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

• Published in: Molecular psychiatry 2020-11, Vol.25 (11), p.3053-3065
• Main Authors: van der Meer, Dennis, Rokicki, Jaroslav, Kaufmann, Tobias, Córdova-Palomera, Aldo, Moberget, Torgeir, Alnæs, Dag, Bettella, Francesco, Frei, Oleksandr, Doan, Nhat Trung, Sønderby, Ida E., Smeland, Olav B., Agartz, Ingrid, Bertolino, Alessandro, Bralten, Janita, Brandt, Christine L., Buitelaar, Jan K., Djurovic, Srdjan, van Donkelaar, Marjolein, Dørum, Erlend S., Espeseth, Thomas, Faraone, Stephen V., Fernández, Guillén, Fisher, Simon E., Franke, Barbara, Haatveit, Beathe, Hartman, Catharina A., Hoekstra, Pieter J., Håberg, Asta K., Jönsson, Erik G., Kolskår, Knut K., Le Hellard, Stephanie, Lund, Martina J., Lundervold, Astri J., Lundervold, Arvid, Melle, Ingrid, Monereo Sánchez, Jennifer, Norbom, Linn C., Nordvik, Jan E., Nyberg, Lars, Oosterlaan, Jaap, Papalino, Marco, Papassotiropoulos, Andreas, Pergola, Giulio, de Quervain, Dominique J. F., Richard, Geneviève, Sanders, Anne-Marthe, Selvaggi, Pierluigi, Shumskaya, Elena, Steen, Vidar M., Tønnesen, Siren, Ulrichsen, Kristine M., Zwiers, Marcel P., Andreassen, Ole A., Westlye, Lars T.
• Format: Article
• Language: English
• Subjects: 45/43; 59/57; 631/208; 631/378; 692/699/476; Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Animal behavior; Association analysis; Behavioral Sciences; Biological Psychology; Brain; Brain architecture; Child; Child, Preschool; Female; Gene polymorphism; Genetic aspects; Genome-Wide Association Study; Genomes; Genomics; Heritability; Hippocampus; Hippocampus - anatomy & histology; Hippocampus - diagnostic imaging; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Medical colleges; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mental disorders; Middle Aged; Navigation behavior; Nervous system; Neurodegenerative diseases; Neuroimaging; Neurosciences; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychiatry; Schizophrenia; Schizophrenia - diagnostic imaging; Schizophrenia - genetics; Schizophrenia - pathology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Spatial memory; Structure-function relationships; Young Adult
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-018-0262-7

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