The search for genetic variation associated with risk for the development of neuropsychiatric disease has lagged behind that of other common complex human diseases. There is much ongoing debate about the reasons for this, including:
▸ A need for much larger cohorts, numbered perhaps in the tens of thousands, to create greater statistical power;
▸ A lack of diagnostic accuracy caused by the inclusion of inappropriate case individuals or through a lumping together of several diseases under the same phenotypic umbrella; and
▸ Inaccurate assumptions about the genetic risk associated with common versus rare genetic variations, the latter of which we have only recently been able to evaluate cost effectively on a genomewide scale.
Dr. Scott-Van Zeeland and her colleagues' report leverages an emerging investigative paradigm that includes the intersection of genetics, neuroanatomy, and functional neuroimaging to address some of these concerns and take a closer look at a gene, CNTNAP2, previously associated with Tourette syndrome, autism, epilepsy, and language development.
In doing so, the investigators unveil a putative functional role of variation at the single nucleotide polymorphism (SNP) rs2710102 within CNTNAP2 that is independent of disease status. In short, the researchers' findings demonstrate that rs2710102 variation is associated with differential frontal lobe functional connectivity. Caspr2, the protein product of CNTNAP2, plays a crucial role in the establishment of the juxtaparanodal region at the nodes of Ranvier through the clustering of the Kv1.1 voltage-gated potassium channels.
The variation of this SNP is shown in this new work to modify the scope of brain frontal lobe connectivity by altering the frequency of the functional establishment of either lateralized, long-range connections with the medial prefrontal cortex (predominant in “nonrisk” allele carriers) or more localized, bilateral connections (predominant in the “risk” allele carriers) during the performance of a reward-guided implicit learning task.
The analytical approach is particularly powerful because it convincingly demonstrates these connectivity effects utilizing functional MRI in moderately sized sample sets. The marriage of genomics, neuroanatomy, and neuroimaging is still in its infancy, but already there are indications of the power of this approach both in this work and in work by others in the field.
Dr. Scott-Van Zeeland and her colleagues suggest a biological mechanism for the development of autism and possibly other disorders in risk allele carriers. These findings present a possible way to further stratify carriers of the risk allele in future studies. For example, what might be different about individuals with autism who carry the risk allele but demonstrate prefrontal connectivity patterns that are more similar to nonrisk allele carriers? This question raises another issue. Based on the high minor allele frequency of rs2710102, carriers of the risk allele likely comprise more than half of the general population. How important is our individual genetics in determining the functional connectivity pattern, and what other genetic factors might predispose to such a pattern? Are these other genes autism risk candidates as well?
In spite of the questions that may remain to be answered, this work provides an important foothold for the mechanistic study of the extremely important public health problem of autism. One can hope that the future will hold additional studies involving neuroimaging and genetics in both healthy and diseased cohorts to help further dissect the functional basis for neuropsychiatric disease.