Genetic variants associated with longitudinal changes in brain structure across the lifespan

Abstract

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Trial registration: ClinicalTrials.gov NCT02534363 NCT02305832.

Extended Data Fig. 1. Demographics and analysis

Overview of demographics (left). Per cohort, an age distribution is displayed, based on mean and standard deviation of the age at baseline. Cohorts of European ancestry are displayed in green, non-European cohorts are displayed in yellow. On the right, the total number of included subjects is displayed and a pie-chart of the distribution of diagnostic groups (pink) and subjects not belonging to diagnostic groups - often healthy subjects (aqua). Overview of analysis pipeline (right).

Extended Data Fig. 2. Correlations between change rates

Pearson correlations between rates of change and between baseline intracranial volume and rates of change in the largest adolescent cohort (top, N = 1068) and the largest cohort in older age (bottom, N = 624) in phase 1. The size of the correlations is displayed by color and size of the circles.

Figure 1:

Phenotypic brain changes throughout the lifespan. Visualization of growth and decline of brain structures throughout the lifespan. The subcortical structures are shown in exploded view.

Figure 2:

Annual rates of change Δ per cohort for each structure (a-o). The estimated trajectories with 95% confidence intervals (in green) are displayed in the top row. Mean values of individual cohorts are displayed as points, with error bars representing standard errors displayed in grey. The size of the points represents the relative size of the cohorts, total sample size N=15640. Means and standard deviations are based on raw data – no covariates were included. Cohorts that were added in phase 2 are displayed in grey. Only cohorts that satisfy N>75 and mean interval > 0.5 years are shown. The estimated trajectories of the volumes themselves are displayed in the bottom row, for all subjects (solid line) and for subjects not part of diagnostic groups (dashed line).

Figure 3:

Genetic effects on rates of brain changes throughout the lifespan. Genome-wide significant SNPs and genes with effects on brain changes at their respective loci across the human genome, from phase 2 (total N=15,100). This plot was created using PhenoGram (http://visualization.ritchielab.org).

Figure 4:

Summary of findings for two top-SNPs. Shown here is a summary of findings for a top-SNP of an age independent effect (rs72772746; intron to GPR139; associated with rate of change of lateral ventricle volume; left column) and a top-SNP of an age dependent effect (13:72353395; intron to DACH1; associated with rate of change in cerebral white matter volume; right column). Displayed are the locus plots (a) and (d), forest plot (b; total N = 14593, means and 95% confidence intervals are displayed for each cohort; confidence intervals that are outside the axis of the plot are marked with an arrow) and plot of meta-regression (e; total N = 13864, center of the circles represent the effect size of the tested allele for each cohort, radius of the circles are proportional to sample size) and inferred lifespan trajectories for carriers (in red) and non-carriers of the effect allele (in black) (c) and (f). Note that 13:72353395 was not in the reference dataset containing LD structure; the displayed LD structure is based on 13:7234009, R2 = 0.87 with the top-SNP.

Figure 5:

Genetic overlap with other phenotypes. P-values for pleiotropy between change rates of structural brain measures (rows, indicated by Δ for change rate) and neuropsychiatric, disease-related and psychological traits (columns on the left). P-values for pleiotropy between change rates of structural brain measures and head size (intracranial volume) and the cross-sectional brain measure are displayed on the right. The colour legend is displayed on the right, indicating the -log₁₀ p-value. Significant overlap (p < 1.6e-04; obtained through permutation testing, two-sided, Bonferroni corrected) is marked with *. P-values underlying this figure can be found in Supplemental Table 16.