Genomic studies across the lifespan point to early mechanisms determining subcortical volumes
Quentin Le Grand
(1)
,
Claudia L. Satizabal
,
Muralidharan Sargurupremraj
(1)
,
Aniket Mishra
(1)
,
Aicha Soumare
(1)
,
Alexandre Laurent
,
Fabrice Crivello
,
Ami Tsuchida
,
Jean Shin
,
Melissa Macalli
(1)
,
Baljeet Singh
,
Alexa S. Beiser
,
Charles Decarli
,
Evan Fletcher
,
Tomas Paus
,
Mark Lathrop
,
Hieab Adams
,
Joshua C. Bis
,
Sudha Seshadri
,
Christophe Tzourio
(1)
,
Bernard Mazoyer
,
Stephanie Debette
Claudia L. Satizabal
- Fonction : Auteur
Alexandre Laurent
- Fonction : Auteur
- PersonId : 801299
- ORCID : 0000-0001-5198-6955
Fabrice Crivello
- Fonction : Auteur
- PersonId : 758712
- ORCID : 0000-0001-6950-984X
- IdRef : 118096427
Ami Tsuchida
- Fonction : Auteur
- PersonId : 801914
- ORCID : 0000-0001-5160-6203
Jean Shin
- Fonction : Auteur
Baljeet Singh
- Fonction : Auteur
Alexa S. Beiser
- Fonction : Auteur
Charles Decarli
- Fonction : Auteur
Evan Fletcher
- Fonction : Auteur
Tomas Paus
- Fonction : Auteur
Mark Lathrop
- Fonction : Auteur
Hieab Adams
- Fonction : Auteur
Joshua C. Bis
- Fonction : Auteur
Sudha Seshadri
- Fonction : Auteur
Christophe Tzourio
- Fonction : Auteur
- PersonId : 758563
- ORCID : 0000-0002-6517-2984
- IdRef : 069829209
Bernard Mazoyer
- Fonction : Auteur
- PersonId : 757140
- ORCID : 0000-0003-0970-2837
- IdRef : 059391170
Stephanie Debette
- Fonction : Auteur
- PersonId : 759687
- ORCID : 0000-0001-8675-7968
- IdRef : 104485833
Résumé
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: (i) estimate the heritability of subcortical volumes in young (18-35), middle (35-65), and older age (65+), and their genetic correlation across age groups; (ii) 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; (iii) 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, ten 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.
Domaines
Santé publique et épidémiologieFormat du dépôt | Notice |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Genomic studies across the lifespan point to early mechanisms determining subcortical volumes
|
Résumé |
en
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: (i) estimate the heritability of subcortical volumes in young (18-35), middle (35-65), and older age (65+), and their genetic correlation across age groups; (ii) 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; (iii) 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, ten 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.
|
Auteur(s) |
Quentin Le Grand
1
, Claudia L. Satizabal
, Muralidharan Sargurupremraj
1
, Aniket Mishra
1
, Aicha Soumare
1
, Alexandre Laurent
, Fabrice Crivello
, Ami Tsuchida
, Jean Shin
, Melissa Macalli
1
, Baljeet Singh
, Alexa S. Beiser
, Charles Decarli
, Evan Fletcher
, Tomas Paus
, Mark Lathrop
, Hieab Adams
, Joshua C. Bis
, Sudha Seshadri
, Christophe Tzourio
1
, Bernard Mazoyer
, Stephanie Debette
1
BPH -
Bordeaux population health
( 476572 )
- Université de Bordeaux - Case 11 - 146 rue Léo Saignat 33076 Bordeaux cedex
- France
|
Audience |
Internationale
|
Vulgarisation |
Non
|
Langue du document |
Anglais
|
Nom de la revue |
|
Comité de lecture |
Oui
|
Date de publication |
2021-10-23
|
Domaine(s) |
|
Projet(s) ANR |
|
Mots-clés |
en
Genomics, Epidemiology, Lifecourse approach, Subcortical volumes, Dementia
|
DOI | 10.1016/j.bpsc.2021.10.011 |
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