Genetic architecture of hippocampal subfields on standard resolution MRI: How the parts relate to the whole.

Published on Apr 1, 2019in Human Brain Mapping4.421
· DOI :10.1002/HBM.24464
Jeremy A. Elman15
Estimated H-index: 15
(UCSD: University of California, San Diego),
Matthew S. Panizzon35
Estimated H-index: 35
(UCSD: University of California, San Diego)
+ 9 AuthorsWilliam S. Kremen70
Estimated H-index: 70
(UCSD: University of California, San Diego)
Sources
Abstract
Author(s): Elman, JA; Panizzon, MS; Gillespie, NA; Hagler, DJ; Fennema-Notestine, C; Eyler, LT; McEvoy, LK; Neale, MC; Lyons, MJ; Franz, CE; Dale, AM; Kremen, WS | Abstract: The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.
📖 Papers frequently viewed together
147 Citations
457 Citations
37 Citations
References75
Newest
#1Alexandre RoutierH-Index: 11
#2Arnaud MarcouxH-Index: 3
Last. Olivier ColliotH-Index: 41
view all 14 authors...
2,592 CitationsSource
#1Jonika Tannous (University of Texas at Austin)H-Index: 4
#2Henrique Amaral-Silva (University of Texas at Austin)H-Index: 1
Last. Jair C. Soares (University of Texas at Austin)H-Index: 85
view all 9 authors...
Abstract The hippocampus has been implicated in various mood disorders, with global volume deficits consistently found in patient populations. The hippocampus, however, consists of anatomically distinct subfields, and examination of specific subfield differences may elucidate the possible molecular mechanisms behind psychiatric pathologies. Indeed, adult studies have reported smaller hippocampal subfield volumes in regions within the cornu ammonis (CA1 and CA4), dentate gyrus (DG), and hippocamp...
33 CitationsSource
#1Valentina Baglivo (University of Udine)H-Index: 3
#2Bo Cao (University of Texas Health Science Center at Houston)H-Index: 21
Last. Paolo Brambilla (University of Texas Health Science Center at Houston)H-Index: 78
view all 21 authors...
Background: Hippocampal abnormalities have been largely reported in patients with schizophrenia and bipolar disorder, and are considered to be involved in the pathophysiology of the psychosis. The hippocampus consists of several subfields but it remains unclear their involvement in the early stages of psychosis. Aim: The aim of this study was to investigate volumetric alterations in hippocampal subfields in patients at the first-episode psychosis (FEP). Methods: Magnetic resonance imaging (MRI) ...
39 CitationsSource
#1Mark W. LogueH-Index: 33
#2Sanne J.H. van Rooij (Emory University)H-Index: 15
Last. Rajendra A. Morey (Duke University)H-Index: 34
view all 54 authors...
Abstract Background Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. Methods We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 co...
146 CitationsSource
#1Florian Kurth (Semel Institute for Neuroscience and Human Behavior)H-Index: 7
#2Nicolas Cherbuin (ANU: Australian National University)H-Index: 50
Last. Eileen Luders (Semel Institute for Neuroscience and Human Behavior)H-Index: 6
view all 3 authors...
Abstract The hippocampal complex, an anatomical composite of several subregions, is known to decrease in size with increasing age. However, studies investigating which subregions are particularly prone to age-related tissue loss revealed conflicting findings. Possible reasons for such inconsistencies may reflect differences between studies in terms of the cohorts examined or techniques applied to define and measure hippocampal subregions. In the present study, we enhanced conventional MR-based i...
16 CitationsSource
#1Robin de FloresH-Index: 14
#2Justine MutluH-Index: 9
Last. Gaël ChételatH-Index: 73
view all 10 authors...
: Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty-six HE and 27 aMCI patients underwent resting-state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was ident...
26 CitationsSource
#1Sejal Patel (U of T: University of Toronto)H-Index: 6
#2Min Tae M. Park (Douglas Mental Health University Institute)H-Index: 18
Last. M. Mallar Chakravarty (Douglas Mental Health University Institute)H-Index: 67
view all 7 authors...
The hippocampus is composed of distinct subfields linked to diverse functions and disorders. The subfields can be mapped using high-resolution magnetic resonance images, and their volumes can potentially be used as quantitative phenotypes for genetic investigation of hippocampal function. We estimated the heritability of hippocampus subfield volumes of 465 subjects from the Human Connectome Project (twins and non-twin siblings) using two methods. The first used a univariate model to estimate her...
15 CitationsSource
#1Bo Cao (University of Texas Health Science Center at Houston)H-Index: 21
#2Ives Cavalcante Passos (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 21
Last. Jair C. Soares (University of Texas Health Science Center at Houston)H-Index: 85
view all 8 authors...
Volume reduction and shape abnormality of the hippocampus have been associated with mood disorders. However, the hippocampus is not a uniform structure and consists of several subfields, such as the cornu ammonis (CA) subfields CA1–4, the dentate gyrus (DG) including a granule cell layer (GCL) and a molecular layer (ML) that continuously crosses adjacent subiculum (Sub) and CA fields. It is known that cellular and molecular mechanisms associated with mood disorders may be localized to specific h...
