neurological disorder whose defining characteristic is a temporary (~24 hours) but total disruption of short-term memory.

TGA from a clinician’s perspective

For complex traits, like memory, we often times found that studying traits with lower prevalence improved our ability to dissect the molecular and genetic underpinnings. A case study is coronary artery disease and familial hypercholesterolemia. We found, via the analysis of multiple population biobanks, that transient global amnesia has a pretty striking heritable component and the genetics pinpoints us to very specific cell types, i.e. pericyte cells and mural cells.

Pericyte cells are increasingly recognized for their roles in brain function, including memory. Their influence on memory primarily relates to their roles in maintaining the blood-brain barrier (BBB), supporting neurovascular coupling, and contributing to the health of brain vasculature.

A simplified neurovascular unit (NVU) diagram showing the interactive cellular network at the level of brain capillaries that comprises vascular cells, glial cells, and neurons. Intricate cell–cell communication and signal transduction mechanisms of NVU cell types are highly controlled to regulate numerous functions in the central nervous system. Source: Nature Neuroscience.

Our manuscript, Genetics of transient amnesia highlights a vascular role in memory, is publicly available on medRxiv.

Here, are the top 9 variant genetic associations:

Variant ID	rsids	nearest_genes	OR	META_pval	Cell type expression
1-201926536-T-C	rs72744832	LMOD1	1.41	7.19E-27	Pericyte cell
14-105488368-C-T	rs55633823	CRIP1	1.19	1.93E-11	Vascular endothelial cells in cerebellum
19-38694171-G-A	rs7251903	ACTN4	0.87	1.24E-10	Vascular endothelial cells in cerebellum
2-203331895-C-T	rs116426890	many	1.22	4.90E-10
6-1366655-G-T	rs192238573	FOXF2	0.79	5.52E-10	Mural cell brain
16-15814272-T-G	rs12919510	MYH11	1.14	3.00E-09	Pericyte cell
11-100639014-A-T	rs10894996	ARHGAP42	0.87	4.06E-09
11-47637583-G-A	rs7118178	many	1.16	4.87E-09
10-58170232-G-A	rs1769016	IPMK	0.86	1.45E-08

Table 1. FinnGen, AllofUS, and UK Biobank meta-analysis associated variants with index SNP.

Protein altering variant p.Ala58Val in CRIP1 is associated with transient global amnesia.