Abstract
Background: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. Methods: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18–35 years), middle (35–65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. Results: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. Conclusions: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.
Original language | English (US) |
---|---|
Pages (from-to) | 616-628 |
Number of pages | 13 |
Journal | Biological Psychiatry: Cognitive Neuroscience and Neuroimaging |
Volume | 7 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2022 |
Keywords
- Dementia
- Epidemiology
- Genomics
- Life course approach
- Subcortical volumes
ASJC Scopus subject areas
- Clinical Neurology
- Biological Psychiatry
- Cognitive Neuroscience
- Radiology Nuclear Medicine and imaging
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In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Vol. 7, No. 6, 06.2022, p. 616-628.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes
AU - Le Grand, Quentin
AU - Satizabal, Claudia L.
AU - Sargurupremraj, Muralidharan
AU - Mishra, Aniket
AU - Soumaré, Aicha
AU - Laurent, Alexandre
AU - Crivello, Fabrice
AU - Tsuchida, Ami
AU - Shin, Jean
AU - Macalli, Mélissa
AU - Singh, Baljeet
AU - Beiser, Alexa S.
AU - DeCarli, Charles
AU - Fletcher, Evan
AU - Paus, Tomas
AU - Lathrop, Mark
AU - Adams, Hieab H.H.
AU - Bis, Joshua C.
AU - Seshadri, Sudha
AU - Tzourio, Christophe
AU - Mazoyer, Bernard
AU - Debette, Stéphanie
N1 - Funding Information: The i-Share study is conducted by the Universities of Bordeaux and Versailles Saint-Quentin-en-Yvelines (France). The i-Share study has received funding by the French National Agency (Agence Nationale de la Recherche [ANR]), via the “Investissements d'Avenir” programme (Grant No. ANR-10-COHO-05) and from the University of Bordeaux Initiative of Exellence (IdEX). This project has also received funding from the European Research Council under the European Union (EU) Horizon 2020 research and innovation programme under Grant No. 640643. The 3C-Dijon study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C-Dijon study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–Institut National de la Santé et de la Recherche Médicale Programme “Cohortes et collections de données biologiques.” CT and SD have received investigator-initiated research funding from the ANR and from the Fondation Leducq. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, the laboratory of excellence DISTALZ, and the Centre National de Génotypage. This project is an EU Joint Programme–Neurodegenerative Disease Research project. The project is supported through the following funding organizations under the aegis of the EU Joint Programme – Neurodegenerative Disease Research (www.jpnd.eu): Australia, National Health and Medical Research Council; Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; the Netherlands, the Netherlands Organisation for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the EU Horizon 2020 research and innovation programme under Grant No. 643417. This project has also received funding from the EU Horizon 2020 research and innovation programme under Grant Nos. 667375 and 754517. This work was also supported by a grant overseen by the ANR as part of the “Investment for the Future Programme” ANR-18-RHUS-0002. The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute (Grant Nos. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). This study was also supported by grants from the National Institute on Aging (Grant Nos. R01AG031287, R01AG054076, R01AG049607, R01AG059421, R01AG059725, U01AG049505, U01AG052409) and the National Institute of Neurological Disorders and Stroke (Grant No. R01 NS017950). The generation of FreeSurfer data was supported by the Alzheimer's Association (Grant No. AARGD-16-443384). Funding for SHARe Affymetrix genotyping was provided by National Heart, Lung, and Blood Institute Grant No. N02-HL64278. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant No. R01HL105756, and NeuroCHARGE is supported in part by the National Institute on Aging Grant No. R01AG033193. AL and AT benefited from a grant from the Fondation pour la Recherche Médicale (Grant No. DIC202161236446). QLG benefited from the Digital Public Health Graduate Program, a PhD program supported by the French Investment for the Future Programme (Grant No. 17-EURE-0019). CLS receives support from National Institute of Health (Grant No. R01AG059727). CD received funding from National Institute of Aging (Grant No. P30 AG0101029). We thank Dr. Mathieu Bourgey, Dr. Hans Markus Munter, Alexandre Belisle, and Rui Li at the McGill Genome Center for processing the i-Share study genome-wide genotype data. We thank Professor Philippe Amouyel for supporting the funding of the 3C-Dijon study genome-wide genotyping. Part of the computations were performed at the Bordeaux Bioinformatics Center, University of Bordeaux, and the Centre de Ressource et Développement en Informatique Médicale at the University of Bordeaux, on a server infrastructure supported by the Fondation