The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan
Abstract
Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single nucleotide polymorphisms-based analyses of 38127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.
Data availability
The following is included in a separate section in the manuscript:Data availabilityThe study comprises many different data sources. The PI does not have the legal right to share these data directly. UK Biobank data can be obtained from www.ukbiobank.ac.uk. The data repository for the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset can be found at www.cam-can.org/index.php?content=dataset. Access to BASE-II data can be obtained at www.base2.mpg.de/7549/data-documentation. Access to VETSA data can be obtained at https://medschool.ucsd.edu/som/psychiatry/research/VETSA/Researchers/Pages/default.aspx. Betula is described at www.umu.se/en/research/projects/betula---aging-memory-and-dementia/. For data from Barcelona brain studies, see www.neurociencies.ub.edu/david-bartres-faz/. For LCBC Lifespan sample, contact information can be found at https://www.oslobrains.no/presentation/anders-m-fjell/. Part of the developmental sample can be accessed through https://www.fhi.no/en/studies/moba/for-forskere-artikler/research-and-data-access/ (As of 2021, we are in the process of transferring MRI data to this repository). Please note that for all samples, data transfer agreements must be signed and proper ethical and data protection approvals must be in place, according to national legislation. Code used for data analysis accompany the submission as separate files. The correlation matrices constituting the basis for the Mantel tests are also uploaded.
Article and author information
Author details
Funding
European Research Council (283634;725025;313440)
- Anders Martin Fjell
- Kristine Beate Walhovd
the Medical Research Council Cognition & Brain Sciences Unit
- Rogier Andrew Kievit
U.S. National Institute on Aging (AG022381,AG050595)
- William S Kremen
EU Horizon 2020 (732592)
- Kristine Beate Walhovd
Knut and Alice Wallenberg foundation
- Lars Nyberg
Norwegian Research Council
- Anders Martin Fjell
- Kristine Beate Walhovd
Spanish Ministry of Science, Innovation and Universities
- David Bartres-Faz
the California Walnut Commission (NCT01634841)
- David Bartres-Faz
German Federal Ministry of Education and Research (16SV5537/16SV5837/16SV5538/16SV5536K/01UW0808/01UW0706/01GL1716A/01GL1716B)
- Ulman Lindenberger
European Research Council (677804)
- Simone Kühn
Biotechnology and Biological Sciences Research Council
- Rogier Andrew Kievit
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The studies were approved by the Norwegian Regional Committee for Medical and Health Research Ethics South. Written informed consent was obtained from all participants older than 12 years of age and from a parent/guardian of volunteers under 16 years of age. Oral informed consent was obtained from all participants under 12 years of age. Non-Norwegian samples were approved by the relevant ethical review board for each country. Norway (2010/2359; 2010/3407; 2009/200)
Reviewing Editor
- Alex Fornito, Monash University, Australia
Version history
- Received: January 12, 2021
- Accepted: June 26, 2021
- Accepted Manuscript published: June 28, 2021 (version 1)
- Version of Record published: July 6, 2021 (version 2)
Copyright
© 2021, Fjell et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,187
- Page views
-
- 144
- Downloads
-
- 4
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Neuroscience
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide repeat expansion disorders.
-
- Cell Biology
- Neuroscience
The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.