Sex-specific effects of the Huntington gene on normal neurodevelopment

Abstract

Huntington disease is a neurodegenerative disorder caused by a gene (HTT) with a unique feature of trinucleotide repeats ranging from 10 to 35 in healthy people; when expanded beyond 39 repeats, Huntington disease develops. Animal models demonstrate that HTT is vital to brain development; however, this has not been studied in humans. Moreover, evidence suggests that triplet repeat genes may have been vital in evolution of the human brain. Here we evaluate brain structure using magnetic resonance imaging and brain function using cognitive tests in a sample of school-aged children ages 6 to 18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. We find that the number of repeats in HTT, below disease threshold, confers advantageous changes in brain structure and general intelligence (IQ): the higher the number of repeats, the greater the change in brain structure, and the higher the IQ. The pattern of structural brain changes associated with HTT is strikingly different between males and females. HTT may confer an advantage or a disadvantage depending on the repeat length, playing a key role in either the evolution of a superior human brain or development of a uniquely human brain disease. © 2016 Wiley Periodicals, Inc.

Keywords: Huntington disease; brain development; intelligence.

Fig. 1

Frequency distribution. Number of participants (y axis) for each of the CAG repeat lengths (x axis) in the (A) female and (B) male participants.

Fig. 2

Cortical thickness mapping. Whole-brain mapping of the relationship between CAG repeat length and cortical thickness in the female sample and the male sample. The maps are of log10(P) where P is the significance, thresholded to showing all vertices with P < 0.05. Red and yellow indicate thicker cortex as repeat increases, and blue indicates thinner cortex as repeat length increases.

Fig. 3

Scatter plots detailing the relationship between the CAG repeat length and (A) general ability index (GAI), (B) cortical thickness, and (C) putamen-to-cerebellum ratio in males (blue) and females (red). The fitted lines map the effect of rank transformed CAG repeat length (corrected for age, parental social class, and individual random effect) depicted against the raw data points. The corresponding absolute value of the CAG repeats are marked on the top part of each plot.

Fig. 4

Results of the median split-group analysis. All measures are converted to z scores based on the mean of the group. The mixed-group regression analysis was used to compare the z scores between the High and Low groups, accounting for return visits. Additional measures controlled for included age and SES (all analyses), sex (all-subjects analysis), and intracranial volume (for subcortical volume measures). Error bars mark the standard errors.

Fig. 5

Possible mechanism of improved function of HTT. PolyQ may act as a flexible hinge where longer length confers increasing optimization of protein conformation. Above disease threshold (CAG ≥ 36), polyQ may act as a rusty hinge creating a nonfunctional conformation. Based, in part, on Caron et al. (2013).