Abstract
Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean ± SD age, 23.6 ± 1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40-65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.
Highlights
Functional magnetic resonance imaging is a powerful tool for interrogating the mechanisms of the brain’s response to different environmental stimuli
For the regions activated by this task, overall MZ twin correlations were more than twice the size of the DZ correlations, suggesting that individual variation in working memory (WM) activation is genetically influenced
We demonstrate for the first time, in the largest twin sample to date, using a voxel-level analysis, and consistent with our preliminary ROI analysis on a small subsample (Blokland et al, 2008), that there is a significant and substantial genetic influence on WM task-related activation across the brain, with genes accounting for up to 65% of the variance, averaging ϳ33%
Summary
Functional magnetic resonance imaging (fMRI) is a powerful tool for interrogating the mechanisms of the brain’s response to different environmental stimuli. It is of considerable interest to know how much of this variability is due to genetic differences between people, how much to their (unique) environmental experience, and how much to measurement error. To tease apart these contributions to individual variability, we measured brain response to an n-back working memory (WM) task. We thank research nurses Marlene Grace and Ann Eldridge for twin recruitment, radiographers Matthew Meredith and Peter Hobden for data acquisition, Daniel Park for IT support, and Peter Visscher and Volkmar Glauche for their helpful suggestions
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