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

Dennis van der Meer*, Jaroslav Rokicki, Tobias Kaufmann, Aldo Córdova-Palomera, Torgeir Moberget, Dag Alnæs, Francesco Bettella, Oleksandr Frei, Nhat Trung Doan, Ida E. Sønderby, Olav B. Smeland, Ingrid Agartz, Alessandro Bertolino, Janita Bralten, Christine L. Brandt, Jan K. Buitelaar, Srdjan Djurovic, Marjolein van Donkelaar, Erlend S. Dørum, Thomas EspesethStephen V. Faraone, Guillén Fernández, Simon E. Fisher, Barbara Franke, Beathe Haatveit, Catharina A. Hartman, Pieter J. Hoekstra, Asta K. Håberg, Erik G. Jönsson, Knut K. Kolskår, Stephanie Le Hellard, Martina J. Lund, Astri J. Lundervold, Arvid Lundervold, Ingrid Melle, Jennifer Monereo Sánchez, Linn C. Norbom, Jan E. Nordvik, Lars Nyberg, Jaap Oosterlaan, Marco Papalino, Andreas Papassotiropoulos, Giulio Pergola, Dominique J.F. de Quervain, Geneviève Richard, Anne Marthe Sanders, Pierluigi Selvaggi, Elena Shumskaya, Vidar M. Steen, Siren Tønnesen, Kristine M. Ulrichsen, Marcel P. Zwiers, Ole A. Andreassen, Lars T. Westlye, For the Alzheimer’s Disease Neuroimaging Initiative, for the Pediatric Imaging, Neurocognition and Genetics Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)3053-3065
Number of pages13
JournalMolecular Psychiatry
Issue number11
Publication statusPublished - 1 Nov 2020

Cite this