Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes

Quentin Le Grand, Claudia L. Satizabal, Muralidharan Sargurupremraj, Aniket Mishra, Aicha Soumaré, Alexandre Laurent, Fabrice Crivello, Ami Tsuchida, Jean Shin, Mélissa Macalli, Baljeet Singh, Alexa S. Beiser, Charles DeCarli, Evan Fletcher, Tomas Paus, Mark Lathrop, Hieab H.H. Adams, Joshua C. Bis, Sudha Seshadri, Christophe TzourioBernard Mazoyer, Stéphanie Debette

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
DOIs
StateAccepted/In press - 2022
Externally publishedYes

Keywords

  • Dementia
  • Epidemiology
  • Genomics
  • Life course approach
  • Subcortical volumes

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Clinical Neurology
  • Cognitive Neuroscience
  • Biological Psychiatry

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