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Article Dans Une Revue Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Année : 2021

Genomic studies across the lifespan point to early mechanisms determining subcortical volumes

Claudia L. Satizabal
  • Fonction : Auteur
Alexandre Laurent
Fabrice Crivello
Ami Tsuchida
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
Bernard Mazoyer
Stephanie Debette

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.

Dates et versions

hal-03466940 , version 1 (06-12-2021)

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Citer

Quentin Le Grand, Claudia L. Satizabal, Muralidharan Sargurupremraj, Aniket Mishra, Aicha Soumare, et al.. Genomic studies across the lifespan point to early mechanisms determining subcortical volumes. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2021, ⟨10.1016/j.bpsc.2021.10.011⟩. ⟨hal-03466940⟩

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