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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the articleThe hippocampus has a key role in learning, memory and spatial navigation [1]
We found that none of these single-nucleotide polymorphism (SNP) were significantly associated with hippocampal volume in the younger age group, whereas three of them were significant in the older age group
Using brain scans from 21,297 individuals, we showed that differences in the cytoarchitecture of the subfields, providing the basis for their segmentation [5], are partly driven by differences in their genetic architecture
Summary
Extended author information available on the last page of the article. The breadth of findings regarding the role of the hippocampus in behaviour and its nonspecific association with a range of brain disorders may result from the fact that it is a heterogeneous structure, consisting of cytoarchitecturally distinct subfields which subserve distinct functions [5, 6]. Lesion studies and intrinsic connectivity patterns support a dichotomy between an anterior section, attributed a role in anxiety-related behaviours, and more posterior regions, important for spatial processing and cognition [7]. Firstepisode schizophrenia has been most strongly associated with the cornu ammonis (CA) region and the subiculum in the anterior hippocampus [9, 10], with longer illness duration more posterior regions appear affected [11]. AD is thought to be primarily associated with volume reductions in CA1 and subiculum, with the dentate gyrus (DG) and CA3 relatively spared [12, 13], opposing findings have been reported [14]
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