Trajectories of anatomic brain development as a phenotype

Abstract

Many cognitive, emotional and behavioural traits, as well as psychiatric disorders are highly heritable. However, identifying the specific genes and mechanisms by which this heritability manifests has been elusive. One approach to make this problem more tractable has been to attempt to identify and quantify biological markers that are intermediate steps along the gene-to-behaviour path. The field of neuroimaging offers several anatomic and physiologic possibilities to quantify. Stability over time has been proposed as a desired feature for these intermediate phenotypes. However, in this paper we discuss the value of looking at trajectories of anatomic brain development (i.e. morphometric changes over time), as opposed to static measures, as a phenotype. Examples drawn from longitudinal anatomic magnetic resonance imaging studies of typical development, attention deficit/hyperactivity disorder, and childhood-onset schizophrenia are used to demonstrate the utility of trajectories of brain development as a phenotypic bridge between genes and behaviour in health and in illness.

FIG. 1

Mean volume by age in years for males (top lines, N = 475 scans) and females (bottom lines, N = 354 scans). Middle lines in each set of three lines represent mean values, and upper and lower lines represent upper and lower 95% confidence intervals. All curves differed significantly in height and shape with the exception of lateral ventricles, in which only height was different, and mid-sagittal area of the corpus callosum, in which neither height nor shape was different. (a) Total brain volume, (b) grey matter volume, (c) white matter volume, (d) lateral ventricle volume, (e) mid-sagittal area of the corpus callosum, and (f) caudate volume. (Adapted from Lenroot et al 2007.)

FIG. 2

Brain maps of clusters where attention-deficit/hyperactivity disorder (ADHD) carriers of the seven-repeat allele of dopamine d4 receptor differ in trajectory of cortical growth and graphs illustrating trajectories for these clusters. (Adapted from Shaw et al 2007.)

FIG. 3

Effect of risk allele status at 420M9-1395 on brain MRI volume trajectories in COS and healthy controls for total (a) grey matter and (b) white matter. (Adapted from Addington et al 2005.)