Decreased white matter connectivity in a single-gene disorder of cognitive development

Cognitive and psychiatric disorders represent a major disease burden across the lifespan. In most cases these disorders are at least partially heritable, with a familial association representing a major risk factor. However, because of the overlapping and highly heterogeneous nature of these disorders it has been extremely difficult to establish specific genes associated with particular elements of cognitive impairment. Furthermore, this heterogeneity has also proven a substantial barrier to identifying the neurobiological pathways by which particular genes influence behaviour and cognition. Whilst rare, neurodevelopmental cognitive disorders of known genetic origin offer a window into these pathways. Knowledge of the genetic cause can highlight cellular and molecular processes critical for typical development. Furthermore, their relative homogeneity allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with a mutation in the ZDHHC9 gene. In addition to the common cause of impairment, these individuals have a shared cognitive profile and set of symptoms, the most prominent of which was substantial language impairment. The individuals with a ZDHHC9 mutation displayed reduced white matter connectivity, particularly in connections of the frontal lobe, relative to typical controls. An analysis of network properties using graph theory measures showed reductions in mean node strength, mean clustering coefficient, and global efficiency in the ZDHHC9 group. Furthermore, regional variation in graph measures across cortical regions were significantly associated with expression of ZDHHC9. The results demonstrate that a mutation in a single gene may impact on white matter organisation across the whole-brain, but with regionally specific effects. We show that white matter connectivity, and structural brain organisation, can provide an important intermediate phenotype for understanding the pathways by which genetic variation impacts upon cognitive ability.


Many cognitive and psychiatric disorders are highly heritable (Lee 2013, Sullivan 2012, Haworth 2009). In some cases, genetic risk factors have been identified, but understanding the link between gene transcripts and cognitive or behavioural outcomes remains challenging. One reason for this is the heterogenous nature of the vast majority of these disorders. This also presents a challenge for establishing the neural endophenotypes that mediate any gene-cognition relationships; any group defined on the basis of a cognitive impairment or behavioural difficulty will likely contain individuals with different genetic and neural causes, making it difficult to establish any significant relationships at the group level. One promising approach has been to study brain organisation in groups of individuals that have rare genetic causes of those impairements (Meyer-Lindenberg 2009, Griffa 2013). These groups, whilst necessarily small, have an homogenous etiology, and can therefore provide a powerful means for studying the neurobiological pathways that mediate cognitive and behavioural phenotypes in the wider population. For instance, the study of brain differences in Williams syndrome has shown distinct pathways for processing of faces (Meyer-Lindenberg 2006). Similarly, the study of a rare familial speech disorder (KE family, FOXP2 mutation) highlighted the importance of striatal networks for emergent higher-order language skills (Watkins 2011, Liegeois 2011).

However, studies of brain differences have so far mostly relied upon group-by-group statistical comparisons of specific areas or tracts with the most pronounced difference between groups.This is true of both genetically defined group comparisons and case-control designs more generally. This approach is limited because alternative routes may compensate for a focal defect. In addition, the organisation of larger brain systems may show meaningful but diffuse differences, that are not detected by focussing on specific tracts or areas. For these reasons, network-based approaches to neuroimaging, which provide a system-level description of the brain, have gained traction in recent years (Petersen 2015, Meyer-Lindenberg 2009).

A number of studies have shown that white matter organisation has a high degree of heritability (Lee 2015, Kochunov 2015, Kochunov 2010, Shen 2014, Chiang 2011), but few studies have combined measures of heritability with a network analysis approach. These studies focused on polymorphisms in trophic factor genes (Meoded 2014), and genes involved the regulation of synaptic weights (Ottet 2013, Meoded 2014, Hong 2014) that are common variants in the general population or risk factors associated with psychiatric conditions.

In the present study we take a network analysis approach to studying brain organisation in a genetically defined neurodevelopmental disorder. Mutations in ZDHHC9 are recurrent cause of X-linked Intellectual Disability (XLID) (Raymond 2007). A systematic assessment of clinical history and cognitive deficits across multiple XLID-associated genes led to the observation that ZDHHC9 mutations are associated with homogeneous cognitive features, including language deficits, attention problems, and a high prevalence of childhood seizures (Baker 2015), alongside reductions to white-matter integrity (citation not found: Bathelt_2015). The ZDHHC9 gene codes for a palmitoylation enzyme, involved in post-translational modification of specific target substrates. Palmitoylation plays an important role in the recruitment of receptors and ion channels at the synapse (Topinka 1998, Young 2013, El-Husseini 2000).

The purpose of the current study was to measure the impact of a mutation in ZDHHC9 on structural brain organisation, taking a network approach. We characterise how this mutation alters the local and global features of the neural network, and explore the relationship between regional variation in the expression of ZDHHC9 and brain organisation.