Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes

Abstract

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

“…It is also possible, however, that hippocampal volume and WM microstructure are independently impacted by stressrelated mechanisms including glutamate excitotoxicity, inflammation, oxidative stress or an increase in glucocorticoids. Recent imaging genetics studies also suggest that a genetic predisposition to such neuroanatomical variations may also be related to the genetic underpinnings of mental illness [54].…”

Multi-trait genome-wide analyses of the brain imaging phenotypes in UK Biobank

“…By searching GWAS catalog [1], we found that three out of six (METTL10, LEMD3, and MYLK2) genes were reported to be associated with volume related IDPs. For example, METTL10 was associated with mean platelet volume [28], total hippocampal volume [29], and dentate gyrus granule cell layer volume [29]. STX6 was identified by all three mapping strategies and contained a significant SNP (rs3789362) with CADD score higher than 20.…”

Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

“…41 The association between snoring genes and heel bone mineral density could be mediated by BMI due to the association between BMI and bone density documented previously. 42 MSRB3 plays a relevant role in protein and lipid metabolism pathways 43 and has been associated with hippocampal volume, [44][45][46] lung function, 40,47,48 Alzheimer's disease, 49,50 brain injuries, 51 novelty seeking, 52 deafness 53 and height. 40 These results could be consistent with the fact that severe snoring may incur in nocturnal oxygen desaturation, 54 diminishing neuropsychological functions and in some cases, resulting in tissue damage 55 and contributing to impairment of memory consolidation processes.…”