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

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?-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.

SUBMITTER: van der Meer D

PROVIDER: S-EPMC6445783 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

van der Meer Dennis D Rokicki Jaroslav J Kaufmann Tobias T Córdova-Palomera Aldo A Moberget Torgeir T Alnæs Dag D Bettella Francesco F Frei Oleksandr O Doan Nhat Trung NT Sønderby Ida E IE Smeland Olav B OB Agartz Ingrid I Bertolino Alessandro A Bralten Janita J Brandt Christine L CL Buitelaar Jan K JK Djurovic Srdjan S van Donkelaar Marjolein M Dørum Erlend S ES Espeseth Thomas T Faraone Stephen V SV Fernández Guillén G Fisher Simon E SE Franke Barbara B Haatveit Beathe B Hartman Catharina A CA Hoekstra Pieter J PJ Håberg Asta K AK Jönsson Erik G EG Kolskår Knut K KK Le Hellard Stephanie S Lund Martina J MJ Lundervold Astri J AJ Lundervold Arvid A Melle Ingrid I Monereo Sánchez Jennifer J Norbom Linn C LC Nordvik Jan E JE Nyberg Lars L Oosterlaan Jaap J Papalino Marco M Papassotiropoulos Andreas A Pergola Giulio G de Quervain Dominique J F DJF Richard Geneviève G Sanders Anne-Marthe AM Selvaggi Pierluigi P Shumskaya Elena E Steen Vidar M VM Tønnesen Siren S Ulrichsen Kristine M KM Zwiers Marcel P MP Andreassen Ole A OA Westlye Lars T LT

Molecular psychiatry 20181002 11

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' ...[more]

PMID: 30279459

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Project description:IntroductionSubanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance.MethodsPatients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction.ResultsPatients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007).DiscussionThese results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Dataset Information

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

Publications

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

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