85 CitationsSource
#1Derrek P. Hibar (SC: University of Southern California)H-Index: 49
#2Hieab H.H. Adams (EUR: Erasmus University Rotterdam)H-Index: 29
Last. M. Arfan Ikram (EUR: Erasmus University Rotterdam)H-Index: 107
view all 332 authors...
The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel....
153 CitationsSource
#1New Fei Ho (NUS: National University of Singapore)H-Index: 8
#2Juan Eugenio Iglesias (Harvard University)H-Index: 24
Last. Daphne J. Holt (Harvard University)H-Index: 33
view all 12 authors...
Progression from selective to general involvement of hippocampal subfields in schizophrenia
78 CitationsSource
Cited By8
Newest
#2Tavia E. EvansH-Index: 3
Last. Grégory OpertoH-Index: 11
view all 8 authors...
There is clear evidence that hippocampal subfield volumes have partly distinct genetic determinants associated with specific biological processes. The identification of genetic correlates of hippocampal subfield volumes may help to elucidate the mechanisms of neurologic diseases, as well as aging and neurodegenerative processes. However, despite the emerging interest in this area of research, the current knowledge of the genetic architecture of hippocampal subfields has not yet been consolidated...
Source
#1Katja Menzler (University of Marburg)H-Index: 19
#2Hajo M. HamerH-Index: 55
Last. Susanne Knake (University of Marburg)H-Index: 43
view all 12 authors...
Abstract Objective The present study validates the results of automated hippocampal subfield segmentation with histopathology in epilepsy patients undergoing epilepsy surgery. Methods We performed an automated hippocampal subfield segmentation on presurgical three-dimensional, T1-weighted Magnetisation Prepared Rapid Acquisition of Gradient Echoes Magnetic Resonance Imaging (MRI) data of 25 patients with unilateral mesial temporal lobe epilepsy due to hippocampal sclerosis (HS), using Freesurfer...
Source
#1Laura E.M. Wisse (UPenn: University of Pennsylvania)H-Index: 19
#2Gaël Chételat (UNICAEN: University of Caen Lower Normandy)H-Index: 73
Last. Valerie A. Carr (SJSU: San Jose State University)H-Index: 13
view all 14 authors...
Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involve...
7 CitationsSource
#2Sebastian Huhn (MPG: Max Planck Society)H-Index: 4
Last. A. Veronica Witte (MPG: Max Planck Society)H-Index: 4
view all 14 authors...
As higher mental demands at work are associated with a lower dementia risk and a key symptom of dementia is hippocampal atrophy, the study aimed at investigating the association between mental demands at work and hippocampal volume. We analyzed data from the population-based LIFE-Adult-Study in Leipzig, Germany (n=1,409, age 40 to 80). Hippocampal volumes was measured via three-dimensional Magnetic Resonance Imaging (3D MP-RAGE) and mental demands at work were classified via the O*NET database. ...
Source
#1Philipp G. Sämann (MPG: Max Planck Society)H-Index: 35
#2Juan Eugenio Iglesias (UCL: University College London)H-Index: 24
Last. Lianne Schmaal (MIT: Massachusetts Institute of Technology)
view all 18 authors...
Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeS...
Source
#1Heidi Foo (UNSW: University of New South Wales)H-Index: 6
#1Heidi Foo (UNSW: University of New South Wales)H-Index: 2
Last. Perminder S. Sachdev (UNSW: University of New South Wales)H-Index: 126
view all 7 authors...
Hippocampal volume is an important biomarker of Alzheimer9s disease (AD), and genetic risk of AD is associated with hippocampal atrophy. However, the hippocampus is not a uniform structure and has a number of subfields, the associations of which with age, sex, and polygenic risk score for AD (PRSAD) have been inadequately investigated. We examined these associations in 17,161 cognitively normal UK Biobank participants (44-80 years). Age was negatively associated with all the hippocampal subfield...
Source
#2Grégory OpertoH-Index: 11
Last. Alfa StudyH-Index: 5
view all 17 authors...
Background: Current evidence supports the involvement of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and the e4 allele of APOE gene in hippocampal-dependent functions. Previous studies on the association of Val66Met with whole hippocampal volume included patients of a variety of disorders. However, it remains to be elucidated whether there is an impact of BDNF Val66Met polymorphism on the volumes of the hippocampal subfield volumes (HSv) in cognitively unimpaired (CU) individ...
Source
#1Emma M. Brown (VA Boston Healthcare System)H-Index: 1
#2Meghan E. Pierce (Harvard University)H-Index: 4
Last. David H. SalatH-Index: 77
view all 8 authors...
Abstract The human hippocampus is vulnerable to a range of degenerative conditions and as such, accurate in vivo measurement of the hippocampus and hippocampal substructures via neuroimaging is of great interest for understanding mechanisms of disease as well as for use as a biomarker in clinical trials of novel therapeutics. Although total hippocampal volume can be measured relatively reliably, it is critical to understand how this reliability is affected by acquisition on different scanners, a...
21 CitationsSource