Developmental neurogenetics and multimodal neuroimaging of sex differences in autism

Abstract

Examining sex differences in the brain has been historically contentious but is nonetheless important for advancing mental health for both girls and boys. Unfortunately, females in biomedical research remain underrepresented in most mental health conditions including autism spectrum disorders (ASD), even though equal inclusion of females would improve treatment for girls and yield benefits to boys. This review examines sex differences in the relationship between neuroanatomy and neurogenetics of ASD. Recent findings reveal that girls diagnosed with ASD exhibit more intellectual and behavioral problems compared to their male counterparts, suggesting that girls may be less likely diagnosed in the absence of such problems or that they require a higher mutational load to meet the diagnostic criteria. Thus far, the female biased effect of chromosome 4, 5p15.33, 8p, 9p24.1, 11p12-13, 15q, and Xp22.3 and the male biased effect of 1p31.3, 5q12.3, 7q, 9q33.3, 11q13.4, 13q33.3, 16p11.2, 17q11-21, Xp22.33/Yp11.31, DRD1, NLGN3, MAOA, and SHANK1 deletion have been discovered in ASD. The SNPs of genes such as RYR2, UPP2, and the androgen receptor gene have been shown to have sex-biasing factors in both girls and boys diagnosed with ASD. These sex-related genetic factors may drive sex differences in the neuroanatomy of these girls and boys, including abnormal enlargement in temporal gray and white matter volumes, and atypical reduction in cerebellar gray matter volumes and corpus callosum fibers projecting to the anterior frontal cortex in ASD girls relative to boys. Such factors may also be responsible for the attenuation of brain sexual differentiation in adult men and women with ASD; however, much remains to be uncovered or replicated. Future research should leverage further the association between neuroanatomy and genetics in girls for an integrated and interdisciplinary understanding of ASD.

Keywords: Autism; Brain development; Neurogenetics; Neuroimaging; Sex differences.

Figure 1

Overall prevalence rate of ASD is increasing over time in the U.S., and this increase is mainly driven by male diagnosis. Data are from the U.S. Center for Disease Control, Autism and Developmental Disabilities Monitoring Network (CDC 2007, CDC 2007, CDC 2009, CDC 2009, CDC 2012, CDC 2014). Information for 2012 is not included because diagnostic method is different from previous years.

Figure 2

The graph displays overall, male, and female prevalence rates of ASD in South Korea (Kim, Leventhal et al. 2011), the U.S.(CDC 2014), Canada (NEDSAC 2013), Australia (ABS 2011), the U.K. (Taylor, Jick et al. 2013), Taiwan (Lai, Tseng et al. 2012), Venezuela (Montiel-Nava and Peña 2008), Iran (Samadi, Mahmoodizadeh et al. 2012), China (Li, Chen et al. 2011), and Oman (Al-Farsi, Al-Sharbati et al. 2011) from 2005 to 2010. Underdeveloped countries such as Oman and Iran tend to have the lowest prevalence rates because of minimal attention to diagnosing the disorder (Al-Farsi, Al-Sharbati et al. 2011, Samadi, Mahmoodizadeh et al. 2012). Reasons for the high prevalence rate in South Korea are unknown, although usage of Western diagnostic tools may have introduced cultural biases. Limitation of this graph includes different sampling methods among countries.

Figure 3

Percentage of males with ASD (relative to females) varies by country depending on economic development (higher prevalence for developed countries), but in all locations, male prevalence is substantially higher than female prevalence.

Figure 4

In the U.S., the greatest sex differences in prevalence occur in ASD individuals with normal or high intellectual ability (Yeargin-Allsopp, Rice et al. 2003). For those with very low intelligence, there is about equal representation of males and females diagnosed with ASD. Other countries like Sweden and England show similar trends, although a few recent studies do not, most likely because of low sample sizes or failure to test individuals with the most severe intellectual functioning.

Figure 5

Loci highlighted in red indicates susceptibility to ASD for males, while loci highlighted in yellow indicates susceptibility to ASD for females. Loci colored in blue signifies risk for either males or females depending on hormonal levels. Source of images comes from National Institute of Health’s NCBI Map Viewer. RYR2 = 1q43, SRD5A2 = 2p23, UPP2 = 2q24.1, DRD1 = 5q35.1, ESR1 = 6q25.1, RORA = 15q21-22, SHANK1 = 19q13.33, MAOA = Xp11.3, androgen receptor gene = Xq12, NLGN3 = Xq13.1.