TY - JOUR
T1 - Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes
AU - For the Alzheimer’s Disease Neuroimaging Initiative
AU - for the Pediatric Imaging, Neurocognition and Genetics Study
AU - van der Meer, Dennis
AU - Rokicki, Jaroslav
AU - Kaufmann, Tobias
AU - Córdova-Palomera, Aldo
AU - Moberget, Torgeir
AU - Alnæs, Dag
AU - Bettella, Francesco
AU - Frei, Oleksandr
AU - Doan, Nhat Trung
AU - Sønderby, Ida E.
AU - Smeland, Olav B.
AU - Agartz, Ingrid
AU - Bertolino, Alessandro
AU - Bralten, Janita
AU - Brandt, Christine L.
AU - Buitelaar, Jan K.
AU - Djurovic, Srdjan
AU - van Donkelaar, Marjolein
AU - Dørum, Erlend S.
AU - Espeseth, Thomas
AU - Faraone, Stephen V.
AU - Fernández, Guillén
AU - Fisher, Simon E.
AU - Franke, Barbara
AU - Haatveit, Beathe
AU - Hartman, Catharina A.
AU - Hoekstra, Pieter J.
AU - Håberg, Asta K.
AU - Jönsson, Erik G.
AU - Kolskår, Knut K.
AU - Le Hellard, Stephanie
AU - Lund, Martina J.
AU - Lundervold, Astri J.
AU - Lundervold, Arvid
AU - Melle, Ingrid
AU - Monereo Sánchez, Jennifer
AU - Norbom, Linn C.
AU - Nordvik, Jan E.
AU - Nyberg, Lars
AU - Oosterlaan, Jaap
AU - Papalino, Marco
AU - Papassotiropoulos, Andreas
AU - Pergola, Giulio
AU - de Quervain, Dominique J.F.
AU - Richard, Geneviève
AU - Sanders, Anne Marthe
AU - Selvaggi, Pierluigi
AU - Shumskaya, Elena
AU - Steen, Vidar M.
AU - Tønnesen, Siren
AU - Alzheimer’s Disease Neuroimaging Initiative
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
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UR - https://www.ncbi.nlm.nih.gov/pubmed/30279459
U2 - https://doi.org/10.1038/s41380-018-0262-7
DO - https://doi.org/10.1038/s41380-018-0262-7
M3 - Article
C2 - 30279459
SN - 1359-4184
VL - 25
SP - 3053
EP - 3065
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 11
ER -