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Mol Psychiatry. 2018 Oct 2. doi: 10.1038/s41380-018-0262-7. [Epub ahead of print]

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

Author information

1
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. d.v.d.meer@medisin.uio.no.
2
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
3
Department of Psychology, University of Oslo, Oslo, Norway.
4
Department of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, USA.
5
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
6
Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.
7
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
8
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
9
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
10
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
11
Sunnaas Rehabilitation Hospital HT, Nesodden, Norway.
12
Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
13
Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands.
14
University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
15
University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, Groningen, Netherlands.
16
Department of Neuromedicine and Movement Science, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
17
Department of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim, Norway.
18
Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
19
Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
20
Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
21
Department of Biomedicine, University of Bergen, Bergen, Norway.
22
Departments of Radiation Sciences and Integrative Medical Biology, Umeå Center for Functional Brain Imaging (UFB), Umeå University, Umeå, Sweden.
23
Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Emma Neuroscience Group at Emma Children's Hospital, department of Pediatrics, Amsterdam Reproduction & Development, Amsterdam, The Netherlands.
24
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
25
Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland.
26
Life Sciences Training Facility, Department Biozentrum, University of Basel, Basel, Switzerland.
27
Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
28
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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.

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