Abstract
The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer’s disease in which brain shrinkage is a key biomarker.
Highlights
The brain structure aspect alters throughout life
Between 47 and 73 years old, the sulcal opening increases on average of 0.025 mm/year, while the grey matter (GM) thickness decreases on average of 0.015 mm/year (Table S1)
Note that the missing genotype threshold is traditionally more stringent to estimate the kinship in genome-wide complex trait analysis (GCTA) analysis than to perform genome wide association studies (GWAS)
Summary
Grey and white matter volumes are known to shrink with age in diseased and normal brains (Ge et al 2002; Fjell and Walhovd 2010; Lockhart and DeCarli 2014). Numerous cross-sectional and longitudinal studies have confirmed this trend by either studying grey matter volume changes (Lemaitre et al 2012) or cortical sulci widening (Kochunov et al 2005; Shen et al 2018). Multiple factors related to the environment or to genetics likely play a role in these changes. Such genetic effect is characterized in the hippocampus atrophy with the apolipoprotein E, ε4 allele (ApoE-ε4), which is associated with an increased risk for developing late onset Alzheimer’s disease (AD) (Moffat et al 2000).
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