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

for the Alzheimer’s Disease Neuroimaging Initiative, for the Pediatric Imaging, Neurocognition and Genetics Study

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
Early online date2 Oct 2018
Publication statusPublished - Nov 2020


Acknowledgements The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement number 609020 - Scientia Fellows; Research Council of Norway (223273, 226971, 248778, 249711, 248980, 249795, 177458/V50); South East Norway Health Authority (2013054, 2014097, 2015044, 2015073, 2016083, 2017112); The Kristian Gerhard Jebsen Stiftelsen, SKGJ_MED_008; and the European Community’s Seventh Frame-work Programme (FP7/2007–2013) under grant agreement #602450 (IMAGEMEND). This work further made use of data sharing from ADNI (funded by National Institutes of Health Grant U01 AG024904 and DOD ADNI Department of Defense award number W81XWH-12-2-0012), PING (National Institutes of Health Grant RC2DA029475), PNC (grant RC2MH089983 awarded to RG and RC2MH089924 awarded to HH), and UKB (under project code 27412). Acknowledgments of funding sources for all cohorts participating in this study are listed in Table S3.

FundersFunder number
DOD ADNI Department of DefenseW81XWH-12-2-0012
European Community’s Seventh Frame-work Programme602450
South East Norway Health Authority2015073, 2017112, 2016083, 2013054, 2015044, 2014097, SKGJ_MED_008
National Institutes of HealthU01 AG024904
National Institute on Drug AbuseRC2DA029475
CIEE Ping FoundationRC2MH089983, 27412, RC2MH089924
Alzheimer's Disease Neuroimaging Initiative
Seventh Framework Programme
Norges forskningsråd223273, 226971, 248980, 249795, 249711, 177458/V50, 248778


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