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Under the influence of genes and a varying environment, human brain structure changes throughout the lifespan. Even in adulthood, when the brain seems relatively stable, individuals differ in the profile and rate of brain changes 1 . Longitudinal studies are crucial to identify genetic and environmental factors that influence the rate of these brain changes throughout development 2 and aging 3 . Inter-individual differences in brain development are associated with general cognitive function 4,5 and risk for psychiatric disorders 6,7 and neurological diseases 8,9 . Genetic factors involved in brain development and aging overlap with those for cognition 10 and risk for neuropsychiatric disorders 11 . A recent cross-sectional study showed brain age to be advanced in several brain disorders. Brain age is an estimate of biological age based on brain structure, which can deviate from chronological age. Several shared loci were found between the genome-wide association study (GWAS) summary statistics for advanced brain age and psychiatric disorders 12 . However, information is still lacking on which genetic variants influence an individual's brain changes throughout life, because this requires longitudinal data. Discovering genetic factors that explain variation between individuals in brain structural changes may reveal key biological pathways that drive normal development and aging and may contribute to identifying disease risk and resilience-a crucial goal given the urgent need for new treatments for aberrant brain development and aging worldwide.As part of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium 13 , the ENIGMA Plasticity Working Group quantified the overall genetic contribution to longitudinal brain changes by combining evidence from multiple twin cohorts across the world 14 . Most global and subcortical brain measures showed genetic influences on change over time, with a higher genetic contribution in the elderly (heritability, 16-42%). Genetic factors that influence longitudinal changes were partially independent of those that influence baseline volumes of brain structures, suggesting that there might be genetic variants that specifically affect the rate of development or aging. However, the genes involved in these processes are still not known, with only a single, small-scale GWAS performed for longitudinal volume change in gray and white matter of the cerebrum, basal ganglia and cerebellum 15 . In this study, we set out to find genetic variants that may influence rates of brain changes over time, using genome-wide analysis in individuals scanned with magnetic resonance imaging (MRI) on more than one occasion. We also aimed to identify references

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