Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Abstract

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/catenin, TGF- and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Sex differences in Variability of Brain Structure Across the Lifespan

“…These interactions in children and youth may relate to differential rates of development (and regional differentiation), which are 'slower' in males compared to females (55) . This aligns with previous reports of sexually dimorphic trajectories of development, at least for surface area (43) , and the notion that different regions are under semi-independent genetic control (29,40,41,56) . In the latest life groups of older adults (OASIS-3), variability in the relationship among regions (in global volume and surface area) was greater in males than females.…”

Cellular correlates of cortical thinning throughout the lifespan

“…The human cerebral cortex undergoes constant remodeling throughout the lifespan. Magnetic resonance imaging (MRI) enables the estimation of structural properties of the human cerebral cortex that can, in turn, be related to cognitive, clinical and demographic data [1][2][3][4] , and used as high-fidelity phenotypes for genomic studies [4][5][6] . Yet, we lack data necessary for guiding interpretation of MRIbased phenotypes with regard to the underlying neurobiology 7,8 .…”

Personality and local brain structure: their shared genetic basis and reproducibility

“…Also, conform previous studies (Panizzon MS et al 2009;Kremen WS et al 2010;Winkler AM et al 2010;Eyler LT et al 2012;Strike LT et al 2018), we observe high (h2>0.4) heritability of cortical thickness, with highest values in primary sensory areas. The heritability patterns highlight high heritability of cortical thickness in unimodal cortices, whereas variance in association cortices is on average less influenced by genetic factors (Panizzon MS et al 2009;Kremen WS et al 2010;Eyler LT et al 2012;Fjell AM et al 2015;Hofer E and e al. 2018;Strike LT et al 2018;Teeuw J et al 2018).…”

“…Also, conform previous studies [49][50][51][52][53] , we observe high (h2>0.4) heritability of cortical thickness, with highest values in primary sensory areas. The heritability patterns highlight high heritability of cortical thickness in unimodal cortices, whereas variance in association cortices is on average less influenced by genetic factors [49][50][51][52][54][55][56] .…”