Claude Pompidou. The computational work reported in this article was performed on the Shared Computing Cluster, which is administered by Boston University's Research Computing Services. We also thank all the Framingham Heart Study participants. The authors report no biomedical financial interests or potential conflicts of interest. Funding Information: The i-Share study is conducted by the Universities of Bordeaux and Versailles Saint-Quentin-en-Yvelines (France). The i-Share study has received funding by the French National Agency ( Agence Nationale de la Recherche [ANR]), via the “Investissements d’Avenir” programme (Grant No. ANR-10-COHO-05) and from the University of Bordeaux Initiative of Exellence (IdEX). This project has also received funding from the European Research Council under the European Union (EU) Horizon 2020 research and innovation programme under Grant No. 640643 . The 3C-Dijon study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C-Dijon study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés , Direction Générale de la Santé , Mutuelle Générale de l'Education Nationale , Institut de la Longévité , Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France , and Ministry of Research–Institut National de la Santé et de la Recherche Médicale Programme “Cohortes et collections de données biologiques.” CT and SD have received investigator-initiated research funding from the ANR and from the Fondation Leducq . This work was supported by the National Foundation for Alzheimer’s Disease and Related Disorders , the Institut Pasteur de Lille , the laboratory of excellence DISTALZ, and the Centre National de Génotypage. This project is an EU Joint Programme–Neurodegenerative Disease Research project. The project is supported through the following funding organizations under the aegis of the EU Joint Programme – Neurodegenerative Disease Research ( www.jpnd.eu ): Australia, National Health and Medical Research Council ; Austria, Federal Ministry of Science , Research and Economy; Canada, Canadian Institutes of Health Research ; France, French National Research Agency ; Germany, Federal Ministry of Education and Research; the Netherlands, the Netherlands Organisation for Health Research and Development; United Kingdom, Medical Research Council . This project has received funding from the EU Horizon 2020 research and innovation programme under Grant No. 643417 . This project has also received funding from the EU Horizon 2020 research and innovation programme under Grant Nos. 667375 and 754517 . This work was also supported by a grant overseen by the ANR as part of the “Investment for the Future Programme” ANR-18-RHUS-0002 . The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute (Grant Nos. N01-HC-25195 , HHSN268201500001I , and 75N92019D00031 ). This study was also supported by grants from the National Institute on Aging (Grant Nos. R01AG031287 , R01AG054076 , R01AG049607 , R01AG059421 , R01AG059725 , U01AG049505 , U01AG052409 ) and the National Institute of Neurological Disorders and Stroke (Grant No. R01 NS017950 ). The generation of FreeSurfer data was supported by the Alzheimer's Association (Grant No. AARGD-16-443384 ). Funding for SHARe Affymetrix genotyping was provided by National Heart, Lung, and Blood Institute Grant No. N02-HL64278 . Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant No. R01HL105756 , and NeuroCHARGE is supported in part by the National Institute on Aging Grant No. R01AG033193 . AL and AT benefited from a grant from the Fondation pour la Recherche Médicale (Grant No. DIC202161236446 ). QLG benefited from the Digital Public Health Graduate Program, a PhD program supported by the French Investment for the Future Programme (Grant No. 17-EURE-0019 ). CLS receives support from National Institute of Health (Grant No. R01AG059727). CD received funding from National Institute of Aging (Grant No. P30 AG0101029). Publisher Copyright: © 2021
PY - 2022/6
Y1 - 2022/6
N2 - Background: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. Methods: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18–35 years), middle (35–65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. Results: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. Conclusions: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.
AB - Background: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. Methods: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18–35 years), middle (35–65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. Results: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. Conclusions: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.
KW - Dementia
KW - Epidemiology
KW - Genomics
KW - Life course approach
KW - Subcortical volumes
UR - http://www.scopus.com/inward/record.url?scp=85122472334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122472334&partnerID=8YFLogxK
U2 - 10.1016/j.bpsc.2021.10.011
DO - 10.1016/j.bpsc.2021.10.011
M3 - Article
C2 - 34700051
AN - SCOPUS:85122472334
SN - 2451-9022
VL - 7
SP - 616
EP - 628
JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
IS - 6
ER -